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

Modeling LSC heterogeneity at unprecedented resolution in AML

Our goal is to perform high-resolution molecular characterization of human leukemia stem cells (LSCs). We have developed an integrated set of single-cell techniques that will assess transcriptional, genomic, and phenotypic features of primary LSC populations obtained from patients undergoing varying forms of treatment. We expect to create a molecular atlas of primary LSCs that will provide the leukemia research community with a powerful resource for the development of improved therapies.

Program: Discovery
Project Term: Start Date: October 1, 2024 End Date: September 30, 2027

Epigenetic Mechanisms and Targeting in Hematological Malignancy

Blood cancers can be caused by aberrant regulation of genes that control cell growth and development. The root cause of this problem may be the presence of mutant regulator proteins in the cell and abnormal switching on or off of target genes. Our SCOR studies the molecular basis of this gene deregulation using cell cultured in the laboratory, in human specimen and animal models.

Melnick will study the complex of proteins evolve in looping DNA segments to put gene regulatory sequences in proximity of genes critical for the development of antibody producing B cells. Abnormalities of this apparatus lead to lymphoma. Roeder will study multi-protein complexes involved in “bookmarking” chromatin (the complex of DNA and histones found in the cell nucleus) by chemical modification. He studies the proteins that initiate transcription of DNA into RNA and that assure the passage of the polymerase that creates messenger RNA across genes. Soto-Feliciano studies TRIM28, a protein essential for growth of acute leukemia will identify its mechanisms and target genes. Licht will study the role of chromatin regulators in the response of the immune system to multiple myeloma and how inhibitors of chromatin regulator inhibitors affect the tumor immune response. Patel will study in explore the three-dimensional structures of these protein complexes critical for gene regulation in blood malignancies to understand their mechanisms and develop new small molecules to modulate their action.

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

Memory-like NK cells after hematopoietic cell transplant to eradicate measurable residual disease

Relapse in patients with acute myeloid leukemia (AML) after hematopoietic cell transplant (HCT) is associated with extremely poor prognosis and thus remains a major unmet need. Natural killer (NK) cells are attractive for treating relapse in the post-HCT setting as these cells are not associated with causing graft-versus-host-disease. Cytokine-induced memory-like (CIML or memory-like) NK cells described by our group, demonstrate enhanced anti-leukemia activity, and persist for up to several months in an immune compatible post HCT setting (when derived from the stem cell donor). The goal of this trial is to evaluate donor CIML NK cells early after HCT in AML patients with measurable residual disease (MRD) and therefore otherwise with a high risk of relapse.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027

Harnessing METTL3 inhibition in acute megakaryoblastic leukemia driven by the t(1;22) fusion involving a member of the m6A writer complex

I want to understand how the t(1;22) translocation that involves a member of the m6A writer complex drives acute megakaryoblastic leukemia (AMKL). To identify culprit genes and pathways I will use multi-omics, including RNA, eCLIP, and TimeLapse Seq and proteomics. I will dissect the RBM15-MKL specific effects of a novel METTL3 inhibitor in primary murine and human AMKL in vitro and in vivo. My ultimate goal is to cure this rare infant leukemia by harnessing METTL3 inhibition.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026

Investigating the dependency for protein synthesis in Venetoclax/Azacitidine-resistant acute myeloid leukemia

Relapsed and/or refractory acute myeloid leukemia (AML) display resistance to Venetoclax and Azacitidine (Ven/Aza) with approximately one third of patients demonstrating upregulated protein synthesis. This proposal will investigate the mechanism(s) underlying the dependence of Ven/Aza-resistant AML on protein synthesis as well as the functional consequences of targeting this pathway. Successful completion of these studies will provide novel insights into Ven/Aza resistance mechanisms.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027

Targeting SF3B1 splicing factor mutant myeloid malignancies through dependency on GPATCH8

Mutations in RNA splicing factors, particularly those involving the core splicing factor SF3B1 are amongst the most common mutations found in myeloid neoplasms. We recently identified a cofactor protein known as GPATCH8 which is required for the aberrant function of mutant SF3B1. We now seek to understand and target the ways in which GPATCH8 and SF3B1 interact. In so doing we hope to develop new treatments for leukemias containing mutant splicing factors.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027

Targeting TP53-Y220C mutant AML

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.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027

