Omar Abdel-Wahab, MD Memorial Sloan-Kettering Cancer Center
The Role of ASXL1 mutations in leukemia patients
The development of genomic technologies has uncovered a number of genetic abnormalities in patients with cancer, including acute myeloid leukemia (AML). In large-scale genomic studies we have found that the gene ASXL1 (Addition of Sex Combs-Like 1) is commonly mutated in AML patients. Moreover, we have identified that patients with ASXL1 mutations have a significantly worse survival. We have therefore performed studies to understand the function of ASXL1. In addition to furthering our knowledge of AML development we hope to identify strategies to aid in the therapy of AML patients with this genetic abnormality.
NYU Cancer Institute, New York University School of Medicine
Iannis Aifantis, PhD, BS NYU Cancer Institute, New York University School of Medicine
Modeling T-Cell A.L.L.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that preferentially affects children and adolescents. The leukemia is commonly associated with specific genetic abnormalities. Dr. Aifantis’ research focuses on one particular gene, known as Notch1, which is found in more than half of T-ALL patients and which has been generally recognized as a key trigger for the induction of the disease. Dr. Aifantis and his team have recently shown, using mouse models, that not all individuals with Notch1 mutations develop leukemia. Why is that? What mechanism actually pulls the trigger? The doctor’s previous research has identified another gene, the pre-T-cell receptor, as possibly involved. This research project made possible by [Gabrielle’s Angel] Foundation will use mouse models to try to answer this question by unraveling the relationship between the two genes. Better understanding of the pathways between these genes could lead to the design of new treatments for T-ALL patients.
Samah Alimam, MBChB (Hons) Guy's & St. Thomas' NHS
Clinical and molecular characterization of Myeloproliferative Neoplasms in Adolescent and Younger Adult Patients (>16 and <40 years) compared to patients aged over 40 years
MPNs are typically diagnosed in patients around 60-years old; therefore, scientific knowledge about MPN and changes in genetic codes are derived from patients around this age and data about younger patients is lacking. We will investigate younger patients who have developed an MPN and compare this with older individuals.
Arash Ash Alizadeh, MD, PhD Stanford University School of Medicine
Prospective Validation and Genetic Basis of a Novel Molecular Risk Predictor for Diffuse large B-Cell Lymphoma
Drug-development is time consuming and costly, consuming on average 10-years and $800-million for each drug to reach patients. We can circumvent these barriers by designing risk-adapted clinical trials testing new therapies. We developed a method for predicting outcomes for the commonest lymphoma, aiming to validate and understand its genetic basis. To learn more, please visit our lab online.
NYU Cancer Institute, New York University School of Medicine
Jennifer Amengual, MD NYU Cancer Institute, New York University School of Medicine
Therapeutic Targeting of the BCL6; p53 axis with Histone Deactylase Inhibitors in Diffuse Large B-Cell Lymphoma
Diffuse large B-cell Lymphoma (DLBCL), the commonest form of lymphoma, affects 20,000 people yearly. Bcl6, a critical protein involved in DLBCL, allows cancer cells to grow uncontrollably. p53, another crucial protein, turned off in DLBCL, ordinarily destroys pre-cancerous cells. Identification of the Bcl-6:p53 axis establishes an inverse relationship essential to the development of lymphoma. These proteins can be modified by novel drugs leading to silenced-Bcl6 and activated-p53, thus promoting cancer cell death. Understanding specific effects of these drugs on lymphoma will establish rationale to integrate them into conventional care, and lead to discovery of complimentary partners for future development.
Scott A. Armstrong, MD, PhD Children's Hospital, Dana Farber Cancer Institute
Epigenetic Programs in MLL-rearranged leukemias
The Armstrong lab is using high throughput approaches that assess gene activity and chromosome structure in leukemias. Recent data suggest that certain mutations induce acute myelogenous leukemia (AML) by altering chromosome structure. The proteins that control the abnormal chromatin structure in these leukemias are enzymes (called histone methyltransferases) that present a tremendous opportunity for new drug development. The studies supported by Gabrielle’s Angel Foundation will assess histone methylation as a new therapeutic target in AML.
Targeting the Secretory Apparatus in Multiple Myeloma
Dr. Holger Auner is finding new ways to treat multiple myeloma. His research is focusing on a process called the protein degradation pathway that acts like a ‘waste disposal system’. Blocking this process in myeloma cells causes a toxic build-up of molecules which makes the cells self-destruct. Dr. Auner wants to reproduce this effect in patients to see if this could lead to new treatments.
This grant is administered through Cancer Research UK, the world’s largest independent cancer research charity.
Daniel Bachovchin, PhD Memorial Sloan Kettering Cancer Center
Long non-coding RNAs in T-cell lymphoma
Mutations of lncRNA Rmrp and its associated factors result in immune-deficiencies and blood malignancies in human. We propose to investigate how this molecule facilitates the normal development and function of white blood cells in the immune system and determine how changes to its structure promote lymphoma.
Arnob Banerjee, MD, PhD University of Maryland School of Medicine
Genomic and Functional Identification of Critical Targets in Peripheral T Cell Lymphoma
Peripheral T cell lymphoma (PTCL) is a disease of increasing incidence and poor prognosis. We will combine molecular biology and genomics approaches to analyze the mutations and gene regulatory disruptions that contribute to the malignant biology of PTCL. Armed with novel mechanistic insights into PTCL biology, we will move towards developing new treatment approaches for patients.
Juliet N. Barker, MBBS (Hons), FRACP Memorial Sloan-Kettering Cancer Center
Double Unit Grafts for the Treatment of High Risk Hematologic Malignancies
Umbilical cord blood (UCB) collected from healthy newborns is an alternative source of blood-forming stem cells and UCB transplant is a very promising treatment strategy in children with leukemia. However, early experience in UCB transplant in adults has not been successful in many patients due to insufficient number cells in a single UCB collection (known as a UCB “unit”). Early experience in a new way of doing UCB transplants in adults by combining UCB collections from two different babies has been encouraging. This proposal will further investigate these “double” unit UCB transplants after high dose therapy to treat patients with leukemia and myelodysplasia, and UCB will be studied in the laboratory in order to better understand how these “double” unit transplants work. Finally, the extent to which UCB extends access to transplant in patients without other suitable donors, and what patients remain without donors, will be analyzed. This work is important as successful UCB transplant in adolescents and adults will significantly extend access to curative therapy for many patients with cancers of the blood and bone marrow.
David M. Barrett, MD, PhD Children's Hospital of Philadelphia
Cytokine Release Syndrome in Immunotherapy
Most children with cancer can be cured by standard therapies yet some cancers will be resistant or will relapse. Recent therapies using modified immune cells have shown great promise, but also make patients very ill. I propose to investigate these modified immune cells in order reduce untoward side effects.
Jeffrey Bednarski MD, PhD Washington University St. Louis
“B Cell Specific DNA Damage Responses Prevent Leukemic Transformation”
Pediatric acute lymphoblastic leukemia occurs as a result of genetic mutations that block normal development of immune cells and promote continued expansion of cancer cells. The goals of Dr. Bednarksi’s project is to understand how cells prevent generation of these mutations and how cells are eliminated if mutations do occur.
Evaluating the Effectiveness of an Integrative Approach to the Treatment of Lymphoma and Leukemia Utilizing a Comprehensive Retrospective and Prospective Study Design
Integrative Medicine is the application of additional approaches to mainstream conventional care in an integrated fashion. These approaches may include nutritional therapy, exercise, herbal medicine, spiritual healing, vitamin therapy, acupuncture, meditation, massage, and homeopathy, and others. Dr. Iris Bell’s team proposes to test the effectiveness of such an integrative approach to the treatment of lymphoma and leukemia. This study will begin by looking at the medical records of approximately 100 cancer patients who received treatment from physicians enrolled in a two-year fellowship program at the University of Arizona’s Program in Integrative Medicine (PIM). Using these records, Dr. Bell’s team will identify the integrative approaches provided to these patients and evaluate their effectiveness. They will also interview patients and family members regarding their experiences, their responses to treatment, and their overall satisfaction with the treatment they received. Patients’ needs and preferences regarding the delivery of an integrative approach to cancer treatment will also be identified and weighted. Additionally, all new patients coming to the PIM for treatment will be surveyed regarding their expectations of PIM, their knowledge of Integrative Medicine, and other factors that may contribute to the success of the program. This information will also be used to design study protocols that can be used to compare the integrative approach to treatment to other conventional and non-conventional forms of treatment. The ultimate goal of this research is to refine and implement the approach and generate data to support its effectiveness and acceptability to patients.
Daniel Herranz Benito, PhD Rutgers Cancer Institute of New Jersey
“The role of SIRT1 in the pathogenesis and treatment of T-Cell Acute Lymphoblastic Leukemia”
T-Cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive blood cancer where 20-50% of patients relapse, and there are few therapeutic options at this stage. Notch1 activating mutations are the main driver in T-ALL. However, responses observed with targeted therapies against NOTCH1 have been limited, such that the identification of novel targets and combination therapies is one of the most urgent goals in T-ALL. In this context, we have identified Sirt1 as a critical mediator of resistance to NOTCH1 inhibition. Thus, we propose to dissect the role of Sirt1 in the pathogenesis of T-ALL and as a therapeutic target in vivo.
Andreas Beutler, MD Mount Sinai School of Medicine
An Integrative Approach to the Control of Intractable Pain from Cancer such as Multiple Myeloma
The relief of suffering is a high priority for patients with cancer and their families. Advanced cancers frequently cause severe chronic pain because of cancer spread to the bones and internal organs. Progress in pain treatment has been achieved over the past decades through increased public awareness, better education of doctors and nurses, and more generous use of strong pain medication of the opioid type, like morphine or oxycontin. However, recent research studies have shown, that many patients suffer from the side effects of these pain medications so severely, that they are reluctant to take the high doses needed to control their agony. Our proposal is to develop a new pain treatment for patients with advanced cancer based on gene therapy that does not cause side-effects, controls symptoms for many months, and can either be used alone or combined with existing treatments to multiply their efficacy tenfold or more (without increasing side effects). To this end, we are using an opioid gene that is targeted to the pain-control center in the spinal cord. Pain impulses caused by cancer anywhere in the body have to travel through the spinal cord before they reach the brain. We have developed a new artificial gene for pain control that can act on the spinal cord, closes the “pain gate” there, and blocks the entry of pain impulses into the central nervous system. The gene is targeted to the spinal cord by a gene vector that would be administered to patients by a spinal tap, a common procedure that can be performed by most doctors in the outpatient office. Furthermore, we will investigate the reaction of the spinal cord to advanced multiple myeloma, a particularly painful type of blood-born cancer that typically affects the bones.
William S. Blaner, PhD Columbia University, Institute of Human Nutrition
Complementary Approaches for Treating Acute Lymphoblastic Leukemia (ALL): A Mouse ALL
The aim of this project is to develop and employ complimentary and alternative approaches for treating pediatric ALL (Acute Lymphoblastic Leukemia patients). However, prior to testing such approaches in pediatric patients, potential therapies should be tested in animal models. In recent years, several good transgenic mouse models for ALL have been developed and used to study the biochemical and cellular processes responsible for ALL development and progression. For one of these mouse strains, the Em-ret mouse, Dr. Blaner proposes to establish the strain as a useful animal model for present and future studies of holistic therapies for potential use in pediatric patients with ALL. He further proposes to ask whether consumption of supplements of the antioxidants a-tochopherol (vitamin E) or coenzyme Q and/or the bioflavonoid present in green tea (-)-epigallocatechin-3-gallate (EGCG) and/or the bioflavonoid slavopiridol, a flavoin that is derived from plants which are indigenous to India and which are widely used there in traditional medicine, prevent or slow the development and progression of ALL in the Em-ret mice. Since the pediatric ALL is responsive to contemporary chemotherapy regimens that employ drugs from the anthracycline family, it will also be tested whether supplemental consumption of these food substances can bring added benefit to the patient during the course of drug therapy. Specifically, the investigators hope to understand how the consumption of antioxidants and/or bioflavonoids can have a synergistic effect with the drug to block the development and progression of ALL and if consumption can lessen the side effects of the standard drug therapy
Biological Consequences and Therapeutic Implications of Beta-arrestin2 loss in aggressive Lymphomas
The primary and acquired resistance of lymphoma cells to standard chemotherapy continues to pose a serious problem for patients and clinicians. Our proposed study will explore a novel mechanism by which lymphoma cells become resistant to therapeutic intervention.
Teresa V. Bowman, PhD Albert Einstein College of Medicine
Splicing and Epigenetic Control of Hematopoiesis in MDS and Leukemia
The discovery of new cancer mutations brings the reality of targeted therapy into reach; if we can understand how the mutations work and which other factors are involved. Our research will address these questions and lead to new therapies that will selectively kill mutant cells in patients with myelodysplastic syndromes and leukemia.
Anthony G. Brickner, PhD University of Pittsburgh Cancer Institute
Identifying stop codon-generated minor histocompatibility antigens capable of eliciting potent GVL or GVHD alloresponses
Minor histocompatibility antigens (mHAgs) are molecules on the surface of cells that differ between donor and recipient during allogeneic hematopoietic cell transplantation (HCT), and can elicit either a potentially curative graft-versus-leukemia (GVL) effect or life-threatening graft-versus-host disease (GVHD). Effectively separating GVL from GVHD is a major goal in curing hematologic malignancies with HCT. With the financial support of a grant from Gabrielle’s Angel Foundation for Cancer Research, the goal of Dr. Brickner’s team is to identify and characterize mHAgs which differ dramatically between donor and recipient due to normal genetic variations in the length of proteins, and to assess the impact of these so-called “stop codon-generated” mHAgs on GVL and GVHD. These studies will help lead to a better understanding of mHAgs, and will hopefully identify of a number of new clinically relevant mHAgs that can be therapeutically targeted to enhance GVL effects while reducing GVHD in HCT patients.
