Research we fund

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.

Genetic mutations in various RNA splicing factors occur in a significant percentage of patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations can create abnormal proteins that contribute to disease development. Our research focuses on identifying these faulty proteins, specifically the small pieces (peptides) that are displayed on the surface of MDS and AML cells. We developed a novel method to uncover these faulty cell-surface peptides, and engineered specialized immune cells, called T cells, that recognize and kill leukemic cells carrying these faulty peptides. The goal of this proposal is to develop and translate into the clinic new T cell-based therapies to improve the outcomes of patients with high-risk leukemia.

STAT5-driven B-ALL, T-LGL, and T-cell lymphomas exhibit poor outcomes and lack effective targeted therapies. We discovered that the PTPN1/2 inhibitor ABBV-CLS-484 (AC484), originally developed to enhance anti-tumor T-cell responses in solid tumors, unleashes STAT5-signaling and selectively kills STAT5-driven lymphoid malignancies. Unlike solid tumors, STAT5-driven B-ALL, T-LGL and T-cell lymphomas exhibit a unique dependency on their ability to curtail oncogenic STAT5-signaling. We propose that AC484 will exploit this vulnerability while also enhancing anti-leukemia T-cell responses. This dual mechanism may provide the first targeted strategy for STAT5-driven T-LGL and T-cell lymphomas, and synergize with immunotherapies such as blinatumomab (Fig. 2) and CD19 CAR T cells (Fig. 3) in B-ALL.

Mantle Cell Lymphoma (MCL) is an aggressive blood cancer with especially poor outcomes in patients with TP53 gene alterations. Our studies show that loss of TP53 reduces the activity of SHP1, a key protein that helps restrain cancer cell growth, leading to resistance to BTK inhibitors. This project will test SHP1-activating medicines that can both suppress MCL cells and reprogram immune cells to attack the tumor, with the goal of developing a more effective and lasting treatment strategy for patients with relapsed, treatment-resistant MCL.