Grant: 3363-16 | Career Development Program (CDP):
Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215
Project Title: Mechanistic Basis Of Cohesin-mediated LeukemogenesisProject Summary:
We have made tremendous progress in describing the genetic basis of human leukemias with the advent of new technologies, such as next generation sequencing (NGS). However, we currently do not understand how most of the genes implicated in leukemia development actually cause leukemia, and how to best target them with new therapies. In this project, we will focus on acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and specifically answer the question why patients who carry a single abnormal copy of one of the cohesin genes, such as STAG2 and SMC3, develop leukemia. We will use AML and MDS cells from patients who carry normal versus abnormal copies of these cohesin genes to answer this question. Treatment options for patients with MDS and AML are limited, and better understanding of the mechanisms by which leukemia causing genes, such as cohesins, contribute to leukemia development in patients will inform the design of urgently needed new treatments. The impact of this work might also extend to patients with other blood cancers, including chronic myelomonocytic leukemia (CMML) and chronic myeloid leukemia (CML), which are also frequently found to have abnormal copies of one of the cohesin genes.
Grant: 2313-16 | Career Development Program (CDP):
Location:The Ohio State University, Columbus, Ohio 43210
Project Title: Developing CRM1 Inhibitors In Acute Myeloid LeukemiaProject Summary:
Over the past 20 years there has been little improvement in AML treatments, especially for elderly (>60) patients or for patients with refractory disease with only a few of them survival for more than 2 years. Lack of significant improvement in the current results calls attention to the need for development of novel therapeutic strategies. The overall goal of this proposal is to test in the clinic a novel approach to target leukemia mechanisms using a new class of drugs called CRM1 inhibitors. These agents are able to restore the expression of cancer protectors (tumor suppressors) and block cancer promoter genes (oncogenes). We are planning to test the CRM1 inhibitors in combination with drugs that have been already approved for use in mankind, but combined in a new manner that may enhance their antileukemic activities and improve the outcome of AML patients.
Grant: 9003-16 | Transforming CURES Initiative (TCI):
Location:Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202-2915
Project Title: Mechanisms By Which Acute Myeloid Leukemia Alters The Bone Marrow MicroenvironmentProject Summary:
Genetic alterations (also known as mutations) play an important role in the pathogenesis of acute myeloid leukemia (AML). AML occurs in multiple steps. After the initial insult in the form of genetic or epigenetic changes (i.e. DNA alterations) to the hematopoietic stem cell, several additional alterations may impact these cells, providing them with a growth/survival advantage. In addition, the hematopoietic microenvironment (HM) is involved in the pathophysiology. The HM controls the formation of blood cells through the production and secretion of cytokines and matrix molecules. The HM is composed of mesenchymal stem cells (MSCs), osteoblasts (OBs) and endothelial cells (ECs) among other cell types. The HM can regulate hematopoiesis by interacting directly with stem cells and/or by secreting regulatory molecules that influence, in a positive or negative manner, the growth of stem cells. How AML cells that carry defined genetic mutations such as FLT3ITD and/or Tet2 influence ME cells and thereby contribute to AML and/or normal hematopoiesis is unclear. Furthermore, how presence of epigenetic mutations such as Tet2 in the cells of the BM ME contributes to the transformation of a pre-leukemic cell to frank AML is also unknown. Our proposed studies will attempt to define these mechanisms.
Grant: 6495-16 | Translational Research Program (TRP):
Location:Università degli Studi di Torino- Dipartimento di Biotecnologie e Scienze per la Salute, Torino, 10126
Project Title: Clonal Evolution Analysis And Heterogeneity Of Mutational Profiles In Multiple Myeloma (MM) Patients Receiving Immunomodulatory Drugs (IMiDs)Project Summary:
Multiple Myeloma (MM) is a malignant monoclonal plasma cell disorder whose pathogenesis is only partially understood. Although the use of conventional treatments, few, if any, patients with MM are cured. The recent introduction of novel drugs overcome cell resistance to conventional treatments and has improved responses and outcome of MM patients. Importantly, there is a class of novel agents that target cells involved in immune response (immunomodulatory drugs [IMiDs]), which are profoundly active in MM. Several studies have reported that the combination of pomalidomide (a new generation IMID) and dexamethasone in patients who have progressed after multiple treatment options has important benefits in term of outcome. However, most of MM patients considered to have an ”high risk” disease develop resistance over time.
New and sensitive techniques, such as next generation sequencing (NGS), allow the study of intrinsic and biological characteristics of several cancers and its monitoring over time providing insights into molecular mechanism of disease behaviour and novel therapeutic targets.
We are planning to perform a biological sub-study in the context of a clinical trial, which will involve MM patients at relapse during lenalidomide (an IMID agent). Then, these patients will receive pomalidomide in association with other drugs (dexamethasone alone or cyclophosofamide and dexamethasone) but importantly some will be treated at early relapse (without clinical symptoms) while some at late relapse (in presence of organ damage) to compare the best strategy.