Johns Hopkins, Sidney Kimmel Comprehensive Cancer Center
Patrick Brown, MD Johns Hopkins, Sidney Kimmel Comprehensive Cancer Center
Investigating promoter hypermethylation in the biology of MLL-rearranged leukemia, and as a novel target for therapy
While the overall cure rate for childhood leukemia is about 80%, children with leukemias that carry mutations in a gene called “MLL” have a much worse prognosis. We have recently discovered that MLL leukemias have a unique tendency to turn off, or “silence”, many of their genes through a mechanism known as “hypermethylation”, and that this tendency may explain why the MLL leukemias do not respond well to current treatments. There are new drugs that can reverse this process of hypermethylation, and “re-express” the abnormally silenced genes. Dr. Brown’s lab would like to find out whether these drugs will improve the cure rate for the children with MLL leukemias. The experiments being performed with the support of Gabrielle’s Angel Foundation will answer this important question, and will hopefully lead to new, more effective treatments and the translation of our work into more cures for children with cancer.
Acute myeloid leukemia is a devastating illness with approximately 600 pediatric and 13,000 adult diagnoses, and 10,000 deaths, yearly. In this proposal we will develop prototype drugs that destroy the aberrant components, or proteins, within the cell that drive the malignant phenotype laying the groundwork for development of first-in-class drugs.
Children's Hospital Boston, Dana-Farber Cancer Institute
Alan B. Cantor, MD PhD Children's Hospital Boston, Dana-Farber Cancer Institute
Inhibition of Runx1 Tyrosine Phosphorylation in the Treatment of Human Leukemia
Normal gene expression is controlled by proteins, called transcription factors, which bind to DNA and turn on or off nearby genes. Mutations in transcription factors occur frequently in cancer, leading to disordered gene expression. The transcription factor Runx1 is one of the most common mutated genes in human leukemias, accounting for ~20-25% of cases. In many of these leukemias, the residual Runx1 activity is either inhibited or is insufficient to promote normal cell maturation. The Cantor laboratory recently discovered that a group of enzymes, called tyrosine kinases, modify Runx1 and inhibit its function. Importantly, drugs that block the activity of this class of tyrosine kinases are under active clinical development, or have already been approved, for the treatment of other types of cancer. This proposal explores the potential use of these drugs to enhance residual Runx1 activity as complementary treatment for Runx1 related human leukemias.
University of New Mexico Cancer Research & Treatment Center
Eric C. Carnes, PhD University of New Mexico Cancer Research & Treatment Center
Targeted Nanotherapeutics for Treatment of Acute Leukemia
Dr. Carnes’ research employs materials developed using state-of-the-art nanotechnology combined with cutting-edge cell recognition systems to create microscopic suitcases which carry drugs directly to cancer cells. Control over simple properties such as the size and appearance of these tiny packages will allow us to deliver virtually any combination of therapeutics and drugs to any type of cancer without the damaging side-effects associated with current chemotherapy and radiation treatments.
Martin Carroll, MD University of Pennsylvania Medical Center
Activation of Signal Transduction Pathways in Leukemia
Leukemia is a disease in which the bone marrow produces an abnormally high number of white blood cells that do not mature into normally functioning white blood cells capable of fighting infection. There is considerable evidence that both normal hematopoietic cells (precursor cells that mature into functional blood cells) and leukemic white blood cells require substances known as cytokines to support their growth. Cytokines are hormones that act locally on cells, causing different effects depending on the cytokine and the type of cell it is acting on. Cytokines stimulate specific receptors on cells, activating a chain of biochemical events known as a signal transduction cascade, that ultimately brings about an intended effect. Because the growth and survival of leukemic blood cells may depend on cytokines and the signal transduction cascades they trigger, it is reasonable to believe that a greater understanding of cytokines and signal transduction pathways may lead to novel treatments for leukemia. At the same time, it may lead to new ways to protect normal cells in patients undergoing chemotherapy. Dr. Carroll proposes to examine the role of different signal transduction pathways in the growth and survival of leukemic cells. He will also evaluate, both alone and in combination with conventional chemotherapeutic agents, agents that inhibit different signal transduction pathways for their potential as therapeutic agents in malignancies of the blood.
Grant A. Challen, PhD Washington University St. Louis
The Role of Mutations in Epigenetic Regulators in Myeloid Leukemia
Cure rates for AML patients have not substantially improved in the last 40 years. To keep pace with the genomics revolution, the focus of this project is to develop model systems that more closely resemble the natural history of cancer to understand how different mutations co-operate to cause AML.
Aude Chapuis, MD Fred Hutchinson Cancer Research Center
WT1-targeting adoptive T cell therapy for AML patients at high risk for relapse
Although aggressive chemotherapy and stem cell transplantation can cure AML, toxicity is significant and most patients still don’t survive long-term. Transplantation cures are largely due to leukemia-killing immune T cells from the donor. We can genetically engineer a patient’s own T cells that may be safer and destroy AML better.
The Role and Targets of APL-specific miRNAs in Leukemogenesis
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), and is characterized by an excess of immature cells called promyelocytes, a form of white blood cells. Dr. Chen has recently found that a set of small RNAs, namely microRNAs, are specifically overexpressed in APL. With the support from Gabrielle’s Angel Foundation, Dr. Chen’s lab will investigate the role of those APL-specific microRNAs in the development of APL leukemia and to determine their critical target genes and relevant pathways. These studies may provide valuable targets for the development of future treatment strategies, which may lead to more effective therapy for leukemias, particularly APL leukemia.
Wei Chen, MD, PhD The University of Minnesota Cancer Center
Immunotherapy of Leukemia with Dendritic Cell-Tumor Hybrid Vaccines
This research project will develop a new type of human leukemia vaccine using a novel electrofusion technology. Leukemia cells will be fused with the cells that regulate body immune system function to form a hybrid cell. The hybrid cells will carry tumor-derived information (proteins) to activate the immune white blood cells and direct these immune cells to kill leukemias. In this research proposal, Dr. Chen and his team will study how to use such hybrid cells as a vaccine for potential use in the treatment of human chronic lymphocytic leukemia. This study will form the basis for initiating clinical trials to apply this vaccine strategy for, but not limited to, the treatment of leukemia. Dr. Chen will fuse human chronic lymphocytic leukemia (CLL) cells with autologous or allogeneic dendritic cells for study. The proposed experiments will (1) investigate the immunogenicity and antigen presentation capacity of the human DC-CLL fusion hybrids: (2) determine whether leukemia-specific T cells can be effectively induced by priming with autologous or allogeneic DC-CLL hybrids; and (3) study the integrins, chemokines and extracellular matrix in DC, CLL, and their fusion hybrids in migration, adhesion, and T cell activation. This study will form the basis for initiating clinical trials to apply this vaccine strategy for, but not limited to, the treatment of leukemia.
Xiaochun Chen, PhD University of Maryland School of Medicine
Development of drugs that downregulate microRNAs associated with drug resistance
A key issue in the treatment of acute leukemias, as well as other cancers is the development of resistance. Recently a small set of microRNAs (miRs) including miR-125b were found to be associated with drug resistance in acute lymphoblastic leukemia patients. In this proposal, Dr. Chen will conduct a high-throughput screen to identify clinically-approved compounds that can decrease the levels of these drug resistance-associated miRs, starting with miR-125b. These novel targeted miR-downregulating drugs may decrease the impact of chemotherapeutic drug resistance
Introducing next generation sequencing for the diagnosis of myeloproliferative neoplasms (MPN)
We wish to improve the accuracy and cost-effectiveness of tests to diagnose the pre-malignant and malignant blood cancers, known as the myeloproliferative disorders (MPD). Together with two other large UK clinics, we will assess modern techniques (next generation sequencing) as a replacement for the current laborious and costly laboratory assays.
Gene editing in ALL to promote immunomodulatory forms of lytic cell death
Cell death removes damaged, pre-malignant, and infected cells. The study of apoptosis has yielded significant insight into the formation and maintenance of leukemia cells: many chemotherapeutics activate apoptotic cell death. We will harness a novel type of inflammatory lytic cell death to promote immunity to T-cell leukemia.
Closing the Knowledge Gap in Post-genomic Research: Fast-track Functional Characterisation of Genes Implicated in Human Blood Formation and Pathologies Using Zebrafish as an in vivo Model
Dr. Ana Cvejic is hunting down genes involved in the development of leukaemia, by studying zebrafish. The processes taking place in zebrafish cells are remarkably similar to those in humans, so this work can tell us a lot about what goes wrong in cancer. She plans to use these results as a launch pad to find equivalent human cancer genes.
This grant is administered through Cancer Research UK, the world’s largest independent cancer research charity.
Dr. Angieszka Czechowicz Stanford University School of Medicine- 2019
Title of Grant: “Development of anti-KIT antibodies and immunotoxins as therapeutics and HSCT conditioningagents for pediatric acute myeloid leukemia (AML)”
Acute myeloid leukemia (AML) is a frequent type of leukemia with harsh treatments and poor outcomes. We have pioneered several new antibody therapies targeting an important receptor found both on blood stem cells and AML, which may cure the disease. We propose testing these antibodies in various models of AML.
David Dominguez-Sola, MD, PhD Mount Sinai School of Medicine
MYC-dependent replication stress as a pathogenic driver and therapeutic target in aggressive B cell lymphomas
B cell lymphomas with MYC gene alterations are very aggressive and not curable using current therapies. Targeting MYC would thus be an ideal therapeutic strategy in these patients. Here, we describe a cellular process representing a unique vulnerability in MYC-driven lymphomas and propose to determine its therapeutic value.
Benjamin L. Ebert, MD, PhD.* Dana-Farber Cancer Institute
Identification of genetic dependencies in leukemia stem cells
Leukemia cells reside in the bone marrow and derive signals from the surrounding bone marrow cells that are important for their survival and growth. We aim to identify molecules on the surface of leukemia cells that are required for interaction with the bone marrow. Blocking these interactions could provide potential new therapies to treat patients with leukemia. To learn more, please visit our lab online.
Aimee Edinger, VMD, PhD University of California, Irvine
Role of regulated nutrient transporter expression in suppressing leukemia and lymphoma development.
Because cancer cells grow very rapidly, they are very dependent on a high rate of nutrient flux into the cell. The Edinger Lab hopes to identify the molecular tricks that leukemia cells use to import nutrients more efficiently than normal cells. By understanding how this is accomplished, they hope to identify new drugs that will prevent cancer cells from accessing their food supply, starving them to death.
Targeting MLL-Cofactor Interaction to Selectively Block Mixed Lineage Leukemia
Leukemia often occurs due to chromosomal breakage, which results in mutations that cause blood cells to grow in a disordered and uncontrolled manner. One gene that is often involved in chromosomal translocations that occur in childhood leukemia is the MLL (Mixed Lineage Leukemia) gene. Conventional chemotherapy is very ineffective at curing this disease, and as a consequence most patients relapse. Using a mouse model, Dr. Ernst’s lab has shown that the normal (wild-type) mouse MII gene is essential for maintaining the growth of blood cells. The normal MLL protein operates as part of a complex, with several essential cofactors or facilitating proteins. They are investigating whether blocking the interaction between MLL and its cofactors will selectively kill leukemia cells. Some cofactors have been shown to be essential for the leukemia to develop after expression of MLL fusion oncogenes. This lab will use several genetically engineered mouse models to study the effects of removing these cofactors on normal blood cell development. This comparative analysis will identify genetic pathways that can be exploited to find new ways to treat leukemia.
Todd Fehniger, MD, PhD Washington University St. Louis
Cytokine-Induced Memory-Like NK Cells For Adoptive Immunotherapy of AML.
Recent scientific advances have shown that cytokine activation results in cytokine-induced memory-like (CIML) NK cells with superior anti-leukemia activity. We will translate CIML NK cells into a first-in-human clinical trial for acute myeloid leukemia patients. Correlative studies will evaluate CIML NK cells expansion, survival, activation, and function in patients.
The Development of STAT Inhibitors as Novel Anti-Leukemia Agents: Use of Semi-Random Synthesis Technology
In recent years, tremendous advances have been made toward understanding the molecular abnormalities occurring in tumor cells. During this time, however, relatively little progress has been made in the treatment of leukemias and other forms of cancer. The challenge, therefore, is to translate advances in understanding the biology of the cancer cell into a new generation of more effective and less toxic anti-cancer agents. A family of proteins, termed STATs, is key mediators of the growth of normal cells. Recent work in Dr. Frank’s laboratory and others’ has shown that STATs are activated inappropriately in leukemias and many other forms of cancer. In experimental systems, the inhibition of STATs leads to the death of the tumor cells. By contrast, normal cells are relatively insensitive to inhibition of STAT function. Thus, blocking the STAT pathway is an extremely attractive approach for the rational design of anti-cancer agents. Given this background, Dr. Frank proposes to develop molecular inhibitors of STAT function. He will use a novel chemical approach called Semi-Random Synthesis to generate unique molecules likely to function as STAT inhibitors. In this process, molecular building blocks derived from compounds that can inhibit STAT activation are combined under conditions of very high energy. This process will generate unique structures that have a high likelihood of blocking the STAT pathway. In addition, he has developed a system to screen compounds for their ability to inhibit STAT function. These technologies will be combined to isolate compounds that are specific inhibitors of the STAT pathway, and which will be tested for their effects in leukemia and other cancer cells. In this manner, Dr. Frank hopes to identify compounds that might lead to more effective and less toxic treatments for these forms of cancer.
Exploring the role of UCHL1 in leukemia and lymphoma
Cellular proteins must occasionally be destroyed in order to maintain the proper functioning of the cell. This is especially true of cancer cells where the destruction of proteins that halt cell division is required for the continued expansion of the cancer. Specific protein removal is the task of the ubiquitin-proteasome pathway. Because of the importance of protein breakdown in cell division, much attention has turned towards gaining a better understanding of the way proteins are targeted for destruction and conversely how their fates are spared. Dr. Galardy’s lab has identified an enzyme in the ubiquitin-proteasome pathway that is highly expressed in most common forms of leukemia and lymphoma. This enzyme, called UCHL1, promotes the development of these cancers through mechanisms that are still unclear. More importantly, it is also unknown whether an inhibitor of UCHL1 could effectively prevent lymphoma from developing, or kill cancers that have already developed. In this proposal Dr. Galardy and his lab seek to answer these questions using novel mouse models so that they can establish the feasibility of targeting UCHL1 in these aggressive cancers.
