Research we fund

Based on our preliminary data, we hypothesize that IRAK4 inhibition leads to LSPC reprogramming in MDS and AML. Aim 1 will evaluate the mechanism by which IRAK4 inhibition leads to LSPC reprogramming in cell lines, mice, and PDX samples. Aim 2 will concentrate on understanding of how IRAK4 inhibition creates synthetic lethal dependencies with the CELMoD CC-885 and how neosubstrates of CC-885 mediate the synergy upon IRAK4 inhibition in leukemic cells.

Our recent studies have identified specific bacteria that can potentially promote the growth of human myeloma tumor cells. We are now testing if eradicating these bacteria in MGUS patients will be effective for prevention of myeloma.

Survival rates for those afflicted with MDS have not improved despite extensive effort to identify the key genetic events in its pathogenesis. This project elucidates the contributions of aberrant NPM1 to hematological disorders, with a focus on mitochondrial fitness and inflammasome activation. The resulting insights into the metabolic, genetic and proteomic requirements of homeostasis that are critical to preventing aging will have a major impact on the treatment of hematological malignancies.

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.

Overactivation of the inflammasome is seen in CMML and leads to worsening of this condition. We will explore the potential of a new inflammasome inhibitor drug, HT-6184, in CMML patient samples and in animal models. Our preliminary results show that this drug can decrease inflammation and improve red cell development in CMML models. The new drug is approved for clinical trial use and our work will potentially lead to its use in clinical investigations in CMML.

Chronic myelomonocytic leukemia (CMML) is a rare but poorly understood blood cancer often presenting with crippling inflammatory symptoms that frequently evolves into acute leukemia. In an ongoing clinical trial, we have compelling molecular and clinical data that this disease responds effectively to blockade of GM-CSF with lenzulimab, a well-tolerated and safe antibody, in combination with azacitidine. Here, we propose an integrated research program to investigate targeting of the GM-CSF pathway in high risk CMML using our carefully matched patient samples, proprietary GM-CSF tools, and humanized in vivo CMML models.

This project will significantly advance the treatment and prevention of CNS lymphomas in two key areas. One, we will further develop and validate candidate genomic biomarkers that identify high risk disease and that are useful in risk stratification in future clinical investigations in primary CNS lymphoma. Two, we will evaluate novel pharmacologic interventions that we hypothesize will: a) potentiate both the anti-lymphoma immune response, including agonists of the toll like receptor 7 and 8 pathway, as well as the combination of the anti-CD19 monoclonal antibody tafasitamab plus lenalidomide; and b) antagonize the NFkB pathway, via the orally-administered BTK degrader, Nx-5948, that we have demonstrated to be active in preclinical models using patient-derived CNS lymphomas.

A major limitation of immunotherapy approaches for AML has been the lack of known targetable cell surface antigens specific to AML cells. This project characterizes the pathologic and biologic effects of a novel cell surface antigen complex uniquely present on AML cells but not normal hematopoietic precursors, known as the U5 snRNP complex. Furthermore, we will interrogates U5 snRNP complex components as novel AML-associated antigens and CAR T cells targets for AML treatment.

p>SIRT5 is a master regulator of central energy metabolism. The survival and growth of Acute Myeloid Leukemia (AML) cells depend on SIRT5. I will employ genetic SIRT5 disruption and small molecule inhibitors to target SIRT5 in Acute Lymphoblastic Leukemia (ALL) cells and primary samples. This study aims to 1) determine the effects of SIRT5 inhibition on ALL in vitro and in vivo, and 2) identify SIRT5-regulated pathways and mechanisms underlying SIRT5 dependency in T-ALL.

AML risk stratification established by previous studies do not reflect survival outcomes observed in Black patients. Exome sequencing of 100 Black AML patients revealed the novel variants previously not affiliated with AML, including PHIP. Using multiomic patient sample captures and GEMMs, we will functionalize variants in PHIP and assess if they drive leukemogenesis and/or therapy resistance. The overall goal of this work is to implement inclusive genetic assessment tools for AML diagnosis.