LRF's Newest Grantees Summer 2012 – The Future of Lymphoma Research

The Lymphoma Research Foundation (LRF) is pleased to introduce our seven newest grantees. In the fall of 2011, LRF's Scientific Advisory Board (SAB) reviewed applications for two different grant programs: the Clinical Investigator Career Development Award (CDA) and the Post-Doctoral Fellowship.

In January, LRF's CLL, DLBCL, and FL leadership issued Request for Proposals (RFPs) for high quality research studies in respective disease-specific areas. Applicants to all three research initiatives were required to include the study of primary patient samples to assure relevance to the human disease. In addition, all applicants needed to explicitly delineate how the proposed research project would involve collaborative interactions between/among investigators in different disciplines (e.g. pathology and hematology/oncology; basic science researchers and clinical investigators) and/or different institutions.

Sami Malek, MD from the Regents of the University of Michigan, Sean Post, PhD from the University of Texas, MD Anderson Cancer Center, and Catherine Wu, MD from Dana-Farber Cancer Institute were each awarded two-year $250,000 CLL Collaborative Grants. In addition, Izidore Lossos, MD from the Miller School of Medicine of the University of Miami and Laura Pasqualucci, MD from Columbia University each received DLBCL Explorations Grants for $250,000 over two years. FL Pathways Grants for $750,000 over three years were awarded to Arash Alizadeh, MD, PhD from Stanford University and Hans-Guido Wendel, MD from Memorial Sloan-Kettering Cancer Center.

Chronic Lymphocytic Leukemia Collaborative Grants

LRF's CLL leadership sought proposals for its two-year CLL Collaborative Grant. The proposed study was required to investigate the pathogenesis, epidemiology, diagnosis, or therapy of CLL or monoclonal B-cell lymphocytosis (MBL). Priority areas identified for funding included genomic/genetic analysis; biologic features; host-tumor interactions; transformation; heterogeneity of CLL behavior; drug resistance; development of cell lines and animal models of untransformed CLL; enhancement of accrual of CLL patients to clinical trials; novel therapies; or MBL in CLL families.

Sami Malek, MD
The Regents of the University of Michigan; Ann Arbor, MI
Integration of epigenetic and genomic changes in CLL

Dr. Malek is an Associate Professor in the Department of Internal Medicine at the University of Michigan Health System. He received his MD from the University of Hamburg-Eppendorf in Germany. Following medical school he completed a postdoctoral program in molecular biology and genetics at Johns Hopkins University, a residency and chief residency at Baylor College of Medicine, a fellowship in oncology/hematology at Johns Hopkins Oncology Center, and a postdoctoral program in cancer genetics at Columbia University.

Dr. Malek's CLL project will measure gene modifications in CLL genes that are due to a process called methylation that often results in changes in gene expression. "This is important as it will complement our understanding of molecular changes that constitute CLL and may also afford therapeutic intervention using drugs specifically designed to reverse these processes," he said. "This grant will help us fuse knowledge of genomic aberrations with epigenetic changes in CLL and make use of complementary expertise of the two research groups involved (Sami Malek, University of Michigan and Rita Shaknovich and Ari Melnick, Weill Cornell Medical College)."

Sean Post, PhD
The University of Texas, MD Anderson Cancer Center; Houston, TX
Evaluation of biomarkers for CLL progression in the p53 pathway: a genetic approach in mice and man

Dr. Post is an Assistant Professor in the Department of Leukemia, Division of Cancer Medicine at the University of Texas, MD Anderson Cancer Center. He received his PhD in molecular medicine from the University of Texas Health Science Center at San Antonio. "My research interests as a graduate student and as a postdoctoral fellow have focused on the p53 pathway," he said. The p53 gene is one of the most important genes in the natural defense mechanism against cancer.

His CLL project will utilize variations in genes to identify patients at risk for poor survival and optimize their treatments. "We are using a systematic approach (human samples and animal models of CLL) to investigate how p53 impacts the disease," he said. "Specifically, we are comparing patient samples for normal variations in the p53 pathway and generating animal models to those variants. Using these methods, we will be able to determine the importance of these genetic variances in CLL progression. Directly dissecting the impact of p53 pathway alterations in CLL and developing new treatments in this context will greatly increase the survival rates of CLL patients."