Amanda Gedman Larson, PhD St. Jude Children's Research Hospital
The Molecular Genetics of Acute Megakaryocytic Leukemia
AMkL accounts for 15% of childhood AML and has a very poor prognosis. Although a few chromosomal abnormalities have been identified in AMkL, the genetic lesions underlying most cases remain unknown. Recent transcriptome analysis of AMkL performed in Dr. Larson’s laboratory identified a novel inv16(q24.3;p13.3) encoding a CBFA2T3-GLIS2 chimeric protein in 50% of cases. In the remaining cases, translocations were identified that targeted genes playing a direct role in normal megakaryocytic differentiation (GATA2 and FLI1) or previously implicated in leukemogenesis (MN1, NUP98, HOXA9, and HOXB9). This work will focus on defining the role of these genetic alterations in leukemogenesis.
George Georges, MD Fred Hutchinson Cancer Research Center
T-Cells to Control the Graft-Versus-Host Effect of Nonmyeloablative Hematopoietic Cell Transplantation
The aim of this project is to develop T cells to help further reduce the toxicity of bone marrow transplantation. Bone marrow transplantation, also known as hematopoietic cell transplantation, is the only curative treatment available for many patients with passive apostraphe leukemia and lymphoma. Using the dog model of bone marrow transplantation, Dr. Georges’ laboratory has recently pioneered the development of a clinically successful type of hematopoietic cell transplantation that uses substantially lower and less toxic doses of chemotherapy and radiation to treat patients with leukemia and lymphoma. To further improve upon the success of this low-dose non-toxic treatment for patients with leukemia and lymphoma, they want to study if T cells can be engineered to specifically help the donor marrow graft attack the blood cells containing leukemia or lymphoma without attacking the rest of the patient. The dog model of transplantation has been an excellent tool for the study of bone marrow transplantation and has been the basis for the successful translation of much laboratory research to the clinic. In this project Dr. Georges proposes to study T cells from the bone marrow donor dogs, grown in the laboratory, that are especially trained to recognize the recipient’s blood and immune cells. The recipient dogs will have marrow and blood cell production that is a combination of part donor and part recipient. After infusion into the recipient dog, the first aim will be to ask if the laboratory-grown donor T cells can eliminate the recipient’s residual blood and immune system cells. This would serve as a model for eradication of a patient’s leukemia or lymphoma cells. In the second set of experiments, the donor T cells will be genetically modified to make them safer with respect to graft-versus-host disease. If this strategy is successful in the dog, Dr. Georges and his team will then be able to study if the dose of radiation/chemotherapy can be further decreased to make bone marrow transplantation for patients with leukemia and lymphoma even less toxic yet much more effective.
John F. Gerecitano, MD, PhD Memorial Sloan-Kettering Cancer Center
Targeting DNA Repair mechanisms and Tumor Protein Regulation to Treat Patients with Lymphoma
Important differences exist between cancerous and normal cells in DNA repair and protein regulation. Dr. Gerecitano is currently exploiting these differences in three clinical trials: 1) Combining ABT-888, which disables the DNA repair enzyme PARP, with bendamustine, which causes genetic damage that then goes unrepaired and causes death in cancer cells. 2) Combining chemotherapy with bortezomib, which blocks protein degradation. Buildup of toxic proteins in cancer cells then causes their death. 3) A first-in-man study of PU-H71. This drug inhibits heat shock protein 90 (HSP 90), a ‘chaperone’ required by cancer cells for protein stabilization and survival.
Luke Gilbert, PhD University of California, San Francisco
Applying synthetic lethality to eradicate high risk NF1-deficient B-cell acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is a leading cause of cancer-related pediatric death. Many ALL patients are cured but specific sub-types of ALL are lethal. We have developed a new therapy that exploits a common feature of these poor prognosis pediatric leukemias and propose to test this in preclinical ALL models.
Saar I. Gill, MD, PhD University of Pennsylvania School of Medicine
Novel approaches to enhancing the therapeutic index of chimeric antigen receptor T cell therapy for acute myeloid leukemia
The aim of this project is to develop a technology that will allow a powerful immune cell attack against leukemia without damaging normal bone marrow cells, thereby increasing the safety of cancer immunotherapy.
Julia L. Glade-Bender, MD New York Presbyterian/Columbia
A Pilot Study of Investigating the Effects of Glutamine and Vincristine-induced Neuropathy in Pediatric Patients with Cancer
Patients with cancer are amongst the highest users of complementary/alternative therapies. Recent surveys have found 84% of pediatric oncology patients on standard anticancer protocols are taking some form of complementary/alternative medicine. However the safety of these therapies combined with chemotherapy is unknown. Today more than 70% of children diagnosed with cancer are long-term survivors of their disease. Despite the increase in survival, at least 60-70% of patients will have at least one disability as a result of their cancer therapy. Efforts to avoid long-term toxicity may necessitate a reduction of chemotherapy or delays in their treatment protocols. This deviation from recommended optimal therapy can decrease efficacy and increase a child’s risk of relapse. Thus, innovative adjunctive therapies that enable optimal doses of cancer therapy to be administered without compromising the efficacy of the anticancer agents and mitigate the toxicity associated with certain cancer therapy regimens are of increasing interest to the clinician. The nutritional supplement, glutamine, is classified as an alternative medicine in that it is currently not an established supportive care agent in use with conventional chemotherapy protocols. Preliminary laboratory and human data has suggested that glutamine may have a promising role as a prophylaxis against VCR-induced neuropathy. We are proposing to conduct a double-blind, placebo controlled randomized trial to determine the efficacy of glutamine supplementation in children encountering neurotoxicity due to vincristine-containing chemotherapy regimens. Patients will be randomized to receive either a placebo (inactive substance) or the active supplement, glutamine. Patients will take the supplement for a one-month period. Measures of neuropathy will be assessed throughout the study at their routine visits. Patients will also be routinely monitored for any adverse effects. Our hypothesis is that glutamine supplementation in pediatric patients with cancer encountering dose reductions or delays in therapy due to neuropathy from vincristine-containing chemotherapy regimens will benefit and allow the patient to withstand their recommended chemotherapy schedule.
Shari Goldfarb, MD Memorial Sloan-Kettering Cancer Center
Reproductive and sexual concerns of young women treated for lymphoma, leukemia and breast cancer
Dr. Goldfarb’s team will document the impact of cancer treatment on reproductive and sexual health in young women treated for lymphoma, leukemia and breast cancer. Premature ovarian failure and sexual dysfunction are serious problems that reduce their quality of life. They will obtain information from patients shortly after diagnosis and through treatment into survivorship. They will assess the problems experienced and the use and effectiveness of assistance, to which we will refer study patients. Dr. Goldfarb will characterize and compare sexual dysfunction by diagnosis and treatment type, and document factors that influence decisions regarding fertility preservation.
Douglas K. Graham, MD, PhD University of Colorado Health Sciences Center
Mer Tyrosine Kinase as a Cooperative Oncogene in Leukemogenesis
Tyrosine kinases are a family of proteins that are directly linked to multiple types of human cancer. Dr. Graham is investigating the role of a tyrosine kinase, Mer, in childhood T cell leukemia and lymphoma. The Mer protein is not expressed in normal lymphocytes but is expressed in many acute lymphoblastic leukemia (ALL) cell lines and patient samples. Dr. Graham’s lab has made a transgenic Mer mouse model which has abnormal Mer expression in lymphocytes (similar to the leukemia patient samples) and has found that the mice develop leukemia and lymphoma, suggesting a causative role of the Mer proto-oncogene. With the assistance of a grant from Gabrielle’s Angel Foundation for Cancer Research, Dr. Graham will clarify the role of Mer in cooperating with other oncogenes in leukemia development. Abnormal expression of Mer and oncogenes thought to be important in T cell leukemia will be evaluated from a national pediatric oncology cell bank. In addition, overexpression of known ALL oncogenes will be combined with Mer overexpression in mouse models to determine which oncogenes Mer may cooperate with to lead to leukemia or lymphoma. These studies will help lead to a better understanding of the biology of T cell leukemia and lymphoma, and will hopefully lead to new therapeutic targets for this disease.
Timothy Graubert, MD Washington University in St. Louis
The Role of AML/1ETO in the Pathogenesis of t(8;21) Acute Myeloid Leukemia
This year, approximately 10,500 adults will be diagnosed with acute myeloid leukemia (AML) in the U.S. Despite incremental improvements in the care of these patients over the past three decades, most will die of their disease. My laboratory is studying the AML subtype characterized by an exchange of genetic material between chromosomes 8 and 21 which leads to production of a new protein called AML1/ETO. We have generated a new strain of mice that express the human AML1/ETO protein in their bone marrow cells. These mice, unlike strains previously produced by other laboratories, develop a disease that resembles a “preleukemic” syndrome in humans. We are carefully analyzing these mice to determine what AML1/ETO is doing at the molecular level. We will find out whether production of AML1/ETO is just an early event in the development of leukemia, or whether it must remain present at all times for the leukemia cells to survive. To ask this question, we are developing a tool that can specifically shut off the AML1/ETO protein in the mice. If we find that the AML1/ETO protein remains an “Achilles heel” in these cells, this tool could be refined into a novel therapy for AML. Just as new, molecularly targeted therapies have revolutionized the care of patients with chronic leukemias, a better understanding of AML at a molecular level should help us find therapies that are more effective and have fewer side effects.
Tanja A. Gruber, MD, PhD St. Jude Children's Research Hospital
Defining the role of the inv(16)-encoded CBFA2T3-GLIS2 chimeric transcription factor in the pathogenesis of pediatric acute megakaryoblastic leukemia
We have identified a mutation that fuses two genes together resulting in an aberrant protein, CBFA2T3-GLIS2, in ~1/3 of pediatric acute megakaryoblastic leukemia patients. We have demonstrated that this protein enhances the cell’s ability to self-renew. Our research is focused on determining how CBFA2T3-GLIS2 causes the cell to acquire this trait.
Alejandro Gutierrez, MD Boston Children's Hospital
Therapeutic Activation of the PP2A Tumor Suppressor in High-Risk T-cell Acute Lymphomblastic Leukemia
High‐risk T‐cell acute lymphoblastic leukemia (T‐ALL) is typically incurable with current therapy. We performed a zebrafish drug screen, which revealed that perphenazine (a clinical antipsychotic) has anti‐T‐ALL activity via reactivation of PP2A, an important tumor suppressor. Here, we will investigate the biology and therapeutic utility of PP2A reactivation in T‐ALL.
Boglarka Gyurkocza, MD Fred Hutchinson Cancer Research Center
Reducing Relapse of Acute Myeloid Leukemia after Hematopoietic Cell Transplantation
We are conducting two clinical trials with novel, minimally toxic conditioning regimens – combining treosulfan or clofarabine, instead of fludarabine, with hematopoietic cell transplantation (HCT). Our goal is to reduce the incidence of recurrent leukemia following HCT, thereby increasing the likelihood of long-term survival.
Improving the Efficiency of Alkylation Anticancer Chemotherapies
Alkylating agents are extensively used against a number of malignancies such as lymphoma, brain tumors, melanoma and Hodgkin’s disease. These agents kill tumor cells by damaging their DNA. However, repair of the DNA damage induced by these alkylating agents by human DNA repair proteins, especially the human AGT protein, significantly limits the efficacy of these treatments. Thus inhibiting these DNA repair activities in tumor cells is crucial for obtaining the maximum therapeutic effect for these treatments. By adopting a multidisciplinary approach that integrates chemistry, biology and structural study, Dr. Chuan He plans to fully elucidate the detailed interaction between the human AGT protein and its DNA substrates. With this knowledge more efficient inhibitors will be designed, prepared and tested to block the activity of this protein. Dr. He also plans to search for other DNA repair functions that could play major roles in tumor resistance towards DNA damaging chemotherapeutic agents. A proteomic technique that looks at proteins in the whole cell will be developed to achieve this goal.
Elizabeth Hexner, MD Hospital of the University of Pennsylvania
T cells to Enhance Umbilical Cord Blood Transplantation
Umbilical cord blood transplantation is potentially life-saving for patients with otherwise incurable leukemia and lymphoma, but is still limited by delayed recovery of normal blood cells, risk of infections and the risk of disease returning. My research focuses on understanding, employing and activating T cells to address these obstacles.
H. Courtney Hodges, PhD Baylor College of Medicine
Revealing novel SMARCA4-related dependencies in mixed-lineage leukemia
Mixed-lineage leukemia (MLL) is an aggressive blood cancer affecting ~ 5,000 infants in the U.S. each year. Unlike other types of childhood leukemia, MLL has few treatment options and a five-year survival rate of only 40%. Through our studies, we will identify and validate entirely new precision approaches for treating MLL.
Daniel Hodson, PhD, MRCP, FRCPath University of Cambridge
Pathogenesis of Aggressive B Cell Lymphoma
We seek to understand how the control systems of normal cells become corrupted during the process of lymphoma development. In doing so, we aim to identify cancerous pathways that can be inhibited by novel drugs in a way that specifically targets the cancerous cells while leaving normal cells intact.
Dr. Sahand Hormoz Dana-Farber Cancer Institue - 2019
“Reconstructing the differentiation dynamics and genealogy of cancer cells
in individual patients with myeloproliferative neoplasms using single-cell
In a type of blood cancer called myeloproliferative neoplasm, the same genetic alteration results in drastically different forms of the disease in different patients. To understand this discrepancy, we will measure the molecular profile of individual cells obtained from patients and reconstruct the genealogical history of the cancer cells.
Alex Y. C. Huang, MD, PhD Case Western Reserve University
Modulation of Immune Cell Homing and Interaction by Mesenchymal Stem Cell within CNS Tumor Microenvironment
Cancer cells manage to evade detection and elimination by the immune system whose job is to recognize and eliminate the threat of foreign invaders and cancer cells in the body. Dr. Huang’s laboratory proposes to take advantage of a unique imaging tool, the intravital 2-photon laser scanning microscopy, to directly observe in real time how brain tumor cells hijack various immune-suppressive components of the immune system and stem cell pool to evade immune detection. Success in this effort to understand how cancer cells and immune system communicate with one another in the tumor-bearing host will promise to accelerate development of novel therapeutic approaches to anti-tumor immunotherapy.