Cotargeting oncogenic protein translation and apoptosis in acute myeloid leukemia

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.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026

Mechanisms of oncogenic transcription in NPM1-mutant myeloid leukemia

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: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026

TCR-like CARs targeting GvL mHAgs for the treatment of post-transplant AML relapse

AML recurrence is a devastating event after allo-HCT. I hypothesize that it could be counteracted through targeting of leukemia-restricted mHAgs via TCR-like CARs. I will identify scFVs recognizing mHAg:HLA complexes using a cell-free nanobody screening platform, and test the anti-leukemia activity and safety of CAR-Ts bearing such scFVs in vitro and in vivo. Through this approach, I will build a library of CAR constructs able to provide population-scale coverage for at-risk allo-HCT patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026

Novel targeted therapies for acute myeloid leukaemia and multiple myeloma

Outcomes for acute myeloid leukemia (AML) and multiple myeloma (MM) patients remain inadequate and new treatment options to combat resistance against existing agents are urgently needed. My research aims to identify and target selective vulnerabilities of AML and MM cells. I am particularly interested in epigenetic and metabolic pathways that control self-renewal and differentiation of hematopoietic cells and that can be leveraged to modulate cell fate for therapeutic benefit.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 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

New Targeted Therapies for Pediatric Acute Myeloid Leukemia

Our research focuses on the preclinical evaluation of new targeted therapies for high-risk subtypes of childhood AML. We are deploying screening approaches to delete each gene, one-by-one, to identify genes whose deletion leads to death of the leukemia cells. We will evaluate drugs developed against these targets in state-of-the-art models of pediatric AML. Our goal is to translate the most promising findings to clinical trials for children with these very poor outcome subsets of AML.

Program: Dare to Dream
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025

NK cell immunotherapy to reduce relapse after haploidentical transplant for high-risk pediatric AML

Leukemia recurrence remains the most common type of treatment failure after allogeneic hematopoietic cell transplant for children and young adults with high-risk acute myelogenous leukemia (AML), occurring in 40-50% of patients. Novel treatment strategies are needed to attain durable remissions and provide long-term cure. We have developed a novel memory-like (ML) NK cell immunotherapy that has demonstrated potent activity against AML in preclinical and early clinical studies. We propose a new clinical trial combining donor-derived ML NK cells adoptive cellular therapy with modified αβT cell-depleted haploidentical HCT to enhance graft-versus-leukemia and reduce relapse in pediatric and young adult patients with high-risk AML.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026

Strategic combinations to overcome therapeutic resistance and relapse in acute myeloid leukemia

Acute myeloid leukemia (AML) is the most fatal type of leukemia and has a high rate of relapse following current therapies. We have recently uncovered that RSPO3-LGR4 pathway is a key regulator of leukemia-initiating cell activity and is exclusively activated in relapsed and refractory AML. Our project aims to investigate the mechanistic link between the pathway activation and therapy resistance, and design combination therapies that would overcome resistance and improve the treatment of relapsed leukemia.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026

Memory-like natural killer cells and venetoclax to eradicate measurable residual disease in AML

This proposal is to conduct a phase I (early phase) clinical trial to test whether the combination of the approved targeted therapy venetoclax with memory-like Natural Killer (NK) cells is safe and active in patients with acute myeloid leukemia (AML). Based on laboratory research at Dana-Farber Cancer Institute, we believe that the addition of memory-like NK cells obtained from an haploidentical (‘half matched’) donor will be able to eradicate residual leukemia cells left over after prior venetoclax treatment and hence prevent a future relapse of the disease. A total of 10 patients will be treated with two different doses of NK cells and a constant dose of venetoclax. We also plan scientific studies on patient samples to learn more about the function of NK cells when combined with venetoclax, evaluate for clearance of residual leukemia cells with this combination therapy and explore potential resistance mechanisms.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026

Uncovering mechanisms of DNMT3A stability in hematologic malignancies

DNMT3A is a critical tumor suppressor in hematologic malignancies; DNMT3A protein levels affect both tumor latency and type. DNMT3A is regulated in part by protein stability, but the mechanisms remain incompletely understood. Here, I will dissect the mechanisms that regulate DNMT3A protein turnover using CRISPR screening and genetically engineered mouse leukemia models. This work will reveal whether its stabilization could contribute to a new therapeutic approach for hematologic malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026

