Research We Fund

Understanding Leukemia in Children with Down Syndrome to Develop Better Therapies

This Specialized Center of Research is focused on identifying the contributions of chromosome 21, which is present in three copies in individuals with Down syndrome (DS), to acute leukemia. Children with DS are at a 20-fold increased risk of leukemia compared to the overall pediatric population and frequently have other health issues that complicate leukemia treatment. Although acute myeloid leukemia in children with DS (ML-DS), which frequently evolves from transient abnormal myelopoiesis (TAM), has a better outcome than acute myeloid leukemia (AML) in children without DS, those who relapse following treatment face an extremely poor prognosis. Similarly, children with DS who develop B-ALL have a worse prognosis than those without DS due to excessive treatment-related mortality and increased risk of relapse. Our overarching, united goal is to develop novel therapies to cure DSassociated leukemias and to reduce the side effects of treatment in this vulnerable population. In addition to children with DS, our study has major implications in other cases of pediatric and adult leukemias. For example, chromosome 21 amplification is one of the most significant gains in several classes of malignancies, including certain subtypes of AML, hyperdiploid ALL, and iAMP21. Amplification of chromosome 21 is also a feature of the acute leukemia phase of a disease named myelofibrosis. Therefore, insights we gain from this research will impact a large group of patients with acute leukemia.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2024 End Date: September 30, 2029

Development of a clinical program for myeloid cancer prevention

The majority of myeloid cancers remain incurable. We previously showed that individuals at risk can be identified years in advance, indicating that prevention may be a viable alternative to treatment. Here, we propose a program of work to establish a clinical platform for myeloid cancer prevention. This includes development of a screening strategy, improved understanding of myeloid cancer evolution, identification of treatment targets and establishment of a specialized clinic to deliver therapy.

Program: Specialized Center of Research Program
Project Term: Start Date: February 1, 2024 End Date: January 31, 2029

Therapeutic targeting of AML stem cells 2023

The goal of this SCOR project is to identify and eradicate the root cause of acute myeloid leukemia, the so-called leukemia stem cell (LSC). In the previous cycle of this SCOR grant, we developed two unique strategies, each of which efficiently eradicates LSCs in the laboratory. Going forward, we will expand our scientific efforts to further improve these approaches and also conduct clinical trials to determine whether our approaches to killing LSCs will benefit AML patients.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2023 End Date: September 30, 2028

Understanding and Overcoming Mechanisms of Immune Evasion after Allogeneic Transplant

Outcomes for patients with acute myelogenous leukemia who relapse after transplantation are dismal. This SCOR brings together an international group of collaborators with deep expertise in genomics, epigenetics, antigen presentation, and immune-regulation. They will focus on mechanisms of immune evasion by leukemia cells, identifying effective T cell responses to those evasive processes, and providing critical insights into the optimal approaches to model new and promising targets for immunotherapy with a goal of eliminating leukemia recurrence.

 

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2022 End Date: September 30, 2027

Translational Discovery in Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) are poorly understood and patients with PTCL are underserved by current therapies. The most common subtypes (among >20) are PTCL-not otherwise specific (NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALK- ALCL). Rational treatment strategies for these lymphomas are lacking, largely due to the insufficient characterization of PTCL pathobiology and historic paucity of faithful models. Over the past 4 years, our groups and others have identified recurrent alterations in PTCL subsets, developed targeted agents against PTCL and established an unprecedented repository of PTCL models for in vitro and in vivo interrogation. A clinical trial led by director Dr. Horwitz established a new standard-of-care for upfront treatment of CD30+ PTCLs. Additional trials developed through this SCOR have advanced therapeutics targeting PI3 kinase (duvelisib), JAK1/2 (ruxolitinib) and IDH2 (enasidenib) for relapsed/refractory PTCL. The central goal for the next 5 years of support is to establish informed combination strategies that eradicate resistant populations and thereby extend the duration of meaningful responses.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026

Targeting Epigenetics in Myeloid Malignancies

We have a highly collaborative team of investigators, whose goal is to develop novel therapeutic approaches to MDS and AML as well as to improve current therapies for these diseases based on a detailed understanding of how epigenetic dysregulation contributes to myeloid neoplasia. We are focusing on the clonal MDS or AML cell and on the bone marrow microenvironment (BMME), including immune cells that could contribute to or limit the progression of these disorders. Our Center brings together chemists, biochemists, cellular biologists and molecular biologists, who are supported by three core facilities, including an Administrative core, an Epigenomics core and a Bioinformatics and Big data sharing core. To advance our Center’s ability to implement personalized therapies for patients with myeloid malignancies, we have generated and will generate novel reagents, and utilize state-of-the-art in vitro and in vivo assays to identify key modulators of drug sensitivity or resistance. We will focus on so-called “epigenetic-focused” therapy, realizing that many of the enzymes that regulate epigenetic control of cell fate, influence signal transduction pathways, RNA splicing events, and the activity of key cellular proteins, such as BCL2 family members and p53.