Study of the Inhibitory Role of miR-26 in the Development of MLL-associated Leukemia
Approximately 10% of human acute leukemias are involved in chromosomal translocation between the MLL (mixed lineage leukemia) gene and over 50 partner genes. These leukemias occur preferentially in infant and young children and are often associated with poor outcome. MicroRNAs (miRNAs) are recently identified, very small RNA molecules which regulate gene expression. Dr. Huang’s lab found that one of these small RNAs (miR-26) is specifically under-expressed in MLL-associated leukemia. Previous studies have shown that pathological repression of miR-26 antagonizes apoptosis and facilitates carcinogenesis in breast cancer and nasopharyngeal carcinoma through targeting GATA4, GSK3b, and EZH2. His preliminary results suggest that miR-26 may also have an inhibitory function in leukemogenesis. Therefore, Dr. Huang and his team will investigate the inhibitory role of miR-26 and its relevant target pathways in the development of MLL-associated leukemia. His studies will clarify why miR-26 is repressed and what are its downstream targets in this leukemia, which may lead to the identification of critical targets for the effective treatment of leukemias, particularly MLL-associated leukemias.
Wendy Jia Men Huang, PhD University of California, San Diego
Long non-coding RNAs in T-cell lymphoma
Mutations of lncRNA Rmrp and its associated factors result in immune-deficiencies and blood malignancies in human. We propose to investigate how this molecule facilitates the normal development and function of white blood cells in the immune system and determine how changes to its structure promote lymphoma.
The Function and Regulatory Mechanism of miR-495 in Acute Myeloid Leukemia (AML)
MLL-rearranged leukemia, accounting for approximately 10% of human acute leukemias, is often associated with poor prognosis.MicroRNAs (miRNAs) are a class of small RNAs mediating gene silencing. I found that miR-495 was significantly down-regulated in most AML cases with MLL rearrangements. It dramatically inhibited human leukemic cell growth and delayed MLL-fusion-mediated leukemogenesis. The major goal of this project is (i) to identify its critical target genes and (ii) to reveal relevant molecular mechanism(s) underlying its repression in MLL-rearranged AML.
Therapeutic effect of Boswellia Carterri Birdw in Acute Myelocyctic Leukemia
Traditional Chinese Medicine is a potential source for modern cancer therapies but western technology and clinical trials are required properly to identify, understand, and evaluate the active components. This is best exemplified by the dramatic clinical responses to all trans retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia, now standard worldwide treatments. Arsenic trioxide was an important component of Traditional Chinese Medicine and became clinically effective, proven, and mechanistically understood when “traditional” clinical data was confirmed in clinical trials and experimentation. In this case, “Boswellia Caterri Birdw, an herb used in Traditional Chinese Medicine to treat cancer was recently found to contain boswellic acid acetate (BA) as a possible in vitro active component. Therefore, in keeping with the practice of traditional western clinical studies in proving the efficacy of Traditional Chinese Medicine, this experiment will demonstrate that crude extract of Boswellia Caterri Birdw and Boswellic acid acetate have potent and broad anti-leukemia activities based on the induction of differentiation and apoptosis. At this time we have the opportunity to extend the initial studies on Boswellic acid by creating structural analogues to determine which portion of the molecule is required for differentiation or apoptotic induction. This will be done in collaboration with the Shenyang Pharmaceutical University in China that has already demonstrated the ability to produce structural analogues of great purity. It is the goal of this experiment to expand and continue an active program to test agents for differentiation and apoptotic induction and define their mechanism in various leukemia cell lines. Furthermore, increased funding will help identify appropriate molecules to use in more extensive pre-clinical and eventually clinical studies that would have impact on the treatment of leukemia.
Targeting Mammalian SWI/SNF (BAF) Chromatin Remodeling Complexes in Leukemia and Lymphoma
Several types of leukemia are dependent on protein complexes inside the cell that regulate the architecture of the genome, called chromatin remodeling complexes. Our work seeks to understand the mechanisms underpinning the importance of these complexes in leukemia, which will inform new therapeutic strategies.
Naama Kanarek, PhD Boston Children's Hospital - 2019
“A simple dietary supplement to improve pediatric blood cancer therapy”
We propose to improve the use of methotrexate – the standard pediatric leukemia drug – with a simple dietary supplement. By enhancing methotrexate’s efficacy, and better monitoring patients’ responses to the drug, we aim to reduce the therapy’s long-term side effects and offer hope to young patients with a severe prognosis.
Cell Death Regulation by Pro-Apoptotic BOK in Multiple Myeloma
Although the chemotherapeutic bortezomib has dramatically improved the survival of myeloma patients, nearly everyone develops resistance. We identified that a protein called BOK, which is frequently deleted in cancer, coordinates multiple ways cells die in response to bortezomib. We aim to identify therapeutic targets to re-activate BOK-driven cell death pathways.
Alex Kentsis, MD, PhD Memorial Sloan Kettering Cancer Center
Dr. Kentsis researches the blockade of autocrine signaling for curative therapy of acute myeloid leukemia.
Acute myeloid leukemia (AML) is a blood cancer that frequently affects both children and adults. Current treatment of AML with chemotherapy is toxic, and new therapies are direly needed for patients whose disease is resistant to intensive chemotherapy. Our research into molecular signaling pathways that drive leukemia cell survival has revealed a new set of therapeutic targets based on requirements of autocrine signaling. The support of Gabrielle’s Angel Foundation will enable us to precisely define autocrine signaling that sustains AML cell growth and develop new treatments for its blockade to effect cure.
Clodagh Keohane Guy's and St. Thomas' NHS Foundation Trust
A Study of the Immunological Consequences of JAK inhibition in the Myeloproliferative Neoplasms
MPNs are a type of cancer that can develop into leukaemia and cause serious blood clots. We believe that the immune system is not normal in MPN. An efficacious new treatment is available and we want to see what effect this treatment has on the immune system of patients.
The University of Texas M. D. Anderson Cancer Center
Issa Khouri, MD The University of Texas M. D. Anderson Cancer Center
Nonablative Allogenic Blood Stem Cell Transplantation for Patients with Indolent Lymphoid Malignancies
Chronic lymphocytic leukemia (CLL) is a relatively slowly progressing form of leukemia affecting specialized white blood cells known as lymphocytes. CLL mainly affects older people. One of the most effective treatments for some leukemias, including CLL, is the use of allogenic transplants, in which stem cells or bone marrow from a matching donor are used. This technique was originally developed to replenish the bone marrow after the use of extremely high dose chemotherapy or radiation to eradicate the malignant cells, thereby permitting higher doses of chemotherapy or radiation than could otherwise be used. Unfortunately, even with the use of allogenic transplants, these high dose chemotherapy and radiation regimens are associated with serious side effects, even death. Thus, they are usually reserved for younger patients in general good health. There is a growing body of evidence suggesting that allogenic transplants may succeed on their own in some leukemia and lymphoma patients, by causing the body’s own defense systems to launch an immune response against the malignant cells (in leukemia, this is referred to as a graft-versus-leukemia, or GVL, effect). Dr. Issa Khouri has conducted a small initial study of allogenic transplants without the use of drastic high dose chemotherapy or radiation regimens, with promising results. Dr. Khouri is proposing to build on this preliminary data by studying conventional chemotherapy regimens plus allogenic transplants in patients up to the age of 75 with advanced chronic lymphocytic leukemia and low grade lymphoma. It is hoped that this research will lead to more effective and better tolerated treatment strategies in older patients.
Nigel Killeen, PhD University of California, San Francisco
The Development of Murine Models of Recurring Myeloid Leukemia-Associated Chromosomal Deficiencies
Tumor cells in patients with leukemia or lymphoma frequently have abnormal chromosomes. There are recurring abnormalities that typify certain kinds of malignancies. Deletions of parts of chromosomes 5 and 7 are common in patients that develop leukemia months or years after treatment for other forms of malignant disease as a result of chemotherapy treatment. Dr. Killeen is interested both in understanding how these deletions contribute to leukemia and would also like to use the insights to devise better therapies for leukemia. Dr. Killeen proposes to create novel lines of mutant mice that carry specific chromosomal deletions that are analogous to those found in human leukemia cells. These mice will be used to determine the molecular mechanisms that underpin myeloid leukemia. They will also be used to develop and test new therapeutic approaches. Funds from the [Gabrielle’s Angel] Foundation support both the development of the mouse strains, and also improvements in specific aspects of the chromosome engineering technology used to create such mice.
Tami Kingsbury, PhD University of Maryland School of Medicine
Identification of microRNAs that can inhibit T-cell acute lymphoblastic leukemia (T-ALL) cell survival and proliferation
Leukemia cells exhibit altered growth requirements. Using a functional screening approach, we will identify microRNAs that inhibit growth of T-ALL cell lines as a method to discern which microRNAs have potential therapeutic value. Analysis of microRNA targets will elucidate intracellular signaling pathways critical for T-ALL cell survival and proliferation.
Heidi D. Klepin, MD, MS Wake Forest University School of Medicine
Minimizing Physical Function Decline in Older Adults Receiving Chemotherapy
Older adults often develop chemotherapy-associated disability during treatment for acute leukemia which contributes to poor outcomes for these patients. We propose addressing this understudied issue by testing an adaptable exercise program during chemotherapy treatment to improve physical function and quality of life. We anticipate that patients will be able to better tolerate intensive medical therapies if their physical function and quality of life are optimized through exercise.
Birgit Knoechel, MD, PhD Dana-Farber Cancer Institute
Enhancer rewiring in drug resistant T-ALL and its therapeutic implications
T-cell acute lymphoblastic leukemia (T-ALL) is a disease that affects children and young adults, for which outcome has remained poor, often due to rapid development of resistance to existing therapies. We propose to determine the epigenetic alterations responsible for drug resistance in T-ALL, and develop strategies for their therapeutic targeting.
Young Jik Kwon, PhD University of California, Irvine
Killing Two Birds with One Stone: Dual Modal Gene Therapy for Leukemia Using Chimeric Nanoparticles
Genetic mutations in cancer cells reduce activity of molecules that cause cell death, leading to imbalanced cellular signals and prolonged leukemia cell survival. This project aims to genetically re-balance the molecular signals toward programmed death in leukemia cells. We will increase pro-cell death molecules and simultaneously silence activity of pro-survival proteins using dual modal cancer gene therapy. We use novel virus core/synthetic shell nanoparticles that co-deliver a pro-cell death gene and anti-pro-survival nucleic acids to leukemia cells at the same time. Successful application of this synergistic and targeted gene therapy will potentially lead to a clinical leukemia treatment.
H. Daniel Lacorazza, PhD Baylor College of Medicine
Role of Proliferation in the Pathogenesis of T-cell Acute Lymphoblastic Leukemia
In spite of successful management of children with acute lymphoblastic leukemia (ALL), a fifth of diagnosed patients relapse after induction treatment. We propose to test the hypothesis that a deregulated response to childhood infections can induce expansion of pre-leukemic cells and overt leukemia. We previously described a gene that controls proliferation of T cells during homeostasis and following infection or vaccination. We plan to investigate whether gene deletion primes pre-leukemic cells to expand upon activation of the immune system and/or increases resistance of leukemia-initiating cells to chemodrugs. This project will provide a molecular framework to design adjunctive therapies in high-risk patients.
A Pilot Study Evaluating the Microbiome and Obesity in Pediatric Acute Lymphoblastic Leukemia
Pediatric ALL is a risk factor for the development of obesity. Children who develop obesity have reduced survival and increased side-effects. The intestinal microbiota has a role in the development and treatment of obesity. We propose to evaluate the intestinal microbiota so as to identify future targets for clinical investigation.
Andrew A. Lane, MD, PhD Dana-Farber Cancer Institute
Identifying vulnerabilities in hematologic malignancies driven by heterotrimeric G proteins
Blood cancers arise from cells that acquire mutations before becoming a leukemia. We study a gene called GNB1 that is often mutated in patients with “pre-leukemic” blood cells, and in leukemia and lymphoma. We will determine how best to target GNB1 mutant cells to treat and possibly prevent blood cancers.
Dawn Lemanne, MD, MPH Memorial Sloan-Kettering Cancer Center
A Randomized Trial of Physical-Activity Motivation in Breast Cancer Patients.
Research shows that exercise can prolong survival in cancer patients. A major challenge, however, is to engage patients in sustained physical activity. Research has yet to determine which motivators are optimal. We propose to fill this gap with a randomized study of two incentives that seem most promising in helping survivors boost their chances of doing well.
Anthony G. Letai, MD, PhD Dana-Farber Cancer Institute, Harvard University
Detecting blocks in Apoptosis in Leukemia Stem Cells
Cancer biologists are beginning to appreciate that at least in some cancers, including acute myelogenous leukemia (AML), there are certain special cells, called “cancer stem cells”. These cancer stem cells can repopulate the entire cancer, and cure will likely require the eradication of these cells. Dr. Letai will study whether these AML cancer stem cells are somehow conditioned to die less readily than the rest of the AML cells, and whether this is a possible explanation for the fact that many people with AML have great initial responses to chemotherapy, but experience a relapse later on.
Ross L. Levine, MD Memorial Sloan-Kettering Cancer Center
Genomic characterizations of myeloproliferative neoplasms
The Levine Lab studies chronic leukemias which manifest as an excess of red blood cells, platelets, and white blood cells, respectively. Importantly, these patients are at high risk for developing bone marrow failure (due to increased scar tissue in their bone marrow) or transformation to acute leukemia; when patients develop these complications there are no curative treatments. The goal of this proposal is therefore to use state-of-the-art genomic technologies in order to identify additional mutations in leukemia patients and to develop novel, molecularly targeted therapies. The long-term goal of their research efforts are thus to use genetic insights in order to improve outcomes and reduce toxicities for all patients with these chronic leukemias.