Bone Marrow Stromal Cell Senescence Induced by Dnmt3a-Mutant Hematopoiesis Drives Clonal Hematopoiesis and Transformation to Myeloid Malignancy

This project focuses on how age-associated clonal hematopoiesis (CH) alters the bone marrow (BM) microenvironment, and whether this promotes transformation of CH to acute myeloid leukemia (AML). I will utilize single cell RNA-seq data, genetic knockout models, and targeted inhibitors to perturb the non-hematopoietic and hematopoietic compartments of a mouse model of CH. The goal is to determine if manipulation of the BM microenvironment can attenuate CH and prevent AML transformation.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026

Molecular basis and new therapeutic strategies in lineage ambiguous leukemia

Lineage-ambiguous leukemias are high-risk blood cancers with unclear biologic basis and suboptimal treatment options. Here, I will identify the cell of origin of lineage ambiguous leukemia and investigate new therapeutic strategies through in vitro and in vivo experimental modeling approaches and preclinical drug studies in patient-derived xenografts. These studies will clarify the cellular and molecular alterations driving lineage ambiguity and advance a new, rational therapeutic approach.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025

Investigating the impact of hotspot mutations in a chromatin reader on leukemogenesis

The goal of this proposal is to investigate the consequence of the chromatin reader eleven-nineteen-leukemia (ENL) gain-of-function mutations in the pathogenesis of leukemia. Our studies leverage the expertise in the molecular and chromatin biology of chromatin reader in leukemia utilizing mouse model, high resolution image, epigenomic and transcriptomic approaches. Our goal is to understand how chromatin reader contributes to cancer development, progression, and therapeutic outcome.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025

Epigenetic Mechanisms in Acute Myeloid Leukemia

The goal of this project is to investigate the role of the epigenetic regulator Eleven-Nineteen-Leukemia (ENL) and its cancer mutations in acute myeloid leukemia (AML). Our studies leverage the expertise in chromatin biology, functional genomics, and AML modeling, as well as unique chemical compounds and mouse models. Results from this project will provide novel biological insights into our understanding of AML pathogenesis and facilitate the development of novel epigenetic therapies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028

Metabolic Regulation of Leukemic Cell Fate

Cell-intrinsic metabolic processes are dysregulated in acute myeloid leukemia (AML) and can act to sustain an oncogenic state of differentiation arrest. Using AML cell lines and patient-derived material grown in sophisticated liquid culture medium that mimics human plasma, we will perform metabolically focused in vitro and in vivo CRISPR-Cas9 screens to reveal metabolic regulators of AML cell fate that can be exploited via dietary or pharmacologic intervention as a novel therapeutic strategy.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026

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

Discovering the function and targeting dysregulated nuclear condensates in myeloid leukemia

Although molecular targeted therapy has dramatically changed how we treat cancer, the treatment for acute myeloid leukemia (AML) remains focused on the use of cytotoxic drugs with many patients eventually relapsing with their disease. Our studies have a uncovered a new nuclear structure that is dysregulated in myeloid leukemia. This proposal studies the identity and function of this nuclear body in human AML and strives to identify novel therapeutic strategies and targets in leukemia.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025

Role of the AML "Immunome" in response and failure of chimeric antigen receptor T cell therapy

Most patients with acute myeloid leukemia (AML) are not cured with chemotherapy alone, and most long-term survivors of AML have undergone an allogeneic stem cell transplant (also known as bone marrow transplant). The outlook is quite grim for patients whose AML relapses after transplant. We have developed a new type of treatment for AML called chimeric antigen receptor (CAR) T cells for these patients. The goal of this project is to investigate how to improve CAR T cells for AML.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025

Niclosamide for the Treatment of Relapsed/Refractory Pediatric Acute Myeloid Leukemia

Niclosamide is an FDA approved anti-parasitic drug that is well tolerated and acts synergistically with chemotherapy to kill AML cells. We will conduct a Phase I clinical trial with niclosamide in combination with cytarabine for children with relapsed/refractory pediatric AML. ShRNA/CRISPR screens demonstrated that Bcl-2 is upregulated in niclosamide resistant cells. We will study the effects of the Bcl-2 inhibitor venetoclax in combination with niclosamide in pediatric AML.