The overall goal of this project is to investigate genomic characteristics of MM cells and to correlate biological profile with clinical outcome into a translational method combining deep sequencing of tumor samples at the serial stages of disease progression and evaluating clones change over time. Furthermore we will analyze sensitivity and resistance mechanisms of these two IMIDs in MM cells with the identification of new candidates genes which may impact in prognostic stratification, therapeutic approaches and assessment of disease response to treatment.
Grant: 6494-16 | Translational Research Program (TRP):
Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215
Project Title: Prognostic And Therapeutic Targeting Of AP Endonuclease In Multiple MyelomaProject Summary:
A prominent feature of multiple myeloma (MM) and other cancers is a significant genomic instability which leads to further genetic changes in cancer cell. This is believed to ultimately result in progression of disease, development of drug resistance and metastatic disease in other cancers. Using multiple approaches including sophisticated gene sequencing studies we have described global mutational changes in myeloma and defined genomic heterogeneity and its evolution overtime. We have now identified that a genome repair pathway called homologous recombination (HR), is dysregulated in MM; and inhibition of
HR activity reduces, whereas its induction leads to increased genetic instability. We have further identified that APE1, as a gene that is dysregulatd in myeloma and is involved in the regulation of HR pathway in MM. Moreover, we observe that MM patients with very high APE1 expression have a poor survival and reducing its activity may reduce the rate of mutation. Based on these information we now propose to identify the role of APE1 in MM. We will evaluate the role of elevated AP endonuclease activity as a marker of prognosis using our validated assay, in 700 uniformly-treated MM patient samples collected at the time of diagnosis from patients enrolled in the IFM/DFCI clinical study and correlate it with response, TTP,
and survival (Sp. Aim 1); investigate genomic impact of elevated APE1 in MM and normal cells (Sp Aim 2); and develop and test a small molecule inhibitor of APE1 in MM and normal cells (Sp. Aim 3). We will evaluate these potential drugs for impact on Genome stability, growth, ability to invade/migrate and develop drug resistance, using in vitro assays, and impact on tumor growth in murine model of MM. These studies will improve our understanding of genomic progression, facilitate development of prognostic tests, and identify novel therapeutics to prevent evolution and development of drug resistance in MM.
Grant: 5440-16 | Career Development Program (CDP):
Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215
Project Title: Role Of Sumoylation In The Fanconi Anemia PathwayProject Summary:
Fanconi anemia (FA) is a genetic disorder characterized by anemia, bone marrow failure (BMF), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Sixteen FA proteins act in a repair pathway originally elucidated in the D’Andrea laboratory, and perturbation of this pathway causes defects characteristic of FA. Despite its rare occurrence, identifying the molecular defects underlying FA can guide our understanding and treatment of its associated diseases (BMF, MDS and AML) in the general population. A key feature of the FA repair pathway is an eight subunit core complex whose activity is critical for removal of crosslinks from DNA. New studies from the D’Andrea laboratory have uncovered a link between the degradation of a subunit of this complex and its modification by a protein called SUMO. Disruption of this regulation in humans confers FA, highlighting its clinical relevance. Interestingly, other subunits of the complex are also modified by SUMO, suggesting broader roles for this modification in FA pathway regulation. To define these, we will use a two-pronged approach: at the enzyme level, we will assess the contribution of candidate enzymes that degrade sumoylated proteins in the FA pathway; at the substrate level, we will characterize the function of sumoylation of FA proteins. Together, these studies will shed light on the molecular mechanisms safeguarding the genome and suggest therapeutic strategies for FA and its associated diseases, such as AML and MDS.
Grant: 5437-16 | Career Development Program (CDP):
Location:Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
Project Title: CHARACTERIZATION OF THE TRANSCRIPTIONAL REWIRING FOR LEUKEMIA RESISTANCE TO TARGETING THE MUTANT METABOLIC ENZYME IDH2R140QProject Summary:
Acute myeloid leukemia (AML) is one of the most common types of blood cancer affecting adults, and its incidence is expected to increase as the population ages. As an acute leukemia, AML progresses rapidly and is typically fatal within few months if left untreated. Five-year survival varies from 15–70%, and relapse rate is between 30% and 78%, depending on subtype. The mutant variant of the metabolic enzyme isocitrate dehydrogenase 2 (IDH2R140Q) has a critical role in AML. Even though inhibitors for this mutant enzyme are available, leukemia cells develop drug resistance. This study aims to understand how leukemia cells switch from sensitive to resistant when targeting IDH2R140Q. We will characterize the behavior of leukemia cells in a mouse that is affected by AML. In particular, we will switch on and off the expression of the mutant enzyme at different stages of the disease and we will look for the presence of specific marker that are absent in sensitive cells. For example, we will directly monitor gene expression and track key regulators of gene expression like messenger RNA (mRNAs) and very small RNAs (microRNAs). We will validate our findings on samples from responsive and relapsed patients’ cohorts in clinical trials for IDH2R140Q targeted therapy. This study will be a breakthrough on genetic criteria that stratify patient cohorts for treatments with IDH inhibitors and achieve effective therapeutic regimes.