The role of miR-126 in core-binding factor acute myeloid leukemia
Acute myeloid leukemia (AML), one of the most common types of leukemia, is a cancer of blood cells that originate in the bone marrow. Two common subtypes of AMLs are associated with chromosome rearrangements, such as translocations between chromosome 8 and 21 or inversions within chromosome 16. These chromosome rearrangements result in the disruption of a protein that is a regulator of normal development of the blood system, which leads to a type of AML, namely CBF leukemias. The proportion of CBF leukemias is twice as large in children as in adults, and the disease-free survival at five years is only 55-60%; this fact makes its improved treatment an especially urgent problem. RNA is a biologically important type of molecule that is copied from DNA. MicroRNAs (miRNAs) are recently identified, very small RNA molecules which regulate gene expression. Dr. Li’s lab found that one of these small RNAs (miR-126) is specifically over-expressed in CBF leukemias. Their preliminary results suggest that its overexpression may function as a cancer-associated mutational event in leukemogenesis. Therefore, Dr. Li will determine the importance of the role and the relevant pathways that miR-126 regulates in the development of CBF leukemias. These studies may lead to the identification of critical targets for the effective treatment of leukemias, particularly CBF leukemias
University of North Carolina School of Medicine - 2019
Dr. Pengda Liu University of North Carolina School of Medicine - 2019
“Targeting the Innate Immunity-Independent Function of STING in treating AML”
This proposal is to test if inhibiting a deubiquitinase named OTUD7B retards AML growth. We found that AML growth is controlled by an immunity sensor STING through activating an oncogenic kinase called mTOR. This process is facilitated by OTUD7B. Thus, inhibiting OTUD7B suppresses STING-mediated mTOR activation and subsequent AML growth
Jeffrey Magee, MD, PhD Washington University St. Louis
Development Context and Germline Variation in Infant Leukemogenesis
Infant leukemia is a hard to treat malignancy of childhood with a grim prognosis. The proposed studies will provide insights into how inherited genetic differences among children may predispose to infant leukemia. This will improve our ability to counsel families and treat this disease.
Molecular Rationale for WNT Inhibitor Therapy in B-Cell Lymphoma
The FOXP1 protein is overexpressed in B-cell lymphomas, and patients with high FOXP1 levels often resist therapy and are given a poor prognosis. We discovered that FOXP1 activates the WNT signaling pathway. We will determine whether WNT inhibitors currently in clinical trails for other cancers will benefit lymphoma patients.
Marc R. Mansour, MD, PhD, FRCPath NCL Macmillan Cancer Centre
Discovery and targeting of neomorphic enhancer mutations of oncogenes (NEMOs) in T-cell acute lymphoblastic leukaemia
In acute lymphoblastic leukaemia, we recently discovered mutations in ‘junk DNA’ that can activate cancer-causing genes (oncogenes). Such mutations loosen up tightly knotted DNA, leading to activation of the nearby oncogene. We believe this is a common cause of leukaemia formation that could be exploited therapeutically with newly available drugs
Johns Hopkins, Sidney Kimmel Comprehensive Cancer Center
William H. Matsui, MD Johns Hopkins, Sidney Kimmel Comprehensive Cancer Center
Hedgehog signaling as a stem cell based therapeutic target in myelodysplastic syndrome and acute myeloid leukemia.
In many ways the growth of cancer mirrors the formation of normal organs during embryonic development. Dr. Matsui has found that a specific pathway required during development called the Hedgehog signaling pathway is abnormally turned on in acute myeloid leukemia and myelodysplastic syndrome. His lab will study the Hedgehog pathway in these diseases and test whether inhibitors of this pathway have anti-leukemic activity.
Marcela V. Maus, MD, PhD Massachusetts General Hospital
Identification and correction of T cell defects in patients with chronic lymphocytic leukemia and impact on T cell therapy.
Patients with chronic lymphocytic leukemia can be treated with a variety of regimens, but only cell therapies such as transplant or genetically-modified T cells (CART19) can be curative. Our research proposes to test the combination of ibrutinib and CART19 in the test tube and in mice to identify how and why combining these two types of therapy could cure CLL.
Adam Mead John Radcliffe Hospital, University of Oxford
Unravelling Clonal Complexity in Myelofibrosis Stem Cells Though [sic] Application of Single Cell Transcriptomics
Not all blood cancer cells can cause disease relapse following treatment. Understanding the biology relapse-causing “cancer stem cells” is critical, but is akin to “finding a needle in a haystack.” This grant will support the development of single-cell genetics to better understand the biology of cancer stem cells in myelofibrosis.
Lorenzo Melchor, PhD The Institute of Cancer Research, London
Genetic Complexity of Quiescent Leukaemic Stem Cells
Childhood acute lymphoblastic leukaemia (ALL) patients respond initially well to chemotherapy, but some relapse due to the proliferation of treatment-resistant dormant cells. We have demonstrated that leukaemia patients have different sub-clones, so no we aim to investigate which of these sub-clones contains dormant cells responsible for subsequent relapses.
Ari M. Melnick, MD Albert Einstein College of Medicine
The Bcl-6 oncoprotein as a target for transcription therapy
Dr. Melnick’s research will focus on determining the mechanism of action of transcription factors (master regulatory proteins that govern the activity of the genome) involved in the molecular pathogenesis of hematologic malignancies. Dr. Melnick and his team discovered a key mechanism of action of a factor called Bcl-6, which is frequently mutated in B-cell lymphomas, and engineered peptide inhibitors of this mechanism. These peptides kill malignant lymphoma cells but do not affect normal cells and are non-toxic in animal models. Their preliminary data suggest that Bcl-6 licenses B-cells to enter an extremely vulnerable and unstable state that predisposes to cancer.
Mind-body Medicine for Adolescents and Young Adults (AYA) Coping with Hodgkin Lymphoma
Dr. Milbury will conduct a pilot randomized controlled trial to test the feasibility and initial efficacy of a mind-body intervention targeting the psychosocial needs of adolescents and young adults (AYAs; ages 15-39) with Hodgkin Lymphoma. AYAs with a new Hodgkin Lymphoma diagnosis will complete baseline measures of psychological distress and cancer symptoms and blood draws for biomarker analyses. Then, they will be randomized to the intervention or an attention control group. Both study arms will be delivered in a group setting (5 sessions total; 75 min each) via videoconference. All participants will be reassessed 6 and 12-weeks later.
Steven D. Mittelman, MD, PhD Children's Hospital Los Angeles
Overcoming L-Asparaginase Resistance Caused by Adipocyte Production of Glutamine
Overweight leukemia patients are harder to cure than thin patients. We found that an important chemotherapy, L-asparaginase, does not work as well in overweight mice compared to thin mice. Fat cells produce glutamine, which we think may help leukemia cells resist this important medicine. We will therefore see how much glutamine fat cells make in mice and in children, with and without L-asparaginase treatment. We will also test whether another form of L-asparaginase that breaks down more glutamine might work better in overweight children with leukemia. These studies could lead to improved leukemia treatments in both overweight and lean children.
Jeffrey J. Molldrem, MD University of Texas, MD Anderson Cancer Center
To Collect Peripheral Blood and Bone Marrow Samples from Donors and Recipients of Blood and Marrow Transplants for Laboratory Research
In his ongoing studies of anti-leukemia immunity and CTL antigens, Dr. Molldrem has studied myeloid-restricted normal proteins that are highly expressed leukemia. Myeloid leukemias express a number of differentiation antigens associated with granule formation. He chose to study Pr3, a 26,000 dalton neutral serine protease that is stored in primary azurophil granules and is maximally expressed at the promyelocyte stage of myeloid differentiation. The human gene contains 5 exons, is localized on chromosome 19p and has recently been cloned. Pr3 is over expressed in a variety of myeloid leukemia cells including 75% of CML patients, approximately 50% of acute myeloid leukemia patients, and approximately 30% of the cases of myelodysplastic syndrome patients. Dr. Molldrem has found that PR1, a 9 aa peptide derived from Pr3 that binds to HLA_A2.1, can be used to elicit CTL in vitro from an HLA-A2.1+ normal donor. These PR1-specific CTL show preferential cytotoxicity toward allogeneic HLA-A2.1 myeloid leukemia cells over HLA-identical normal donor marrow. PR1 is therefore the first peptide antigen identified that can elicit specific CTL lysis of fresh human myeloid leukemia cells. More recently, he has identified PR1-specific CTL in the peripheral blood of CML patients using PR1/HLA-A2 tetramers, and detection of these CTL correlates with a cytogenetic response to either interferon or allogeneic BMT (p = 0.002), thus establishing PR1 as the first human leukemia-associated tumor antigen. By FAC sorting CML patients’ PR1-specific CTL to high purity, he showed that PR1-specific CTL could specifically lyse CML but not normal marrow cells, and that they were HLA-A2 restricted. Dr. Molldrem proposes to improve his methods to efficiently grow PR1-specific lymphocytes in the lab. He will also investigate a new laboratory method to isolate only the PR1-specific lymphocytes from peripheral blood using microbeads that are conjugated to the HLA-A2 molecule plus PR1 peptide. These PR1-spcific lymphocytes will then be expanded to high enough numbers to be transferred to patients with relapsed myeloid leukemia after allogeneic transplant in order to induce GVL without GVHD.
Siddhartha Mukherjee, MD, PhD Columbia University Medical Center
DR. Mukherjee has been dissecting the roles of Yes-1, MIIt3 and Ctnnd1 in leukemia stem cell quiescence.
Hematopoietic stem cells are maintained in deep quiescence in the bone marrow. A fundamental feature of leukemias is the disruption of this quiescence, resulting in unchecked proliferation. Our laboratory has used a novel high-throughput screen to identify 3 candidate genes that regulate HSCs quiescence and are dysregulated in leukemias. Here, we will interrogate the roles of these genes – Yes1, Mllt3 and Ctnnd1 – in leukemia stem cell biology. Furthermore, we will determine if these genes are therapeutically amenable in human leukemia models. Using a longitudinal repository, we will query the prognostic and diagnostic roles of these genes in AML and MDS.
“Biology and Therapeutic Targeting of Mutant Calreticulin in Myeloproliferative Neoplasms”
Somatic mutations in celreticulin (CALR)are frequent and disease-initiating in myeloproliferative neoplasms (MPN). Dr. Mullally’s laboratory recently elucidated the mechanism by which mutant CALR is oncogenic and induces MPN. Building on this work and guided by strong preliminary data they have generated, she will now identify unique molecular vulnerabilities in CALR-mutant MPN that arise as a result of (i) the pathogenic binding interaction of mutant CALR with MPL and (ii) the differential protein-protein binding interactions of mutant CALR. Dr. Mullally will exploit this information to target unique molecular vulnerabilities in CALR-mutant MPN stem cells to achieve definitive cure.
James C. Mulloy, PhD Cincinnati Children's Hospital
Microenvironment and Flt3 Signaling in MLL Leukemia
Dr. Mulloy’s lab has recently shown that human blood stem cells can be induced to make leukemia upon introduction of a leukemia oncogene into these cells. This is one of the first models that use human cells rather than mouse cells to produce leukemia. This is a significant advance for the field of leukemia biology, since the signals that are important in mouse cancer can be different from the signals needed for human cancer. Dr. Mulloy will use this model system to study the signaling pathways that are initiated by the leukemia oncogene, and to test novel therapeutic approaches targeted to the key events that occur during the development of leukemia.
We will determine the role of AMPK in AML using mouse models and identify the key metabolic pathway regulated by AMPK that maintains AML-initiating cell population. Our goal is to understand how AML cells maintain metabolic integrity to develop new therapies targeting this common requirement of cancer.
Louie Naumovski, MD Stanford University School of Medicine
Chemo Resistance to Phase I/II Anti-cancer Agents
One of the key limitations of chemotherapy is the development of tumor cells that are resistant to various known chemotherapy drugs. In patients with leukemia or lymphoma who relapse following primary chemotherapy, it is common to try new anti-cancer drugs, many of them in early clinical trials (Phase I/II), in hopes of at least a temporary remission. Unfortunately, many of these cancers prove to be resistant to these drugs as well. A number of genes have been identified that make cancer cells resistant to chemotherapy. Generally, these genes induce resistance by inactivating the chemotherapy agent or causing it to be removed from the cell, or by blocking the process of apoptosis in some way. (Apoptosis is the process of cell death that occurs when cancer cells are exposed to effective chemotherapy.) It is likely that multiple genes for chemotherapy resistance exist. Identifying these resistance genes and elucidating the mechanisms by which they produce resistance should aid in the selection of chemotherapeutic agents for individual patients. This understanding may also lead to the development of methods that can modulate those resistance mechanisms. Dr. Louie Naumovski proposes to use tumor samples from patients who have relapsed and failed to respond to chemotherapy to screen for and isolate genes associated with chemotherapy resistance. These genes and their protein products will then be studied. This will help build a “library” of chemotherapy resistance genes. When patients relapse, tumor samples will be studied to determine if there is any correlation between their response to chemotherapy and the expression of the suspected drug resistance genes. Eventually, it should be possible to use this information to target therapy to individual patients, to avoid exposing them to chemotherapy that is destined to fail.
Kirsten Ness, PT, PhD St. Jude Children's Research Hospital
Vibration Intervention for Bone Enhancement in Childhood Cancer Survivors
Interventions to improve Bone Marrow Density (BMD), and prevent early onset osteoporosis and fracture are essential to promote long, productive lives, free from persistent pain and/or disability. Current treatments for BMD decrements among childhood cancer survivors are limited to those who can tolerate a pharmacologic agent, and to those whose physical abilities allow a vigorous weight bearing physical activity. This innovative intervention is portable, safe, cost-effective, and of low burden to the cancer survivor. It has the potential to be used either alone or as an adjunct to other interventions to improve BMD in this at risk population.
Targeting Cyclin D1 and the DNA Damage Response in Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is rarely curable. Its hallmark is overexpression of the cell cycle regulatory protein cyclin-D1. We uncovered an unexpected role of cyclin-D1 in maintaining MCL genome integrity. We will investigate whether targeting cyclin-D1 simultaneously with proteins that guard against DNA damage will be effective at eliminating MCL.
Tissue-specific immunity to preserve the graft-versus-tumor effect following hematopoietic cell transplantation
Hematopoietic stem cell transplantation (HCT) can cure hematological cancers, but its wider use is limited by the high morbidity and mortality associated with graft-versus-host disease (GVHD). Current therapies for GVHD lead to nonspecific suppression or depletion of T cells, thus potentially compromising the ability of the HCT to eradicate the cancer. Our research addresses the critical need for targeted therapy in GVHD and evaluates the feasibility of generating stable and functional organ-specific regulatory T cells (Treg) that reduce GVHD without affecting the ability of the donor immune system to attack the cancer following HCT.
Panagiotis Ntziachristos, PhD Northwestern University
Post-translational regulation of splicing as a pro-oncogenic mechanism in high-risk T cell leukemia
Chemotherapy for acute lymphoblastic leukemia entails burdensome side-effects, a risk of second cancers and associated resistance. We have identified a mechanism that controls how genes leading to leukemia behave and we aim to exploit this knowledge in order to identify new treatment targets for patients in 3-5 years.