Program: Translational Research Program
Project Term: Start Date: June 30, 2022 End Date: June 30, 2025

Investigating and targeting the histone acetylation reader protein ENL in acute leukemias

Leukemia often results from aberrant gene expression caused by epigenetic alterations. Previously we discovered a novel histone acetylation reader domain in the ENL protein and demonstrated that this domain is essential for the survival of a wide range of acute leukemias, making it an attractive therapeutic target. We will develop specific inhibitors of ENL activity in acute leukemias and will use mouse models to define the role of ENL mutations identified in patients in leukemogenesis.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027

Targeting the interplay between signaling and transcriptional dysfunction in myeloid leukemias

Our research program is focused on understanding the intersection between signaling and transcriptional dysfunction in myeloid leukemias. We leverage murine models, cell lines and human samples to uncover how biological context shapes the manifestation of oncogenic programs at the molecular level. Our long-term goal is to harness this knowledge to identify multipronged therapeutic strategies that improve outcomes for patients with myeloid malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027

Understanding the clonal origin, evolution, and progression of myeloid malignancies

The overarching focus of my research is to understand the clonal origin, evolution, and progression of myeloid malignancies and biological and clinical factors that influence the process. We tackle this question by analyzing patient samples with integrated approach combining single-cell omics, evolutionary genetics, and computational analytics. The ultimate goal of our research is to develop clinical strategies for early detection, prevention, and treatments of myeloid malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027

Mechanisms of Pathogenesis by MYB Fusions in Blastic Plasmacytoid Dendritic Cell Neoplasm

The transcription factor MYB has long been associated with leukemia, but how it contributes to disease is poorly understood. Fusions of MYB to other proteins, causing MYB activation, are found in patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), but rare in other leukemias. I am using recently developed techniques to gain insight into how MYB fusions cause BPDCN. This will enable both new treatments for BPDCN and better understanding of the role of MYB in other leukemias.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2024

Optimizing MICA/B antibody for AML by selective binding to Fc activating receptors

Acute myeloid leukemia (AML) is a blood cancer characterized by poor clinical outcomes. We developed an antibody that inhibits AML in models by triggering anti-leukemia immunity. Now we developed a new version of this antibody with higher affinity to the leukocyte receptors that mediate anti-leukemia immunity. We will establish the ability of this optimized antibody to elicit greater inhibition of AML. The studies will generate important information about how to induce anti-leukemia immunity.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025

Studies on clonal hematopoiesis in the 911 WTC first responders

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to WTC aerosolized dust and gases that contained known and suspected carcinogens including polycyclic aromatic hydrocarbons, polychlorinated biphenyls, polychlorinated furans, dioxins and asbestos. Studies from Dr. Verma's group and others have reported an excess of cancer cases in the WTC-exposed Fire Department of the City of New York (FDNY) firefighters, including a trend towards higher incidence of multiple myeloma and leukemias. He now will be deep sequencing a large group of WTC-exposed firefighters to look for clonal hematopoiesis (CH) which is an acquisition of leukemia associated mutations associated with increases in the risk of hematologic cancer.

Program: Special Grants
Project Term: Start Date: June 1, 2022 End Date: April 30, 2025

SHP2 and BCL2 Inhibition in Acute Myeloid Leukemia

The goal of our work is to use a “bench to bedside and back” approach to develop new treatments for patients with relapsed/refractory AML. Through genetic analysis of patients who relapse or do not respond to standard and investigational treatments, we discover potential resistance mechanisms. In the lab, we test novel drugs and identify new drug targets that may address these resistance mechanisms when used in combination with other therapies. The overall goal of our research program is to improve treatment options and survival of patients with refractory AML.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026

Exploiting Vulnerabilities in RNA Splicing to Treat Hematologic Malignancies

RNA splicing is a central metabolic pathway that is frequently perturbed in hematopoietic malignancies (HMs) that harbor mutations in spliceosome components (most commonly affecting SRSF2, SF3B1, U2AF1, or ZRSR2). These mutations are particularly prevalent in myeloid malignancies (e.g., MDS, MDS/MPN, sAML), but recent pan-cancer studies have implicated aberrant splicing in >30 tumor types. The Project Leaders have probed the molecular consequences of aberrant splicing and identified critical pathways that are amenable to targeted inhibition, including the DNA damage response (Graubert/Walter), the nonsense-mediated RNA decay (NMD) pathway (You/Walter), the spliceosome itself (Abdel-Wahab/Walter/Graubert), and others. To date, effective therapies for HMs have not capitalized on these unique vulnerabilities. The goal of this SCOR is to generate testable clinical hypotheses based on careful mechanistic studies in pre-clinical models and to rapidly move these ideas into the clinic in the near term.

