Research we fund

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.

In September 2025, TAP made an equity investment in Crossbow Therapeutics to "Support Clinical Development of CBX-250 in Relapsed/Refractory AML, MDS and CMML."

Crossbow Therapeutics is a biotechnology company determined to improve the lives of people with cancer by unlocking the therapeutic potential of T-cell receptor (TCR)-mimetic antibodies. The company’s T-Bolt™ therapies are next-generation, easily assembled immunotherapies directed with high precision at previously unreachable cancer cell targets.

CBX-250 is the first candidate developed through Crossbow’s T-Bolt™ platform, a portfolio of novel TCE molecules that uniquely target peptide-loaded human leukocyte antigen (pHLA) complexes on tumor cells, using antibodies that mimic T-cell receptors (TCR-mimetics). Specifically, CBX-250 targets a cathepsin G pHLA complex, abundantly expressed on leukemic cells, but not normal cells. 

The Phase 1, open-label, dose-escalation CROSSCHECK-001 study (NCT06994676) is the first clinical trial for Crossbow and the T-Bolt™ platform . The study is evaluating the safety, tolerability, and preliminary clinical activity of CBX-250 in patients aged 12 years and older with relapsed or refractory AML, high-risk MDS, CMML and CML.

CBX-663 is the second candidate developed through Crossbow’s T-Bolt™ platform. CBX-663 targets telomerase reverse transcriptase (TERT), a protein that drives tumor growth and is overexpressed in approximately 90% of all cancers.

The Phase 1, open-label, dose-escalation TelOscope-001 study (NCT07779798) is evaluating the safety, tolerability, and clinical activity of CBX-663 in patients with relapsed or refractory myeloid malignancies, advanced solid tumors, or recurrent or progressive glioblastoma multiforme.  

Chimeric Antigen Receptor (CAR) T-cell therapy in AML has shown moderate efficacy and significant toxicity. As a result, there is no formal FDA approval, to date.
One major challenge in developing CAR therapy for AML is represented by the lack of leukemia-specific target antigens. Given that genetic alterations impacting mRNA splicing frequently recur in AML, we develop a target discovery pipeline to identify alternatively spliced cell surface proteins as targets of CAR T cells.
By generating mutant hematopoietic stem and progenitor CD34+ cells, we discover novel and unannotated transcripts that we also detect in AML patient cohorts. We propose to define the protein expression levels of lead splice variants in AML patients, upon development of isoform-specific antibodies. We will construct novel CAR T cells recognizing the extracellular unique epitope of these variants not existent in otherwise normal cells.

Large granular lymphocyte leukemia (LGLL) is a rare blood cancer that causes low blood counts and autoimmune disease, which currently lacks FDA-approved treatments. Our research has shown that drugs that change the epigenetic “on/off switches” in DNA, such as azacitidine and cladribine, turn off abnormal growth signals and kill LGLL cells. We have also developed a new nanotechnology version of cladribine, called Nano-Cladribine, which exhibits increased in vitro potency and is designed to reduce side effects. This project will define the efficacy and mechanisms of epigenetic drugs, test new combinations, and advance Nano-Cladribine toward clinical use, with the goal of developing safer, more effective therapies for patients with aggressive or refractory LGLL.

NPM1 is one of the most commonly mutated genes in Acute Myeloid Leukemia (AML); 25-30% of patient samples contain a mutation in this gene. This mutation is generally expressed in all of the AML cells of an affected patient, and therefore is an attractive target for therapy. We will attempt to develop a better understanding of the physical interactions of mutant NPM1 and its partners in AML cells, and exploit this knowledge to develop novel, targeted treatments for NPM1-mutant AML patients.

Complex karyotype acute myeloid leukemia (CK-AML) is an aggressive disease that rapidly develops treatment resistance. We have found that CK-AMLs harbor heterogeneous cell types, including one related to red blood cells; these ‘erythroid’-like cells are more treatment resistant than others. We propose work to gain a better molecular understanding of these erythroid cells and identify new strategies to target them. We believe this knowledge will lead to better outcomes for patients with CK-AML.