Catherine J. Wu, MD
Dana-Farber Cancer Institute; Boston, MA
The role of mutations in RNA splicing pathway genes in CLL

Dr. Wu is an Assistant Professor of Medicine at Harvard Medical School. She received her MD from Stanford University School of Medicine and completed a residency at Brigham & Women's Hospital and a fellowship at Dana-Farber Cancer Institute.

Dr. Wu's research team recently discovered an unusually high frequency of defects in genes that control how specific segments of RNA join together (called 'RNA splicing') to make a full messenger RNA (mRNA) which is then used to make proteins. This observation suggests the novel concept that alteration in RNA splicing likely plays an important role in CLL. "We will focus on uncovering which mRNAs are spliced incorrectly in CLL patients with these defective splicing factors," she said. "By understanding how RNA splicing is altered, we hope to deepen knowledge of how splicing contributes to generation of this and other cancers, and to suggest new treatments for this currently incurable cancer." Dr. Wu's funding will provide her team with the support to take the critical next steps, having already completed large-scale whole tumor sequencing studies. "Only through these studies will we be able to eventually translate our discoveries into potential therapeutic directions that are meaningful to our patients," she said.

Diffuse Large B-cell Explorations Grants

The LRF DLBCL leadership sought proposals for its two-year DLBCL Explorations Grant. Proposals were required to include a clear indication of how the project is clinically relevant to the improvement of outcomes for patients with DLBCL. The proposed study was required to investigate the pathogenesis, diagnosis, or treatment of DLBCL. Priority areas identified for funding included molecular analysis; biologic features; host-tumor interactions; transformed DLBCL; heterogeneity of DLBCL behavior; drug resistance; survivorship; or novel imaging strategies.

Izidore Lossos, MD
Miller School of Medicine of the University of Miami; Miami, FL
Pathophysiological role and targeting of MAPKs in DLBCL

Dr. Lossos is head of the Lymphoma Program and a Professor of Medicine in the Department of Medicine, Division of Hematology/Oncology at the University of Miami Miller School of Medicine with specialization in hematology and oncology. He received his MD from Hadassah School of Medicine in Israel and completed a postdoctoral program at Stanford University. This is the second grant Dr. Lossos has received from the Lymphoma Research Foundation (LRF).

Dr. Lossos' lab is working on pathogenesis of DLBCL, identifying prognostic biomarkers that may allow for identification of patients that may need a different therapeutic approach, trying to identify new molecular targets, and designing a specific targeted therapy that will potentially improve patients' outcomes. "This disease is very heterogeneous and complex and that makes it both attractive and challenging to investigate," he said. His lab has demonstrated constitutive activation of germinal center kinase (GCK) and its downstream target JNK (GCK-JNK MAPK pathway) in DLBCL. This pathway plays a role in DLBCL proliferation and survival. "We have synthesized a novel, potent and relatively specific inhibitor of GCK," he stated. "First, we will determine the prevalence of the GCK-JNK MAPK pathway activation in DLBCL tumors; second, we will determine the pathophysiological role of constitutive GCK activation and the ability to target it in DLBCL tumors; and third, we will determine the efficacy of prototype GCK inhibitor in vivo xenograft models." Ultimately, these studies will establish the pathophysiological role of the GCK-JNK MAPK signaling pathway in DLBCL and the ability to target it as a therapeutic approach.

Laura Pasqualucci, MD
Columbia University; New York, NY
The role of methyltransferase gene inactivation in DLBCL

Dr. Pasqualucci is an Associate Professor of Clinical Pathology and Cell Biology at the Institute for Cancer Genetics and Department of Pathology at Columbia University. She received her MD from the University of Perugia Medical School in Italy.

