Research we fund

I will advance precision combination therapy for blood cancers by computational and experimental pharmacology. In large B-cell lymphoma we will analyze and model subtype-guided pola-vedotin, genome-guided targeted therapy trials, and MRD-based care. In T-cell lymphomas, drug profiling and CRISPR screens will identify response predictors for subtype-specific regimens. In multiple myeloma we will analyze trials to resolve when intensified first-line regimens are superior to sequential therapy.

Our research aims to identify and exploit vulnerabilities that distinguish acute myeloid leukemia (AML) cells from healthy blood cells. We found that targeting protein translation can selectively induce apoptosis in AML cells and are working to translate this into new therapies. Using advanced single-cell sequencing, we track malignant cells across disease evolution to eliminate those that drive relapse. Our overall goal is to develop more effective treatments for patients with AML.

A ketogenic diet, implemented by use of a beta-hydroxybutyrate energy drink (BHB), improves the ability of CAR T cells to fight cancer in laboratory experiments. We now apply this discovery to patients with large B-cell lymphomas who need CAR T cell treatment (CART). The main goals of this clinical trial are to show that BHB, a dietary supplement, in combination with CART improves CART function, is safe for lymphoma patients, and increases the number of patients who are cured.

The objective of this study is to evaluate RSK1 as a therapeutic target in myeloid malignancies. We will utilize PMD-026, a first-in-class, orally administered, small molecule inhibitor of RSK kinases to treat patients with myelofibrosis and other advanced myeloid neoplasms.

Menin inhibitors are a new type of targeted cancer drug designed to block an abnormal protein complex called Menin, KMT2A, and LEDGF, which drives certain genetic forms of acute myeloid leukemia (AML). These drugs can switch off leukemia-causing genes, but by themselves they rarely lead to a cure, and some leukemias develop resistance through mutations in the MEN1 gene that prevent the drug from working properly. Our research has now uncovered additional mutations in MEN1, KMT2A, and LEDGF, genes that help form the same complex, that make leukemia cells resistant in new ways. We believe these changes strengthen the complex’s grip on DNA and blunt the effect of Menin inhibitors. In this project, we aim to understand exactly how these mutations cause resistance and to explore new combination treatments that could make Menin inhibitors more effective for patients with AML.

There is a critical need for new strategies to prevent and treat an aggressive form of leukemia linked to TP53 mutations, which are prevalent in patients who have received cancer treatments and are associated with a poor prognosis. Our preliminary studies suggest that targeting DOCK1 may be a promising therapeutic strategy for eliminating TP53-mutant cells in AML and clonal hematopoiesis, a high-risk condition often preceding AML. In this proposal, we will determine the potential of DOCK1 targeting using both genetic and pharmacologic approaches, and investigate the underlying molecular mechanisms of DOCK1 inhibition to gain a deeper understanding of its function.

Mutations in the ASXL1 gene, among the most common in leukemia patients, lead to the production of abnormal proteins that disrupt the normal function of BAP1, an enzyme that regulates how genes are turned on and off in cells. This project will apply structural, biochemical, and genomic approaches to determine how these mutations alter the ASXL1–BAP1 complex and interfere with normal gene regulation. The findings will advance our understanding of how ASXL1 mutations drive leukemia and guide the development of new targeted therapies.

While T cell engager therapy in multiple myeloma can induce dramatic disease reduction, response duration is variable and curative outcomes remain elusive. The project will explore the novel hypothesis that durable response to T cell engager therapy for patients with myeloma is based on an initial inflammatory response that ignites secondary activation of myeloma specific immune cells. Characterizing this transition and the targets that are recognized is critical for unlocking the curative potential of this treatment.

The proposed studies will address two major issues in treating two hematological cancers: myelodysplasia (MDS) and acute myeloid leukemia (AML): Lack of long-lasting effective treatments; Identification of stable pathways that can be targeted for personalized treatment.

KAT7 has recently been identified as an interesting therapeutic target for the treatment of different types of leukemia. However, the only KAT7 inhibitors described to date are either drugs that cannot be used in vivo (WM-3835), or drugs that can be used in vivo but are not really KAT7-specific, as they inhibit KAT6 with even stronger potency (PF-9363).

Thus, using medicinal chemistry approaches we have designed and synthesized novel compounds with the goal of identifying stronger and more specific inhibitors with favorable pharmacokinetic and pharmacodynamic (PK/PD) properties. We already have lead compounds with verified antileukemic effects in vivo, and here we propose to build on their structures with the ultimate goal of obtaining an in vivo active compound that is ~100-fold more potent against KAT7 than KAT6A with favorable ADME and PK/PD properties, which could be moved into clinical trials in the short term.