The genetic mutations that underlie myeloid malignancies have been identified, and we and others have generated mouse models that have pinpointed the role that these genes and their mutations play in normal and malignant hematopoiesis. Our institutions have biospecimen banks with large numbers of MDS and AML samples, and active clinical trial portfolios, that have led to FDA approval of a variety of novel agents, including IDH1/2 inhibitors. The next step in delineating the pathogenesis and Achilles’ heel of these disorders is to better define the role of epigenetic abnormalities play in disease initiation and progression, and to define how targeting LSD1, the CoREST complex, PRMT5 and inflammation signals may advance current treatment strategies (e.g. VEN/AZA), and to enhance the activity of promising agents currently under investigation (menin inhibitors, etc.). Identifying the dependencies and vulnerabilities created by genetic or epigenetic abnormalities will allow us to more rationally advance the treatment of myeloid malignancies, a disease focus where headway is beginning to be made.

Defining the crosstalk between different epigenetic regulators, and how they affect cellular and extracellular processes other than histone proteins, may identify unique sensitivities that can increase the therapeutic index for novel, epigenetic-focused treatments, and identify potentially synthetic-lethal combination therapies. The individual projects in our Center, cover three key aspects of gene regulation and chromatin structure. Project 1 is focused on the LSD1 demethylase, which plays a role in myeloid differentiation, Project 2 is focused on the role of PRMT5 in regulating LSC self-renewal, proliferation and survival, and the expression of potential immunogens, and Project 3 is focused on the interaction between the BMME and the epigenome in mediating sensitivity to epigenetic agents in CMML and MDS. Thus, our center will span the continuum from basic mechanisms of disease initiation and progression, to clinical issues related to therapeutic sensitivity vs. resistance.

Ramin Shiekhattar first discovered that MAO inhibitor antidepressants such as tranylcypromine (TCP), can inhibit the LSD1 demethylase. This finding led to a recently published clinical trial of AZA + TCP in MDS and AML patients led by Justin Watts, and to a new clinical program, that will be continued at Sylvester and MSKCC. They will work with Phil Cole, who founded a biotech company in 2011 that is synthesizing novel epigenetic-focused therapies, to examine how targeting the CoREST complex can synergize with clinically available MDS/ AML cells differentiation- or apoptosis-inducing agents. Several lead compounds are now being tested in the Shiekhattar and Nimer labs.

Omar Abdel-Wahab and Stephen Nimer have discovered several oncogenic functions of PRMT5, an arginine methyltransferase targeted by several small molecule inhibitors that are now in clinical trials for MDS or AML patients at Sylvester and MSKCC. They will work with Luisa Cimmino to exploit their work implicating PRMT5 in regulating homologous recombination, RNA splicing and p53 function. Maria Figueroa has extensively studied predictors of the clinical response to DNA hypomethylating agents (HMA) and has identified critical mediators of HMA resistance originating in the BMME. She will work with Ross Levine, a leader in delineating the molecular pathogenesis of hematologic malignancies, to evaluate how signals from the BMME impact the responsiveness of MDS and CMML cells to HMA combinations as well as how to overcome primary resistance to HMA by targeting key signals in the niche.

Three Cores will enable the efficient completion of our collaborative studies. Core A, the Administrative Core, will be housed at UM; it will provide infrastructure support, to optimize interactions between the various labs represented here, handle all financial and reporting aspects of the grant, assist with the SCOR site visit and the annual meeting of the Center, and maintain regulatory compliance for the Center (e.g. assuring access to bio-specimens, handling IRB and IACUC approvals, etc.). Both UM and MSKCC continue to collect MDS/AML/MPN bio-specimens. Core B, the Epigenomics Core, led by Sion Williams and Lluis Morey, will perform various NGS-based assays to assess genome-wide changes in gene expression, DNA methylation, and histone post-translational modifications. Core C, the Bioinformatics and Big Data Core, led by Stephan Schürer, will provide bioinformatics support and ensure complete and efficient sharing of data for all three projects in the SCOR.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2022 End Date: September 30, 2027

Pan-heme CAR: Anti-CD38 CAR T cells for myeloid, lymphoid and plasma cell malignancies

Our SCOR team has a razor-sharp focus on an exciting new treatment modality for blood cancers: chimeric antigen receptor (CAR) T cells. T cells can be trained to target cancer cells by genetic modification. In fact, previous support from the Leukemia & Lymphoma Society allowed us to successfully develop CAR T cells targeted to CD19, a pan-B cell marker. This treatment, generically called CART-19, was approved by the FDA in 2017 for the treatment of B-cell acute lymphoid leukemia (B-ALL) and in 2018 for some non-Hodgkin lymphoma (NHL), with promising results in other B cell malignancies such as chronic lymphocytic leukemia (CLL). Thus, the development of a single therapy for a single disease (initially, CLL) paid handsome dividends when translated to a broader range of CD19-expressing malignancies (ALL, NHL).

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2019 End Date: May 31, 2025

Targeting Enhancer Dysfunction in Hematological Malignancy

Blood cancers such as leukemia, lymphoma and myeloma may be caused by abnormal regulation of genes that control normal cell growth and development. Genes that are normally active can be silenced and/or genes normally not present in a blood cell are abnormally activated. The result can be an uncontrolled signal for continued cell growth or survival. Our group studies the molecular basis of this gene deregulation using cells cultured in the laboratory, human specimens, and animal models.

Program: Specialized Center of Research Program
Project Term: Start Date: January 1, 2019 End Date: September 30, 2024