The Role of EGR in establishing a malignant epigenetic program of therapy resistance in CLL
Modification of gene structure constitutes a fundamental way healthy cells are reprogrammed into leukemia and gain therapeutic resistance. We will uncover how modifications associated with aggressive disease and relapse are created by reengineering normal cells. This will further our knowledge of relapse risk, detection, and how to circumvent therapy resistance.
Esther Obeng, MD St. Jude Children's Research Hospital
“Targeting SF3B1 in myelodysplastic syndrome”
Myelodysplastic syndromes (MDS) are a group of pre-leukemia blood disorders with a high risk of progression to aggressive leukemia, SF3B1 mutations are frequent, early events in MDS pathogenesis and ideal therapeutic targets. The proposed studies will evaluate how SF3B1 mutations cause MDS and test novel agents in SF3B1-mutant cells.
Investigating the collaboration between microRNAs and oncogenes in leukemia
Understanding the mutations that cause leukemia is critical to our ability to design novel therapies. We propose to determine the capacity of two molecules, which are found mutated together in human AML patients, to collaborate during initial leukemic transformation and later during resistance to therapies.
Craig Okada, MD Oregon Health & Science University
Tumor Antigen Receptor Vaccines for Active Immunotherapy of T Cell Malignancies
One of the most promising areas of cancer research is the use of immunotherapies-therapies that capitalize on the body’s own immune defenses. An important avenue of immunotherapy research is the use of vaccines to stimulate the immune system to mount its own attack against tumors. Dr. Okada has done preliminary research in the development of a vaccine for patients with T cell malignancies (malignancies that affect specialized immune cells known as T cells found in the blood and lymphoid tissues). T cell malignancies include some forms of leukemia and some non-Hodgkin’s lymphomas. Among lymphomas, peripheral and cutaneous T cell lymphoma are particularly deadly. Normal T cells have antigen receptors on their surface (called TCR, for T cell antigen receptor), which allow them to recognize and bind to antigens, thus triggering an immune response. These antigen receptors have determinants, called idiotypes, unique to the type of lymphocyte and the antigen. The unique configuration of the TCR means that the immune system can mount a specific attack against a particular antigen without harming other cells. Tumor cells also have antigen receptors on their surfaces. Because T cell lymphomas are clonal, the cells of the T cell lymphoma all contain the same unique antigen receptor, making it an ideal target for a vaccine. Thus, if an idiotype-specific TCR vaccine could be developed and injected, it should lead to a specific immune response directed at the tumor. Dr. Okada’s preliminary experiments with idiotype TCR vaccines in a mouse model have been promising. The chief obstacle is producing sufficient quantities of idiotype TCR vaccines and generating a more potent immune response. Dr. Okada is proposing further research to develop new idiotype TCR based vaccines and evaluate their efficacy in a mouse model. By examining and characterizing the specific immune response that is generated, he hopes to find ways to increase the ability of these vaccines to generate a potent and specific immune response against T cell lymphomas. Ultimately, this work may lead to effective TCR vaccines for human T cell lymphomas.
Bilal Omer, MD Texas Children’s Hospital Cancer Center
“Engineering more potent T cells to target lymphoma associated antigens”
We have developed strategies to grow a patient’s own immune cells in the laboratory and then re-inject them into the patient to fight lymphoma. In a clinical trial at our center, 3 of 7 patients with active lymphoma responded to this treatment without the need for chemotherapy. Dr. Omer’s research will now plan to genetically modify these immune cells to make them more powerful.
Etan Orgel, MD, MS Children's Hospital Los Angeles
A Diet and Activity Intervention to Improve Survival and Quality of Life in Obese Adolescents Receiving Therapy for Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia is the most common childhood cancer and relapse is the leading cause of death. Obesity during treatment is associated with relapse and greater side effects. We propose to conduct a clinical trial testing a diet and activity intervention to reduce obesity, reduce relapse, and lessen side effects.
Cambridge Institute for Medical Research, University of Cambridge
Katrin Ottersbach, PhD Cambridge Institute for Medical Research, University of Cambridge
Development and Characterisation of a Mouse Model for Infant Leukaemia
Infants with leukaemia caused by the MLL-AF4 mutation have a poor prognosis. MLL-AF4 alone failed to incite leukaemia in mouse models, impeding research into therapies. We will introduce the reciprocal fusion, AF4-MLL, alongside MLL-AF4 to produce a leukaemia mouse model for drug research to improve treatments.
“Investigating the Impact of Oncologic Therapy on Clonal Hematopiesis and Subsequent Risk of Developing Therapy Related Leukemia”
Dr. Papammanuil will study the key risk factors that lead to the therapy related leukemia development in cancer patient survivors. We will combine clinical, molecular and treatment information in a cohort of 45,000 patients to study disease biology and inform guideline development aimed to prevent this aggressive disease.
Samir Parekh, MD Albert Einstein College of Medicine
Targeting NOXA methylation to overcome Bortezomib resistance in MCL
Mantle cell lymphoma is an aggressive type of non-Hodgkin’s lymphoma characterized by frequent relapses and usually fatal in the majority of patients. We are trying to understand precisely why patients do not respond to Bortezomib, a standard chemotherapy for this disease using cutting-edge next generation sequencing tools. We will then find ways to make cancer cells more sensitive to Bortezomib by switching on our body’s internal cell death mechanisms. Our studies are aimed at ultimately developing clinical trials that will overcome Bortezomib resistance in MCL patients.
Steven R. Pirie-Shepherd, PhD Harvard University Children's Hospital
Cleaved Serpins as Anti-Angiogenic Therapeutics in the Treatment of Cancer
Angiogenesis-the formation of new blood vessels-is critical to the growth and survival of many tumors, and occurs at a much accelerated pace in tumors compared to normal tissue. Angiogenesis inhibitors, investigational agents that starve out tumors by cutting off their blood supply, hold out great hope as effective and relatively non-toxic anticancer treatments. Most angiogenesis inhibitors work by slowing the growth of endothelial cells: endothelial cell growth is a key step in angiogenesis. Dr. Stephen Pirie-Shepherd has identified several structurally related proteins (called serpins), normally involved in the body’s blood clotting system. These proteins are believed to contain fragments capable of inhibiting endothelial growth, and thus, angiogenesis. Interestingly, it has been suggested that cancer cells may themselves produce enzymes capable of cleaving-or splitting-these proteins to generate anti-angiogenic molecules, as part of the body’s own defenses aga inst cancer. To investigate whether these cleaved molecules can ultimately be harnessed as novel cancer treatments, Dr. Pirie-Shepherd proposes to cleave these anti-angiogenic molecules in the laboratory and study their effects on endothelial cells. Cleaved serpins that demonstrate anti-endothelial activity will then be tested as anti-tumor drugs against human cancers in a mouse model system, which is the first step on the road to clinical trials in humans.
Karen E. Popkin, LCAT, HPMT, MT-BC Memorial Sloan-Kettering Cancer Center
The Memorial Sloan-Kettering Cancer Center’s Integrative Medicine Service’s Music Therapy Program brings music to the bedside of hundreds of patients by trained, credentialed professionals who tailor their offerings to the needs of individuals and their family members. This vital service is offered to both patients and their families providing therapists who work closely as part of interdisciplinary MSKCC teams that include physicians, nurses, social workers and chaplains. In addition to their one-on-one patient and family care, they also provide music therapy in the pre-surgical and post-operative suites and elsewhere in the hospital. A free service by the MSKCC Integrative Medicine Service, patients report increased energy, renewed spiritual connection and enhanced hope as a result of these music therapy sessions.
“Modulating Iron Metabolism to Treat Myelodysplastic Syndrome”
In Myelodysplastic Syndrome red blood cell formation is impaired, leading to severe progressive anemia. Mutation of SF3B1 often causes Myelodysplastic Syndrome, and is associated with the appearance of iron-loaded immature red blood cells. We propose to use genetic tools to repair this altered iron metabolism, restoring red blood cell production
The Evolution and Diversification of Pre-leukaemic Clones in a Natural Model of Acute Lymphoblastic Leukaemia
We are interested in the development and evolution of the most common pre-B cell paediatric acute lymphoblastic leukaemia (ALL). We wish to study the similarities and differences in the mutations and sub-clones that develop in identical twins that share a genetically identical pre-leukaemic clone in order to expand our understanding of the development and pathogeneisis of ALL in children.
Anil Prasad, PhD Beth Israel Deaconess Medical Center
Characterization of Cannabidiol (CBD) as a Novel Therapy for Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with a high rate of relapse after currently available treatments. Novel therapeutic strategies are urgently needed for patients who relapse. Recent studies indicate that cannabidiol (CBD), a potent, non-psychotropic component of the plant Cannabis sativa, has anti-neoplastic properties. Dr. Prasad proposes to evaluate CBD as a novel therapeutic for the treatment of MCL. Promising preliminary data in his lab demonstrate that CBD alters the cell cycle of MCL cells and induces cell death. Dr. Prasad and his team will further explore the specific mechanism(s) through which CBD induces anti-MCL effects by analyzing its modulation of apoptotic and oncogenic signaling pathways.
Jeffrey C. Rathmell, PhD Duke University Medical Center
Bcl-2 Family Proteins as Metabolic Targets in Leukemia
It was established in the early 1900s that cancer cells have increased rates of glucose metabolism. While inhibition of this metabolic program in cancer cells may provide a novel avenue for future cancer treatment, a lack of understanding how metabolic stress can cause cell death has precluded rational design of metabolic cancer therapies. In Dr. Rathmell’s studies to address this issue, he has found that inhibition of metabolism in cancer cells can lead to up regulation of two key cell death regulatory proteins, Puma and Bim. Dr. Rathmell’s lab proposes to examine the roles of these cell death proteins in B cell acute lymphoblastic leukemia caused by the Philadelphia chromosome translocation to establish how cancer cell metabolism can be exploited to kill leukemic and other cancer cells.
Andrew Rezvani, MD Fred Hutchinson Cancer Research Center
The Role of Rituximab in Allogeneic Hematopoietic Cell Transplantation for B-Cell Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) is an increasingly common cancer. For many patients, the only potentially curative treatment is blood stem cell transplantation. However, such transplants can fail either because of lymphoma recurrence or because of complications such as graft-vs.-host disease. Dr. Rezvani’s research focuses on using rituximab, a monoclonal antibody, to try to reduce these risks. He and his lab are also performing laboratory investigations to determine the optimal dose of rituximab and to identify the patients most likely to benefit. Ultimately, Dr. Rezvani’s goal is to find safer and more effective ways of performing blood stem cell transplants for people with NHL.
In Vivo Regulation of Myeloid Cell Development and Leukemia
The Rhodes laboratory is using the power of zebrafish genetics to inform on how gene mutation or abnormal activation can affect myeloid cell development and contribute to acute myelogenous leukemia (AML). They have shown that the development of zebrafish myeloid cells is surprisingly similar to humans and discoveries made in this animal model will advance our understanding of human processes. The studies supported by Gabrielle’s Angel Foundation are likely to provide new insights into the myeloid cell biology and transformation, and generate animal models or gene targets that can be used to advance current diagnostic or therapeutic options for AML.
Hacking cytokine pathways for precision cancer immunotherapy
The immune system is controlled by a molecular “internet” of protein messages called cytokines. Here, we propose to “hack” into a specific cytokine signal (IL-18) to instruct killer lymphocytes to attack cancers via a message that cannot be overridden. These “hacked” cytokines may thus represent promising candidates for drug development.
Understanding reciprocal cell-cell interactions in B cell malignancies
Indolent B cell lymphomas are incurable diseases with an increasing prevalence. Our work is aimed at understanding how malignant B cells communicate with normal cells, since interference with this cell-cell communication can be used to indirectly kill tumor cells, a new and alternative approach to cancer therapy.
Jeroen Roose, PhD University of California San Francisco
Therapeutic Targeting of the Oncogenic Ras Pathway in T Cell Leukemia
My research group at UCSF focuses on understanding the biochemical signals inside the cell as they occur in developing cells that divide and differentiate. In parallel, we study how cancer cells have abnormal signals, what the composition is of these signals, and how these underlie the process of tumor formation. We use several cellular systems to study, notably normal T lymphocytes and their cancer-variant: T cell leukemia. The goal is to uncover sufficient insight into these signals so that we can intervene more efficiently, and safer, with T cell leukemia in future treatment programs in the clinic. To learn more, please visit our lab online.
Marcello Rotta, MD Fred Hutchinson Cancer Research Center
New approaches to Haploidentical Hemopoietic Cell Transplant
Allogeneic hematopoietic cell transplantation (HCT) is a potential curative treatment for lymphomas, myeloma and leukemias. In absence of a related or unrelated matched donor, the most relevant hematopoietic cell source is a partially-matched (haploidentical) related donor sibling, child or parent. Unfortunately the use of haploidentical donor is limited graft rejection, due to recipients Natural Killer(NK)-cells and T-lymphocytes reacting to the incoming graft, and lethal graft versus host disease (GVHD) due to donor T-lymphocytes attacking the recipient environment. Using the canine preclinical model, Dr. Rotta’s lab wants to investigate novel and non-toxic ways to overcome immune-mediated rejection using reagents capable of blocking host NK-cell functions and modulating host T-cell functions, both key components in the rejection process. Further, they will address the most crucial complication of successful engraftment: GVHD. Dr. Rotta will use biological reagents capable of both down regulating activated donor T-cells and preventing further recruitment of T-cell specific for host antigens to induce graft-host tolerance without affecting T-cell with memory to pathogens. These studies will lead at novel approaches to haploidentical HCT, that may allow extending this procedure to large number of patients suffering by hematologic diseases without a matched donor.
James L. Rubenstein, MD, PhD University of California, San Francisco
Molecular Therapy of CNS Lymphoma
Dr. Rubenstein’s team is investigating new approaches in the use of Rituximab, a monoclonal antibody which is an important drug in the treatment of non-Hodgkin’s lymphoma. Rituximab is the first antibody to be approved in the treatment of cancer and is currently used in the vast majority of patients with large B-cell non-Hodgkin’s lymphoma, the most common and lethal lymphoid tumor. Once of their approaches is to perform the first clinical trial to evaluate direct injection of this antibody in combination with chemotherapy into the cerebrospinal fluid (the fluid which surrounds the brain) to treat recurrent brain lymphomas, a significant complication of the disease. Results of this study may lead to new approaches to treat and/or prevent dissemination of lymphoma cells into central nervous system. The second study which they will perform is aimed to discover drugs which increase the sensitivity of lymphoma tumor cells to Rituximab treatment.