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

A phase 2 registration-directed clinical study of ziftomenib (KO-539), a menin inhibitor, in patients with NPM1-mutant relapsed or refractory AML

Starting in July 2010, LLS TAP supported a promising University of Michigan research project led by Jolanta Grembecka, PhD, to develop new treatments for patients with a rare and lethal subtype of leukemia. Through TAP, LLS engaged chemists to improve the properties that produced lead compounds that exhibited potent anti-leukemic activity. In 2014, LLS introduced Kura Oncology to the project that ultimately led to Kura Oncology completing a licensing agreement with the University of Michigan to continue to develop these molecules.

Kura Oncology is a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer with a pipeline that consists of small molecule drug candidates that target cancer signaling pathways.

Ziftomenib (KO-539) is selective small molecule inhibitor of menin. Ziftomenib is currently in a Phase 2 registration-directed clinical trial in patients with NPM1-mutant relapsed or refractory AML (NCT04067336). 

Program: Therapy Acceleration Program
Project Term: Start Date: December 22, 2014 End Date: April 30, 2025

A phase 2 study of RVU120, a novel CDK8 inhibitor, in genetically defined cohorts of patients with AML and high-risk MDS

In August 2017, LLS TAP partnered with Ryvu Therapeutics (formerly known as Selvita) to support "A Phase 1b Study of SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome."

Ryvu Therapeutics is a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology using a proprietary discovery engine platform.

RVU120 (SEL120) is a highly selective first-in-class CDK8/CDK19 small molecule inhibitor. Ryvu is currently enrolling several Phase 2 clinical trials: RVU120 as monotherapy in genetically defined cohorts of patients with relapsed/refractory AML and high-risk myelodysplastic syndromes (RIVER-52, NCT06268574), RVU120 in combination with venetoclax for patients with relapsed/refractory AML (RIVER-81, NCT06191263), RVU120 as monotherapy for patients with low-risk myelodysplastic syndromes (REMARK, NCT06243458) and RVU120 as monotherapy and in combination with ruxolitinib for patients with myelofibrosis (POTAMI-61, NCT06397313).

Program: Therapy Acceleration Program
Project Term: Start Date: August 7, 2017 End Date: April 30, 2025

Neonatal origins of pediatric AML

Coming soon.

Program: Career Development Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2026

Multi-modal Immunotherapeutic Targeting of AML-restricted Targets in Infants and Children

Advances in understanding and management of AML in children has been stagnant for decades. Observed improvements in survival are more directly linked to improvements in supportive care or risk identification rather than advances in therapeutics. Excitement around FDA approval of two new IDH1/2 inhibitors did not reach the pediatric oncology community given paucity or absence of such mutations in children. This also highlights the stark differences between AML in older adults and that in younger patients. Thus, “trickle down therapeutics” where therapies that are developed in older adults are used effectively in children is a flawed concept. Discoveries and therapeutic development in younger patients must be prioritized if meaningful advances are to be made in curing AML in younger patients. Given that AML in children is not a priority for the pharmaceutical companies, alternate mechanisms for advancing therapeutics in children and young adults should be implemented.

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

Role of HLX in leukemia induction and maintenance

We and others have shown how HLX overexpression keeps blood cells more immature by blocking their differentiation and promoting their proliferation, a characteristic which is inherent to AML. However, whether there is a causative role of HLX in the induction of AML is still unclear. Hence, the aim of my study is to better understand, using genetically engineered mice models, retroviral models, and human AML patient samples, how HLX drives AML at molecular level. This study will uncover potential therapeutic strategies for AML treatment in future.

