Research we fund

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.

Our laboratory has been focused on the development of compounds directed at blocking mutated MYD88, a mutation found in many B-cell malignancies including Waldenstrom’s Macroglobulinemia (95-97%), primary CNS lymphoma (80%), ABC subtype of diffuse large B-cell lymphoma (40%); marginal zone lymphoma (10%); and chronic lymphocytic leukemia (10%). Over the past 14 years, we have identified and reported on the function of proteins that enable mutated MYD88 to support the growth and survival of malignant cells, including BTK, HCK, IRAK1 and IRAK4. Our previous efforts led to the FDA and EMA approval of BTK-inhibitors for Waldenstrom’s Macroglobulinemia, and our current efforts are focused on the development of inhibitors that target HCK, IRAK1 and IRAK4. We have developed and identified lead compounds including degraders (drugs that degrade protein targets) that target MYD88 itself; both HCK and BTK; and both IRAK1 and IRAK4, which we propose to advance in our proposed grant for the treatment of patients with B-cell malignancies that carry mutated MYD88.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive blood cancer with limited treatment options and poor prognosis. Our studies reveal that aberrant activation of S1PR1 drives tumor cell migration, dissemination, and survival, identifying it as an important element in malignant transformation. Because S1PR1 is a druggable target with FDA-approved inhibitors already in clinical use, this project aims to define its mechanistic role in AITL and evaluate its therapeutic potential.

Chimeric antigen receptor T cell (CAR T) therapy has revolutionized the treatment of multiple myeloma and can lead to deep, long-lasting remissions even in patients with advanced disease. However, some patients experience severe long-term adverse effects, including inflammatory conditions of the gut and brain, Parkinson-like symptoms, and secondary malignancies such as CAR T cell lymphoma, which significantly affect their quality of life. Leveraging one of the world’s largest clinical databases and biorepositories of patients treated with CAR T cells and integrating long-term follow-up with longitudinal and spatially-resolved single-cell multi-omics data, this project seeks to uncover how and why these toxicities develop by tracing the behavior of CAR T cells over time and across different tissues. The insights gained will help improve early diagnosis, prevention, and management of these adverse effects, ultimately making CAR T cell therapy safer and more sustainable for patients.

CAR T cell therapy has changed the outlook for many people with multiple myeloma, but the benefits often fade too soon. This research will determine when in a patient’s treatment course T cells are healthiest, so they can be collected and used to make more powerful, longer-lasting CAR T therapies.

At least half of multiple myeloma (MM) patients have mutations of KRAS or NRAS genes and in our preclinical studies, several types of Ras inhibitors slow MM cell growth in lab cultures and in mice, but resistance eventually develops. Gene-editing or activation (CRISPR) studies indicate that the mechanisms of this resistance can vary substantially between MM cells with different genomic features but, notably, defects in the Bcl‑2 family of genes are a recurrent theme. We will apply a lab method called dynamic BH3 profiling to determine how Ras inhibitors alter the myeloma cell dependence on Bcl-2 proteins to inform combination-based therapies. The results from these studies will be validated in cell lines and patient samples in the lab and in vivo models to identify the most effective combinations and guide future personalized therapies for people with KRAS or NRAS mutant multiple myeloma.