Research we fund

MD Anderson Cancer Center

TP53-Y220C is a recurrent hotspot TP53 mutation observed predominantly in AML and MDS among hematological malignancies. This study aims to investigate the mechanism of action and therapeutic activity of PC14586, a compound designed to bind p53-Y220C protein and stabilize it in the wild-type conformation and to develop mechanism-based combinations that improve its efficacy in TP53-Y220C mutant AML.

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Translational Research Program

Follicular lymphoma is a common form of blood cancer, affecting 15,000 new patients annually in the United States, but it remains incurable with conventional treatments. Bispecific antibodies represent a new class of therapies that engage the immune system to attack lymphoma cells and have shown promising effectiveness in inducing remissions in patients with this disease, but even they are unlikely to be curative. Researchers from the Dana-Farber Cancer Institute here propose to analyze lymphoma cells from patients undergoing treatment with bispecific antibodies on several complementary clinical trials to determine how these cells evade the immune system and develop resistance. It is believed that such mechanisms of resistance may reveal vulnerabilities within the lymphoma cells that novel treatments can overcome in combination with bispecific antibodies to cure patients with follicular lymphoma.

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Translational Research Program

Emory University

Despite remarkable progress in the last 20 years, multiple myeloma remains an incurable disease. In recent years, 2 CAR T cell products that target BCMA on the myeloma cell have been approved. These products result in remarkable initial responses however the duration of these responses has been disappointing. In this proposal, we will take a novel approach to isolate and characterize myeloma cells that interact with CAR T cells but are not killed by them as a potential resistance mechanism.

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Discovery

University of Virginia

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by resistance to standard treatments and short survival. For the 2023 LLS MCLII Synergistic Team Award, we have assembled a team of leaders in basic, translational, and clinical research in MCL to tackle the current significant obstacles in understanding and treating MCL. In the last decade, we investigated the therapy resistance mechanism of MCL, and pioneered clinical trials for targeted therapies (ibrutinib, lenalidomide) and chimeric antigen receptor T-cell (CAR-T) therapy. However, despite these dramatic advancements, resistance to these newer therapies, including targeted therapy and CAR-T cells, is seen in over 50% of patients. Thus, it remains an unmet need to better define the mechanisms of resistance and then develop rationally designed strategies to overcome resistance. The overall goal of this Synergistic Team Award is to develop improved curative therapies for patients with MCL at relapse. The goals will be addressed in three highly focused, independent but highly integrated projects that utilize state-of-the-art genomic technologies, patient-derived xenograft models, clinical data and primary MCL samples. With the joint effort of our laboratories, highly interactive and accomplished scientists, and physician researchers from multiple institutions with expertise in MCL and therapy, we are uniquely poised to develop improved next-generation of combination therapy for relapsed MCL patients.

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Mantle Cell Lymphoma Research Initiative

TAP Partner

In August 2013, LLS began its first European partnership with Affimed that supported two clinical trials for Hodgkin lymphoma (HL) patients. Expanding upon the initial work supported by LLS TAP, Affimed is currently enrolling "A Phase 2 Study of Innate Cell Engager AFM13 in Combination With Allogeneic Natural Killer Cells (AB-101) in Subjects With Recurrent or Refractory Hodgkin Lymphoma and CD30 Positive Peripheral T-Cell Lymphoma."Affimed is a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer by actualizing the untapped potential of the innate immune system using the proprietary ROCK® platform to enable a tumor-targeted approach to recognize and kill a range of hematologic and solid tumors.AFM13 is bispecific tetravalent engager targeting CD30 on tumor cells and CD16A on NK cells and macrophages. AFM13 in combination with AB-101 (allogeneic natural killer cells) is currently in a Phase 2 clinical trial in relapsed or refractory Hodgkin lymphoma or CD30-positive PTCL (NCT05883449).

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Therapy Acceleration Program

New York University School of Medicine

Coming soon.

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Special Grants

The Brigham and Women’s Hospital

The focus of my research is to evaluate the efficacy of and to unravel the molecular mechanisms underpinning a novel drug combination in AML targeting oncogenic protein translation and apoptosis. We will utilize genetic perturbation and other orthogonal approaches, including in vitro and ex vivo assays, and in vivo AML PDX models. The goal of my research is to transform the clinical management of AML patients, particularly for relapsed and difficult-to-treat subgroups.

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Career Development Program

TAP Partner

In July 2012, LLS began its partnership with Constellation to support three first-in-human Phase 1 clinical trials for blood cancer patients and the partnership led to the ongoing trial "A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients."Constellation Pharmaceuticals was a clinical-stage biopharmaceutical company developing novel therapeutics that selectively modulate gene expression to address serious unmet medical needs in patients with cancer. MorphoSys acquired Constellation in July 2021 and continues to enroll patients with myeloproliferative neoplasms in multiple clinical studies.Pelabresib (CPI-0610) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. A Phase 3 clinical trial (NCT04603495) of pelabresib in combination with ruxolitinib for myelofibrosis patients that have not been previously treated with Janus kinase inhibitors completed enrollment.

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Therapy Acceleration Program

University of Colorado Denver, Anschutz Medical Campus

Our SCOR team seeks to fundamentally reinvent the ways in which physicians diagnose and treat acute myeloid leukemia (AML). For over 40 years, AML has been treated with a combination of chemotherapy drugs that have major side effects and usually only provide short-term benefit to patients. Indeed, survival rates for most AML patients are dismal, and quality of life for these patients is poor. Consequently, improved strategies for AML are a huge priority for the field. We believe that the lack of progress against AML is due to a single, fundamental failure of existing therapies: While current therapies attack leukemia cells, they fail to act against the real root of the problem, namely leukemia stem cells. It’s like mowing over weeds in a lawn. If the roots are not removed, the weed (disease) will grow back. And like eradicating the roots of weeds, AML stem cells have proved difficult to treat. This is primarily due to the fact that AML stem cells within a given patient can exist in multiple forms, each of which has a differing response to therapy. In other words, while various drugs can often kill some AML stem cells in a patient, completely eradicating all the AML stem cells can be very difficult.

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Specialized Center of Research Program

Dana-Farber Cancer Institute

NPM1-mutated leukemia is the most common AML in adult and characterized by upregulations of HOXA/B genes and MEIS1. Given the importance of oncogenic transcriptional program, I will determine regulatory molecules that cooperate with mutant NPM1 on chromatin by combining CRISPR/Cas9 screening approach in an innovative model system of endogenous transcription reporters with proteomics approach. This will facilitate identification of novel therapeutic targets specific for NPM1-mutated AML.

Program Name(s)

Career Development Program

University of Miami

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.

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Specialized Center of Research Program

Washington University in St. Louis

New treatments for AML and MDS are urgently needed. We have developed and performed preliminary testing of a novel, patent-protected, trispecific NK cell engager named KT1 which targets AML blasts and leukemia stem cells (LSCs) expressing CD33 and CD123 for elimination by effector cells that express CD16a/b. We plan to test the ability of KT1 to release cytokines and facilitate killing of CD33- and/or CD123-expressing targets by different types of CD16a/b-positive effector cell populations including resting natural killer (NK) cells, cytokine-induced memory-like (ML) NK cells, gamma/delta T cells, and macrophages both in vitro and in leukemic mice. We anticipate that a future treatment of AML and/or MDS with KT1 combined with a donor leukocyte transfer of allogeneic NK, ML NK, or gamma/delta T cells will have excellent therapeutic efficacy and a far better safety profile than many currently studied immunotherapies being tested in patients with AML or MDS.

Program Name(s)

Translational Research Program