“Increasing the Therapeutic Index of Chimeric Antigen Receptor T cells for T cell Lymphomas”
Our goal is to bring the unquestioned power of CAR T cell therapy to bear on T cell lymphomas, a group of diseases with a poor prognosis and few treatment options. We will use the latest gene-editing tools to make an effective and safe immunotherapy.
Ingrid Karen Ruf, PhD University of California, Irvine
Role of Epstein-Barr virus RNAs in the Pathogenesis of Virus-associated Lymphoid Tumors
Epstein-Barr virus (EBV) infections are associated with a number of types of human cancer, including Burkitt lymphoma, nasopharyngeal carcinoma, and Hodgkin’s lymphoma. EBV carries a number of viral genes whose products are known to result in increased cell growth and/or decreased cell death, both of which contribute to the growth of cancer cells. In Burkitt lymphoma the role of EBV in cancer is unclear as the virus does not express those genes known to stimulate cell growth in the laboratory. However, the ability of Burkitt lymphoma cells to cause tumors in an experimental model is strictly dependent on the presence of the virus and is in part due to expression of two small viral RNAs (EBERs). These RNAs, unlike most RNAs, do not result in production of a protein. Rather their function is accomplished as an RNA molecule. Dr. Ruf’s goal is to understand how the virus causes cancer by investigating the mechanisms of action of the EBERs. Dr. Ruf and her team are investigating what cellular gene products are required for EBER function and how the EBERs alter the normal function of these genes to benefit the virus. Dr. Ruf anticipates that the knowledge they gain in these studies will be applicable to all EBV-dependent tumors, as well as to their understanding of the role of the EBERs in maintaining infection in healthy virus carriers. Identification of how this virus causes cancer will lead to targets for future treatment of developing and established tumors and perhaps preventive therapies. Additionally, their work aims to contribute to a relatively new field of research relating to RNA molecules in general function and how they can influence the growth and survival of cells.
Jonathan H. Schatz, MD Memorial Sloan-Kettering Cancer Center
Genomics of Peripheral T-Cell Lymphoma
Peripheral T-cell lymphoma (PTCL) is a group of rare diseases that collectively comprise 15 percent of lymphomas. The diseases are poorly understood and often have poor prognosis. Memorial Sloan-Kettering Cancer Center has one of the highest volumes of PTCL patients the country. This provides opportunity to study the disease by analyzing patient samples. Initially, we will perform sequencing of tumor DNA to identify genes involved in PTCL development. These results will shed new light on these diseases and inspire further studies. The generous award from the Gabrielle’s Angel Foundation will fully fund our initial set of analyses.
Kara A. Scheibner, PhD University of Maryland School of Medicine
miR-23a Cluster and miR-10a Regulation of Self-Renewal and Survival Pathways in Human Hematopoietic Stem-Progenitor Cells and Acute Leukemia Cells
The goals of this project are to investigate the regulation of genes and pathways involved in self-renewal and survival pathway in leukemia stem cells (LSCs) by small molecules called microRNA. Two of these microRNAs, the mir-23a cluster and miR-10a, function as tumor suppressors in leukemia and Dr. Scheibner’s lab proposes that decreased expression of these tumor suppressor microRNAs contributes to de-regulation of self-renewal and survival pathway in LSCs, and that their over-expression will target LSCs and reduce their frequency in the leukemia population. They also predict that these microRNAs will make the LSC population more susceptible to drug treatment. Conversely, her lab predicts that high endogenous levels of the miR-23a cluster and miR-10a found in the normal population of adult blood stem-progenitor cells inhibit their expansion and survival. Dr. Scheibner’s lab is also investigating if manipulation of their expression will lead to expansion of this population. Success of this proposal may lead to novel molecules for developing leukemia treatment strategies, and reveal mechanisms of stem cell expansion, useful not just in adult blood stem cells, but in other stem cell populations, and for the continuing development of stem cell therapies.
Interrupting Survival Signals in Early Stage CLL: A Maneuver to Prevent Progression
Chronic Lymphocytic leukemia (CLL) is the most common sub-type of leukemia in the U.S. and is presently an incurable disease. Building on his preclinical and clinical observations, Dr. Shanafelt has opened a clinical trial of green tea extract in capsule form for patients with early stage CLL and has observed signs of clinical activity. Despite this activity, evidence suggests that the bone marrow nurtures leukemia cells and makes them less vulnerable to this treatment. With this grant, Dr. Shanafelt will determine the mechanism by which bone marrow nurtures CLL leukemia cells and identify how to combine green tea extracts with other treatments to over come stromal mediated protection to enhance the efficacy of this therapy for patients with CLL.
Dorothy Sipkins, MD, PhD* The University of Chicago
Regulation of Leukemia Cell Dormancy by the Bone Marrow Microenvironment
While the majority of patients respond to initial therapy for leukemia, many will experience disease relapse. Leukemia cells need to be actively dividing to be susceptible to most chemotherapies; cells that are not actively dividing, or are “dormant” during chemotherapy, can therefore contribute to recurrence. In this proposal, we will test the novel hypothesis that specific molecules in the patient’s tissues (the “host microenvironment”) control leukemia cell dormancy. We propose a unique approach to intercept “pro-dormancy” signals from the bone marrow to render resistant leukemia cells susceptible to current therapies. To learn more, please visit our lab online.
Stephen X. Skapek, MD Comer Children's Hospital Chicago
Functional and Genetic Analysis of a Novel RB-Associated Transcriptional Repressor in Human Leukemia and Lymphoma
Researchers have identified and studied a gene known as the RB gene that acts as a natural tumor suppressor by regulating cell proliferation (multiplication of cells). Abnormal cell proliferation is one characteristic of cancer, and the inability to “turn off” inappropriate proliferation may be a key step in the formation of some cancers. Research has not yet identified precisely how RB influences cell proliferation; however, there is evidence that other substances interact with RB to regulate its function and help it control cell proliferation. Substances known as transcriptional repressors may interact with RB and help regulate cell proliferation by interfering with transcription, the process by which a gene’s DNA is copied to RNA. Until recently, the idea that transcriptional repressors interact with RB was purely theoretical-no specific transcriptional repressors that interact with RB had been identified. However, Dr. Skapek at St. Jude Children’s Research Hospital in Memphis, Tennessee has cloned a novel gene that codes for a transcriptional repressor, RBaK, that interacts with RB. In vitro tests suggest that RBaK and RB together cooperate to regulate cell proliferation. By studying the mechanisms by which RB functions as a tumor suppressor, specifically with regard to RBaK, Dr. Skapek hopes to shed light on the molecular mechanisms by which RB functions. This may potentially lead to new therapeutic strategies in which RBaK itself could be manipulated. To accomplish this, Dr. Skapek intends to pursue two avenues of research simultaneously. One line of research will examine how RBaK and RB interact to regulate cellular proliferation. The other will evaluate the importance of RBaK in hematologic malignancies by attempting to locate the gene that codes for RBaK on human chromosomes, and examining leukemia/lymphoma samples and tumor-derived cell lines for evidence of abnormalities in this gene.
Targeting leukemic stem cells in infant leukemia by blocking interactions with the microenvironment
While childhood acute lymphoblastic leukemia is very curable, leukemia in infants less than six months of age is very difficult to cure. Better approaches to treatment targeting leukemia cells and leaving normal cells alone are highly desirable for these tiny patients. Dr. Slayton’s work uses medicines designed to block the interaction between infant leukemia stem cells and their microenvironment (normal cells around them) to make the cancerous cells more sensitive to the effects of chemotherapy. By blocking these interactions, Dr. Slayton hopes to set these leukemia cells “up for the kill” while not harming normal cells.
Ulrich Steidl, MD, PhD Albert Einstein College of Medicine
Identification of Functionally Critical Transcriptional Target Genes in Stem Cells in AML & MDS
Despite the use polychemotherapies which reduce the tumor burden, relapse continues to be the most common cause of death in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). Recent evidence demonstrates that rare so-called leukemia stem cells (LSC) give rise to functionally heterogeneous bulk tumor cells with limited life-span. To identify functionally critical LSC pathways, fundamentally novel experimental approaches other than the examination of bulk tumor cells need to be established. The Steidl lab uses a specialized cell sorting method to isolate precisely defined stem cells based on marker molecules on the cell surface, and then examines these fractionated cells by a genome-wide analysis method of gene activity. Genes can be identified that are differentially active in stem cells from patients with MDS and AML in comparison to normal stem cells, and then be tested for functional relevance. The study supported by the Gabrielle’s Angel Foundation will enhance the knowledge of disease-causing mechanisms at the stem cell level in MDS and AML, and identify molecular targets for LSC-directed therapeutic approaches.
David W. Sternberg, MD, PhD Mount Sinai School of Medicine
Translational Regulation of Gene Expression in Acute Myelogenous Leukemia (AML)
Dr. Sternberg’s laboratory is committed to the development of therapeutic strategies for leukemia through knowledge of aberrant information signaling within the cancer cell. The generation of leukemias is caused in many instances by mutation of rogue oncogenes that disrupt normal cell signaling. Two of these, the NPM and FLT3 genes, are among the most commonly mutated targets in patients with acute myelogenous leukemia (AML).
In this effort Dr. Sternberg’s team is exploring the mechanism of leukemia induction by the mutant NPM and FLT3 gene products. In particular, they focus on the conversion of genetic information in the form of messenger RNA into abnormal protein expression. Their hypothesis is that mutant NPM and FLT3 usurp this process, termed translation, in patients with AML. They are using state-of-the-art gene expression profiling technologies to understand how mutant NPM and FLT3 alter normal translation within a cancer cell. Moreover, Dr. Sternberg’s team will develop models to validate the functional role of particular translational targets in the pathogenesis of AML. They anticipate that the insights gained from this study will inform new prognostic and therapeutic strategies for the treatment of these frequently lethal neoplasms.
Sylvester Comprehensive Cancer Center, University of Miami
Ronan T. Swords, MD Sylvester Comprehensive Cancer Center, University of Miami
Targeting NEDD8 protein conjugation: a novel therapeutic strategy for acute lymphoblastic leukemia (ALL).
Acute lymphoblastic leukemia (ALL) is the main cause of cancer related death in children. We have access to a brand new drug that kills these leukemia cells very effectively in the laboratory. We want to study this drug in detail and test it in the clinic to improve cure rates for patients with ALL.
Sarah Tasian, MD Children’s Hospital of Philadelphia
Dr. Tasian is researching FLT3 Receptor-Redirected Chimeric Antigen Receptor T Call Immunotherapy for High Risk Pediatric Leukemias.
Many children with high risk acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) are resistant to chemotherapy and will relapse. We are testing new “killer T cell” immunotherapies in specialized leukemia mouse models with the goal of rapid translation into clinical trial testing in children with relapsed/refractory leukemias.
John M. Timmerman, MD University of California, Los Angeles
Anti-CTLA Monoclonal Antibody Therapy for B Cell Lymphoma
Most non-Hodgkin’s B cell lymphomas are resistant to cure with conventional chemotherapy. Paradoxically however, lymphomas are among the most susceptible of human cancers to destruction by immunologic mechanisms (T cells and antibodies). We are seeking to develop new ways to “jump start” the immune system of lymphoma patients to recognize and destroy their tumors. Lymphoma cells tend to shut down the immune system’s natural defenses against the tumor, and reversal of this process might thereby lead to inhibition of tumor growth. A molecule called CTLA-4 acts as the “brakes” on T cell activation, and blocking this molecule can result in heightened activation of immune responses. Administration of monoclonal antibodies that block CTLA-4 has been found to promote potent anti-tumor effects in animals with many types of cancers. In humans, a new monoclonal antibody which blocks CTLA-4 has been found to exhibit anti-tumor effects in melanoma and prostate cancer. Dr. Timmerman’s team is initiating the first clinical study of anti-CTLA-4 monoclonal antibody therapy for B cell lymphoma. In the laboratory, they will study how anti-CTLA-4 treatment activates patient’s T cells and antibodies to attack and destroy their tumor cells. It is hoped that anti-CTLA-4 therapy may then be combined with other immunotherapies including tumor vaccines and anti-tumor (i.e., anti-CD20) monoclonal antibodies to enhance their effectiveness. Such interventions could offer highly tumor-selective approaches to lymphoma treatment without the toxicities associated with conventional chemotherapeutic agents.
Wei Tong, PhD University of Pennsylvania School of Medicine
Cytokine Signaling in Normal and Malignant Hematopoietic Stem/Progenitor Cells
Dysregulation of signaling pathways that control hematopoietic stem cell expansion leads to leukemia. We aim to investigate novel signaling molecules for their roles in regulating stem cell expansion in normal and malignant blood development. Our studies may provide new insights into strategies to treat malignant and nonmalignant blood cell disorders.
Andrea Ventura, MD, PhD Memorial Sloan Kettering Cancer Center
Investigating the roles of microRNAs in lymphomagenesis
A microRNA is a small RNA that can simultaneously modulate the levels of tens or even hundreds of different proteins. We propose to use multiple experimental approaches to investigate the functions of two families of miRNAs that are suspected to play a key role in lymphomas. To learn more, please visit our lab online.