Program: Career Development Program
Project Term: Start Date: April 1, 2021 End Date: March 31, 2024

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

Targeting kinase-dependent dysregulation of transcription factor control in acute myeloid leukemia

Defining mechanisms of dysregulated gene control are central to understanding cancer and the development of effective therapies. Our research is focused on the mechanisms of gene control dysregulation in acute myeloid leukemia (AML), a refractory form of blood cancer that affects both children and adults. Using new methods for manipulating proteins, we are defining essential mechanisms by which AML cells enable cancer-causing gene expression. This work also allowed us to develop new drugs to specifically block this in cancer, but not healthy cells. Ongoing work aims to define precise mechanisms of cancerous gene control and develop definitive treatments for its control.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024

Therapeutic targeting of AML stem cells 2018

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.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2018 End Date: September 30, 2024

Detection and Targeting of Enzymatic Base Editing Deregulation in Leukemia Stem Cells

Dr. Jamieson is examining the role of two enzymes (APOBEC3 and ADAR1) known to mutate DNA and RNA, and their role in acute myeloid leukemia (AML) and disease relapse, particularly in elderly patients.

Program: Discovery
Project Term: Start Date: July 1, 2020 End Date: June 30, 2024

Reaching out to underserved & minority patients with hematological diseases in the southeastern US

Vanderbilt-Ingram Cancer Center (VICC) is the only NCI designated cancer center that serves both adult and pediatric populations in TN, one of the highest cancer-mortality states in the country. In fact, TN rural dwellers encompass about 30-50% of the states’ population, many with lower per-capita income and high school graduation rates. Influencing cancer care by facilitating underserved and minority populations to access therapeutic clinical trials as well as those focused on screening and prevention strategies remains a cornerstone objective. The Vanderbilt Health Affiliated Network (VHAN) serves as the largest provider for an organized network of hospitals, clinics, and health systems across TN. This network encompasses 12 health systems and 61 hospitals. Within VHAN, the VICC has had a formal affiliation with Baptist Memorial Healthcare Corporation (BMHCC) since 2012. BMHCC is affiliated with 22 hospitals and provides care for 8000 new cancer patients (pts) annually covering 111 counties totaling 4.3 million people. This includes 44% of the 252 counties and parishes in the Delta Regional Authority, congressionally acknowledged as the most indigent population in the US. The primary objective of the VICC community center affiliation with BMHCC is to enhance the regional level of cancer care and to advance cancer research efforts. VICC has provided guidance on a regular basis to assist BMHCC in the establishment and implementation of the Minority and Underserved National Cancer Institute Community Oncology Research Program (NCORP) grant as a successful and sustainable program. BMHCC has become amongst the top recruitment sites for NCORP, with steady growth in the proportion of rural pts seen across the health system. VICC continues to be a resource for BMHCC on providing consultations, training, and best practices for specialized services such as clinical research, radiation oncology, cancer screening, stem cell transplantation and community engagement.

Program: IMPACT
Project Term: Start Date: April 1, 2021 End Date: March 31, 2026

A precision-based all-oral combination of venetoclax, oral decitabine, and IDH1/2 targeted inhibition for patients with IDH1 or IDH2 mutated AML

My ultimate goal is to develop more effective, better tolerated, and individualized treatment for patients with AML. This project focuses on AML patients with IDH1 or IDH2 mutations, with a clinical trial evaluating a combination of three agents which are effective in IDH-mutated AML. While these therapies are not curative on their own, my hope is that this combination will lead to a practice changing all-oral, outpatient, and well-tolerated curative strategy for patients with IDH-mutated AML.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026

Early diagnosis and treatment of pre-leukemia

In the current study we propose, based on our preliminary results, that we can reliably identify pre-AML cases out of the many individuals with age related clonal hematopoiesis (ARCH) based on clinical parameters thereby limiting the population that needs to undergo molecular testing. We have also developed a predictive model that can identify pre-AML cases years before diagnosis. We now propose to utilize this knowledge to treat high-risk individuals with ARCH, at a time point before they have developed disease, by targeting the driving alterations most associated with AML development.

Program: RTFCCR/LLS Prevention
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023

Discovery of Aging-Driven Mechanisms Causing Clonal Hematopoiesis (CH) and its Progression to Hematological Malignancy

My research focuses on why and how risk of acute myeloid leukemia (AML) increases with aging. Studying naturally aged mouse models in combination with mice engineered to express mutations commonly found in human blood stem cells with aging, we are investigating whether certain inflammatory factors that increase during aging increase the risk of leukemia. My goal is to identify biomarkers to assess risk of AML development in aging individuals and define new therapeutic targets to prevent AML.

Program: Career Development Program
Project Term: Start Date: January 1, 2021 End Date: December 31, 2025