Grant: 9002-16 | Transforming CURES Initiative (TCI):
Location:Cedars-Sinai Medical Center, Los Angeles, California 90048
Project Title: ZRSR2 Mutations: MDS And Evolution To AMLProject Summary:
Myelodysplastic syndrome (MDS) is a heterogeneous group of disorders in which blood cell production is ineffective, partly because they die prematurely. Using powerful sequencing techniques, we and others recently identified in MDS samples frequent reoccurring mutations in genes involved in a RNA processing known as RNA-splicing. These mutations are highly specific to MDS, and represent a previously undiscovered pathway for MDS development. ZRSR2 is one of the splicing-factor genes frequently mutated in MDS, and these patients have a high rate of progression to acute myeloid leukemia (AML). We analyzed bone marrow samples harboring ZRSR2 mutations and found that these samples displayed aberrant RNA splicing in a subgroup of 600 genes, some of which are involved in cell proliferation and differentiation. Our aim is to determine the contribution of ZRSR2 mutations to MDS and progression to AML. We are using sophisticated molecular biology approaches and have AML/MDS cell lines and human MDS samples with ZRSR2 mutations. In addition, we developed hematopoietic specific Zrsr2 knockout mice, as well as human and murine cell lines with ZRSR2 mutation in order to model ZRSR2 alterations in MDS. Using ZRSR2 as a focus, we will uncover the role of aberrant splicing in the pathogenesis of MDS and set the stage for the design of specific and potent therapeutic strategies.
Grant: 6491-16 | Translational Research Program (TRP):
Location:Joan & Sanford I. Weill Medical College of Cornell University, New York, New York 10022
Project Title: Targeting Signaling-mediated Transcription In T-cell LymphomaProject Summary:
The majority of T-cell lymphomas are not cured with conventional chemotherapy, in part because most regiments were originally designed for B-cell lymphomas, a different disease. There is a need for new agents that are developed more specifically for T-cell lymphomas. Treatments designed considering the particular biology of T-cell lymphomas would have more chances of being effective in patients. Our group was able to grow T-cell lymphoma cells directly from patients in artificial lymph nodes (organoids) mimicking the environment in which these lymphoma cells grow in patients. Using this methodology we identified proteins that the lymphoma cells expose to the outside. Lymphoma cells use these proteins to capture signals from the environment. These signals tell to the lymphoma cells to reproduce by awakening a set of genes. We also identified that a protein called CDK7 mediates between the signal and the gene activation.
By blocking CDK7 using a compound called THZ1, T-cell lymphoma cells stop their proliferation and die. T-cell lymphoma, unlike other lymphomas and tumors, are addicted to CDK7, therefore THZ1 is more specifically killing T-cell lymphomas. In the research proposed here we would like to understand how to better use this treatment for T-cell lymphoma patients. Since not all T-cell lymphomas are the same, with our studies we will determine what makes a particular type of T-cell lymphoma more likely to respond to THZ1 by analyzing all the genes that change with the treatment. We would like to improve the chances of THZ1 to be effective for most patients, so in this proposal we will also determine what combination of new drugs inhibiting proteins that signal from the environment help THZ1 in killing more T-cell lymphoma cells. Because these proteins are different between several types of T-cell lymphomas, the drugs that target them will also be different. These combinations will therefore be tailored to fit different types of T-cell lymphomas, making the treatment more personalized.
Grant: 6493-16 | Translational Research Program (TRP):
Location:The Johns Hopkins University School of Medicine, Chicago, Illinois 60693
Project Title: GDF15-SOX2 Signaling And Self-renewal In Multiple MyelomaProject Summary:
The recent decade has brought dramatic advances in the treatment of multiple myeloma (MM) with the introduction of several novel therapies. These new drugs have dramatically improved the ability to greatly reduce tumor burden in newly diagnosed MM patients, but even in the case of complete tumor eradication, virtually all patients will eventually relapse. Our laboratory has been interested in developing treatments that can prevent cancer relapse and previously identified a small and unique population of tumor cells termed cancer stem cells (CSCs). CSCs differ from most MM tumor cells since they are capable of extensive grow and the ability to produce more tumor cells. Therefore, we believe that eliminating these cells will prevent tumor regrowth and relapse. Following the discovery of MM CSCs, we have strived to identify factors that regulate their growth, and have recently found that a signaling molecule called Growth Differentiation Factor 15 (GDF15) dramatically increases both the number of MM CSCs and their ability to produce more tumor cells by turning on SOX2, a factor that controls the expression of specific genes in normal stem cells. In this proposal we will examine how GDF15 and SOX2 regulate MM CSCs and will develop novel therapies to that should decrease relapse rates to extend and improve the lives of patients with MM.