Her research studies the DNA of lymphoma cells in search for alterations that may have caused the initial derailment and subsequent uncontrolled expansion of the tumor cell. The identification of several genetic lesions affecting pathways and cellular programs that are critical to DLBCL's survival is a promising avenue for finding a cure. "The subject of my proposal is the role of a new gene called MLL2 in tumor development. This gene is lost in more than one third of all DLBCL patients, a clear indication that the tumor wants to get rid of its normal function, perhaps to reprogram the cell in order to activate a malignant phenotype. In normal cells, MLL2 is involved in the regulation of a vast number of other genes, essentially by marking which genes must be turned on and which ones will remain off." Her proposal is based on recent findings on the presence of mutations disrupting a new class of molecules with putative tumor suppressor function. "The challenge now is to understand how these lesions can cause cancer," she said. "It is a fundamental step and also one that requires significant amount of resources. The support of the LRF will be instrumental to get these functional studies started, and hopefully to pave the way toward the development of novel therapeutics."

Follicular Lymphoma Pathways Grants

LRF's FL leadership sought proposals for its three-year FL Pathways Grant. Proposed studies needed to investigate the pathogenesis, diagnosis, or treatment of FL. Priority areas identified for funding included genomic/genetic analysis of FL; biologic features of FL; host-tumor interactions in FL; transformation of FL; heterogeneity of FL behavior; development of cell lines and animal models of untransformed FL; drug resistance; or enhancement of accrual of FL patients to clinical trials.

Arash Alizadeh, MD, PhD
Stanford University; Stanford, CA
Single cell characterization of clonal evolution in FL

Dr. Alizadeh is an Assistant Professor in medicine, oncology and hematology at Stanford University School of Medicine. He received his MD from Stanford and completed a fellowship at the University of California, San Francisco. His research is focused on attaining a better understanding of the initiation, maintenance, and progression of lymphoid tumors and their response to immunochemotherapy. "My collaborations with other investigators interested in the same question and my patients are what keep me engaged in the field of lymphoma," he said.

Dr. Alizadeh's FL project goal is to uncover differences between FL tumors in order to better understand the disease's pathogenesis, diagnosis, and treatment. "We aim to identify the critical pathways involved in the development of this cancer and to develop molecular predictors of its behavior and patient outcomes by using a combination of novel approaches to analyze genetic mutations," he stated. "This characterization relies on relating genetic mutations discovered in tumor specimens to the functions of individual living cancer cells within patients afflicted with this disease, including novel therapies for this disease." Dr. Alizadeh's research team will use this approach in hopes of defining the factors that determine the variability of clinical behavior of FL, including responsiveness and resistance to novel targeted therapies that are emerging as key anti-lymphoma agents. "Funding from the LRF will be instrumental in facilitating the studies proposed and translation of technologies in disease-related research," he said.

Hans-Guido Wendel, MD
Memorial Sloan-Kettering Cancer Center; New York, NY
Soluble EPHA7 tumor suppressor into an FL therapy

Dr. Wendel is an Assistant Member of the Cancer Biology and Genetics Program at Memorial Sloan-Kettering Cancer Center (MSKCC). He received his MD from the Medical School of the Technical University of Aachen in Germany. As a resident at University Hospital in Aachen he saw many FL patients. "These patients responded to the available chemotherapy, but typically relapsed and had to be treated again and again, leading to complications and sometimes long hospital stays," he recalled. "Clearly, there is a need for better treatment options. We hope to develop therapies that are more specific and powerful and can keep the FL in remission."

Dr. Wendel's lab identified the secreted form of ephrin receptor A7 (EPHA7TR) as a soluble tumor suppressor with therapeutic activity against FL. "We already provided proof-of-concept data for single agent therapeutic activity in vitro and in vivo," he stated. "We now propose a systematic study to develop a new therapy based on EPHA7TR." With his LRF funding, Dr. Wendel will work toward achieving three specific aims: first, examining the therapeutic activity and potential toxicity of EPHA7TR; second, performing a structure-function analysis of EPHA7TR to define the minimum requirements for EPHA7TR tumor suppressive (and therapeutic) activity; and third, developing a fusion antibody that uses the anti-CD20 antibody as a vehicle to deliver EPHA7TR to CD20 positive lymphoma cells. "The goal of this project is a new therapeutic agent that is suitable for clinical development against FL," he said.