Amit Verma, MD Albert Einstein College of Medicine
TGF beta receptor inhibition as a therapeutic strategy in Myelodysplastia
Myelodysplastic syndromes (MDS) are pre-leukemic conditions that lead to decreases in blood counts in the elderly and do not have many treatment options. Dr. Verma has determined that a protein, Transforming Growth Factor-beta (TGF), is partly responsible for suppressing the growth of stem cells in MDS and that the blockade of its receptor can stimulate growth of red and white cell colonies. Thus, he proposes to study the factors regulating the suppressive effects of TGF in MDS and evaluate the effectiveness of a novel drug inhibitor of the TGF receptor, LY 2157299, in MDS
Johns Hopkins University, Bloomberg School of Public Health
Kala Visvanathan, MB, BS, FRACP, MHS Johns Hopkins University, Bloomberg School of Public Health
Modulation of Estrogen Metabolites by Broccoli Sprouts: Novel Intermediate Markers for Chemoprevention
In the last decade the prevention of cancer through the use of chemopreventive agents has become a possibility. We are now faced with how best to begin to assess the effectiveness of potential agents for a variety of cancer sites. With this in mind Dr. Visvanathan plans to explore whether broccoli sprouts, a potential preventive agent against breast cancer alters estrogen metabolite levels in both breast tissue and urine. This study has direct relevance to long term female survivors of Hodgkin’s lymphoma given their increased risk of breast cancer as a result of radiation treatment. At present they are grappling with how to best to screen these young women for breast cancer and reduce their long term risk of breast cancer. From Dr. Visvanathan’s experience, this is clearly a group in need of better preventive strategies. It is unknown whether broccoli sprouts may protect the breast from the long term effects of radiation damage. However in animal models the topical application of a broccoli sprout extract reduced the size of skin cancers. The identification of markers for breast cancer such as estrogen metabolites may also help identify those women more likely to develop breast cancer among female survivors of Hodgkin’s lymphoma. These women could then be targeted with more aggressive screening and risk reduction options.
University of North Carolina, Lineberger Comprehensive Cancer Center
Gang “Greg” Wang, PhD University of North Carolina, Lineberger Comprehensive Cancer Center
Novel Approaches to Target PRC2 Enzymatic Complexes for the Treatment of Hematopoietic Malignancies
Enzymes that modify chromatin (the physiological form of DNA) are commonly found hyper-activated among lymphoma and myeloma. Novel therapeutics needs to be developed for treating these currently incurable malignancies. We investigate the mechanisms for their hyperactivities and develop new ways for their inhibition as novel cancer therapeutic inventions.
Lukas D. Wartman, MD Washington University St. Louis
Integrative Epigenomics: The Consequences of Kdm6a Inactivation on Chromatin Accessibility and DNA Methylation in Hematopoiesis
We will determine if mutations in the gene, KDM6A, which are present in a wide variety of human cancers, are also associated with specific modifications of DNA (DNA methylation) and DNA structure. These associated changes may explain how KDM6A mutations contribute to carcinogenesis and have significant therapeutic implications.
Arun P. Wiita, MD, PhD University of California, San Francisco
Blockade of the HSP70-BAG3 chaperone/co-chaperone interaction to overcome proteasome inhibitor-refractory multiple myeloma
Multiple myeloma still has no cure. Many patients benefit from drugs called proteasome inhibitors, but unfortunately almost all cancers eventually become resistant. Here, we investigate the potential of a new class of drugs, called HSP70-BAG3 inhibitors, to specifically target resistant myeloma leading to deeper remissions and longer survival for patients.
Richard T. Williams, MD, PhD St. Jude Children's Research Hospital
Systematic, High-Throughput Developmental Therapeutics in High-Risk ALL
Tragically, many adult and pediatric leukemia patients still succumb to their disease despite intensive combination chemotherapy, stem cell transplantation and improved supportive care. Failure of current treatments to eradicate all traces of disease in leukemia patients ultimately leads to clinical relapse with drug-resistant leukemic cells. By using leukemic cells precisely engineered in a culture dish to resemble one of the ‘Highest0Risk’ human leukemias, our approach is to screen thousands of drugs and chemicals to identify the most potent, selective and efficient killers of leukemic cells. Our goal is to ‘re-purpose’ known drugs (often approved for other uses) and identify known ‘drug-like’ chemicals for testing in reliable pre-clinical leukemia models as a critical step toward their deployment in needy leukemic patients.
Therapeutic targeting of cancer stem cells in mouse and human myelodysplastic syndromes
Myelodysplastic syndromes is a hematologic malignancy driven by rare cancer stem cells defective in their ability to generate mature blood cells. Our goal is to identify drugable targets that can restore the cancer stem cells’ ability to generate functionally normal blood cells, thereby hopefully eliminating the malignant features of these cells.
Bela Wrench, MBBS, MD (res), FRCPath Barts Cancer Institute, United Kingdom
Investigating Mechanisms of Tumor Dormancy in Adult Acute Lymphomblastic Leukemia
Although many adults with ALL respond to initial treatment disease relapse occurs frequently. We think there are “dormant/non growing tumor cells which can resist chemotherapy to cause cancer recurrence. By working out how dormant cells remain “switched off” we may be able to reverse this process to improve treatment success.
University of Alabama-Birmingham Comprehensive Cancer Center
Eddy Shih-Hsin Yang, MD, PhD University of Alabama-Birmingham Comprehensive Cancer Center
Mechanisms by which GSK3β inhibition enhances nonhomologous end-joining repair of IR-induced double strand breaks
Neurocognitive deficits from cranial irradiation are serious side effects from treatment of leukemias, especially in children. We have previously found that lithium, an inhibitor of the enzyme glycogen synthase kinase-3_ (GSK3_), can protect neurons but not cancer cells from radiation induced cell death and prevent cognitive deficits in irradiated mice. This occurs through enhanced repair of DNA damage generated by radiation. In this proposed study, we will further investigate the mechanism by which inhibition of GSK3_ increases DNA repair and confirm that inhibition of GSK3_ does not protect leukemia cells. Importantly, we will validate our result in transgenic mice. We hypothesize that the effects of GSK3_ inhibition are through stabilizing important proteins involved in DNA repair following radiation. Understanding the pathways involved in neuroprotection will allow for the discovery of novel targets and generation of new compounds for use to prevent the cognitive side effects of cranial irradiation, especially in children.
Fish oil (n-3 fatty acids) and non-Hodgkin lymphoma
A growing body of evidence suggests that inflammation is a key factor in the development of cancer including various types of lymphomas. Fish oil, rich in n-3 fatty acids (eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids), has anti-inflammatory activity through inhibition of cyclooygenase-2 (COX-2) activity and has the ability to inhibit the proliferation of various lymphoma or leukemia cells. The ultimate goal of this proposal is to explore the role of fish oil in inhibiting the proliferation of non-Hodgkin lymphomas, define the optimal composition of fish oil, especially EPA to DHA ratios, and identify an appropriate molecular target of fish oil. This proposal intends to define a novel targeted natural therapeutic or chemopreventive agent that would offer the best prospect for achieving long–term control of this disease.
Albert Einstein College of Medicine of Yeshiva University
Hilda B. Ye, PhD Albert Einstein College of Medicine of Yeshiva University
The Role of BCL-6 Regulated Chemokine Expression in the Pathogenesis of B-Cell Lymphomas
Non-Hodgkin’s lymphoma (NHL) is the most common form of lymphoid malignancy in the adult population. Despite the advent of new drugs and treatment regimens, only 50% of NHL patients are cured, calling for the need of better understanding of the pathogenesis of these cancers and the discovery of therapeutic agents with new mechanisms of action. There is evidence that a proto-oncogene known as BCL-6 plays a role in the pathogenesis of diffuse large cell lymphoma, a lymphoma that affects specialized immune cells known as B-lymphocytes (or B-cells for short). A proto-oncogene is a gene whose protein product is capable of producing some kind of cellular transformation if the gene becomes damaged or mutated. Normal B cells temporarily express BCL-6 protein during their lifetimes. However, in lymphoma cells BCL-6 expression continues, and this continued expression of BCL-6 may be necessary for the continued survival of the malignant cells. Dr. Hilda Ye proposes to study precisely how BCL-6 acts to maintain tumor cell growth, and whether it is essential to the continued growth and survival of tumor cells. Specifically, she plans to investigate whether BCL-6 plays a role in the regulation of apoptosis (the self-destruction of cells) that may explain its effects on tumor survival. She will also look for target genes that may be part of a genetic pathway involving BCL-6. As part of this research, Dr. Ye will also explore the therapeutic potential of using cutting-edge antisense technology to decrease the malignancy of lymphoma B cells. If so, this may potentially lead to future development of antisense therapeutic agents.
Fay Young, MD University of Rochester Medical Center
Integrin and Chemokine-Mediated Homing During B Cell Ontogeny and Leukemogenesis
Acute lymphoblastic leukemia is a form of cancer that affects the lymphocytes and lymphocyte-producing cells in bone marrow. B-lymphocytes (B-cells for short) are white blood cells that produce antibodies and are vital parts of the body’s immune system. Acute lymphoblastic leukemia often affects B-cells and the precursor cells that mature into B-cells. As our knowledge of blood cell formation grows, it is clear that normal hematopoietic cells (cells involved in blood formation) are influenced by regulatory signals derived from special “micro-environments” within the bone marrow. Without these signals, normal blood cells cannot grow and survive. There is increasing evidence that leukemic cells respond to similar regulatory signals in the bone marrow that may influence how they grow, survive, and migrate to other tissues as part of the disease process. Dr. Fay Young is proposing to use a unique mouse model to study the roles of integrin (a substance that promotes adhesion of cells, which is characteristic of some cancers) and signalling molecules known as chemokines in the transformation of B-cell precursors into leukemic cells. Specifically, she will study the relationship between genetic alterations in mice, expression of chemokines and surface adhesion receptors (which facilitate adhesion), and the development of leukemia.
Specific Targeting of the Leukemia-Associated Antigen FLT3 Using Chimeric Antigen Receptor (CAR)-Engineered NK Cells for Treatment of Relapsed Acute Myeloid Leukemia with FLT3-ITD Mutations
Leukemia patients with some mutations routinely relapse and have worse survival. We will engineer immune cells with the ability to specifically bind tumor cells in patients who are resistant to other treatments. This will enable immune cells to specifically and efficiently spot and kill tumor cells without harming normal cells.
The role of ATM kinase in suppression of B cell lymphomas
Our lab is interested in understanding how cells sense DNA double stand breaks, integrate cell cycle progression and cellular survival to facilitate precise DNA repair and to prevent cancer-causing transformation. Defects in DNA repair machinery often lead to primary immunodeficiency and increase the risk for lymphomas and leukemias in children. In this context, we generate and characterize mouse models to study the mechanism of DNA repair and lymphomagenesis.
Chengcheng (Alec) Zhang, PhD University of Texas, Southwestern
Ex Vivo expansion of hematopoietic stem cells for cord blood and allogeneic transplantations
The ability to grow blood stem cells (HSCs) in culture would greatly improve the patient outcome in transplantation, and make cord blood to be useful for adult applications. We have identified several new growth factors, and established a very potent cell culture system for growing human HSCs. We will use a newly developed immunoassay to study how they new growth factors regulate HSC activity. We will also screen conditions to significantly improve the efficiency of our HSC culture system. We will further investigate why our cultured cells greatly enhance allogeneic transplantation, and identify the responsible cell populations facilitating the allograft.
Xuefeng Zhang, MD, PhD Beth Israel Deaconness Medical Center
Targeting Slit2/Robo4 Signaling as a Novel Treatment for Leukemia
Slit2/Robo4 signaling modulates localization of hematopoietic stem cells to bone marrow (BM) vascular niches (VN), which are also involved in the pathogenesis of acute myeloid leukemia (AML). Using a BMVN model, we will examine the effects of Slit2/Robo4
Xianzheng Zhou, MD, PhD University of Minnesota Cancer Center
T-Cell Gene Transfer and Therapy by the Sleeping Beauty Transposon System
The objective of this application is to test whether a novel, naked DNA based vehicle, Sleeping Beauty transposon, can express therapeutic molecules in human T cells for the treatment of leukemia and lymphoma. The rationale for the proposed research is based on Dr. Zhou’s recent finding that the Sleeping Beauty vehicle can transfer and permanently express marker genes in human T cells. To accomplish this goal, blood T cells will be engineered by the Sleeping Beauty vehicle carrying a therapeutic gene and a suicide gene, and tested for efficacy to kill leukemia and lymphoma cells in laboratory tubes and animals. The engineered T cells can also be eliminated by activating the suicide gene if necessary, creating a safe guard for this therapy. Dr. Zhou’s research is expected to develop a novel, simple, inexpensive, efficient, and safe gene therapy using T cells for the treatment of patients with relapsed leukemia and lymphoma after chemotherapy and/or bone marrow transplantation.
Sandra S. Zinkel, MD, PhD Vanderbilt University School of Medicine
The Role of Pro-apoptic BCL-2 Family Bid in the DNA Damage Response
Programmed cell death, also called apoptosis, is a normal process that the body uses to rid itself of damaged cells. Cancer cells acquire the ability to evade this process, allowing them to live too long, as well as to resist therapeutic treatments such as chemotherapy and radiation. Cancer cells have genetic defects in this normal cellular “suicide” program that governs cell death and survival. The discovery of the BCL-2 family of genes uncovered the underlying genetic mechanism of this regulation, as well as an entirely new class of oncogenes: those that govern cell death rather than cell proliferation. The founder of this family, the Bcl-2 gene, was found to be located at the chromosomal breakpoint of t (14; 18)-bearing human B-cell lymphomas. Since then, a whole family of related proteins, called the BCL-2 family after its founding member, has been discovered that regulates cell death. Dr. Zinkel’s work showed that the pro-death BCL-2 family member BID is important in preventing cancer development in the blood cells of mice (leukemia). The best model to test the role of a gene in normal development is an animal model in which the gene of interest has been disrupted. The deletion of BID prolongs the lives of myeloid cells, fostering the accumulation of additional genetic mutation and promoting the development a fatal disorder resembling the human disease chronic myelomonocytic leukemia (CMML). These studies reveal that BID plays a critical role in preserving genomic integrity, maintaining myeloid homeostasis (metabolic equilibrium), and suppressing tumor growth and normal immune (myeloid cell behavior). The occurrence of cancer in the BID-deficient mice underscores the importance of apoptotic control in the development of chronic leukemia and related disorders. Tumor progression is a multi-step process in which a succession of genetic changes leads to uncontrolled cell growth, a hallmark of cancer. Paradoxically, many of the agents currently used to treat cancer can accelerate the acquisition of these genetic changes in the event that the treated cells do not die, potentially leading to further tumor progression and/or resistance to therapy. Dr. Zinkel’s current studies are focused on identifying the proteins that interact with BID following this DNA damage and how BID functions during this process. Dr. Zinkel’s goal is to uncover the genes and the proteins that direct the decision of a cell to repair its DNA or to die, providing important clues in the search for therapeutic targets.
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