Research we fund

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.

Coming soon.

We discovered mesothelin to be expressed on AML cells, but absent on normal cells, thus providing a unique target to eliminate leukemia without causing cytopenia. We demonstrated efficacy of mesothelin-directed immunotherapy (CART) in AML. In collaboration with Eureka pharmaceutical, we will conduct the first trial using a mesothelin-directed CART in childhood AML.

This collaborative program investigates why Hairy Cell Leukemia (HCL) and its variant often relapse despite effective therapies and why bone-marrow fibrosis frequently persists after treatment. This proposal examines fibrosis as both a biomarker and a biological driver of disease. Project 1 determines whether persistent scarring predicts relapse and uses human bone-marrow organoid cultures to test how leukemia and stromal cells interact. Together, these studies connect patient data and experimental systems to reveal how fibrosis contributes to disease persistence in HCL and HCL-v.

Hairy Cell Leukemia (HCL) is a rare blood cancer that affects white blood cells. The usual first treatment is with drugs called purine analogs (PAs). While PAs work well initially, their efficacy decreases with each treatment round, they cause long-lasting immune suppression and increase the likelihood of developing serious infections.

Therefore, safer treatments that can control or even eliminate the disease, and allow the immune system to recover are urgently needed. New targeted oral therapies offer a promising alternative to chemotherapy, and those that induce apoptosis (BCL2 inhibitors) or inhibit B-cell receptor signaling (BTK inhibitors) have shown single-agent activity and excellent tolerability in HCL patients. However, alone, they often result in incomplete responses and require long-term administration. We will test if combining a BTK inhibitor (zanubrutinib) with a BCL2 inhibitor (sonrotoclax) can achieve deeper, longer-lasting remissions and allow treatment to stop after a fixed period rather than continuing indefinitely.

We will examine responses after 6, 12, and 18 cycles (a cycle is 28 days) to assess how quickly the disease resolves and how deep the response is. We will monitor immune recovery using blood tests and advanced techniques to investigate how the treatment affects any remaining leukemia cells.

The ultimate goal is to determine if this drug combination can eliminate HCL and how long treatment needs to continue to achieve this result.

Over the past year, we explored whether there is a biological basis that helps explain why African and African American patients typically present with more aggressive forms of lymphoma, which tend to be less responsive to treatments. Our findings revealed that, in addition to having slightly different mutations in the lymphoma cells, the tissue microenvironment surrounding these cells is rich in cells that suppress the immune response. We were the first to describe this type of cell, which is also commonly observed in other patients with less responsive tumors. We discovered that these mutations might make lymphoma cells more likely to respond to novel targeted therapies that are not yet available in clinical settings. Furthermore, we developed innovative therapeutic strategies aimed at targeting the microenvironment cells to enhance the immune response against these tumors. These studies were conducted using pre-clinical models as a precursor to clinical trials. We anticipate that these studies will benefit patients with high-risk diffuse large B cell lymphoma, regardless of their ethnicity. To help identify patients more likely to respond to these treatments, we are developing minimally invasive biomarkers that use a drop of blood to analyze specific characteristics in both lymphoma and microenvironment cells. This approach is crucial for reducing reliance on biopsies and tissue analysis, which can be challenging or cumbersome to obtain from patients. Over the past year, we have continued to investigate how epigenetic drugs can be used in combination with immune therapies to increase the likelihood of curing lymphoma patients. We have several ongoing clinical trials exploring the concept that administering epigenetic drugs can make tumors more susceptible to being destroyed by immune cells, either naturally present in the body or administered via blood transfusion. In these patients, we also apply biomarkers to determine which individuals can benefit most from epigenetic therapy and to understand how and when the drugs modify the microenvironment, allowing us to decide the optimal timing for immune cell transfusion.

Patients with B cell malignancies who do not fall into a distinct pathological disease category pose a challenge for patient care, and patient classification has been exacerbated by the recent emergence of two separate classification systems. Genome-wide DNA methylation is a stable and information-rich biomarker that has been successfully used to classify other cancer types, however remains understudied in hairy cell leukemia and related splenic B cell lymphoma and leukemia. In this proposal we will investigate the utility of DNA methylation to establish a novel, unbiased, biologically-based classification paradigm for hairy cell leukemia, with a focus on the variant subtype, and investigate novel mechanisms and etiology underlying these rare leukemia patients.

The overall objective of this project is to identify novel pathways that may be targeted for therapeutic benefit in CMML. We have identified abnormal inflammation mediated by RSK1 in CMML patient cells, and we hypothesize that RSK1 drives CMML disease development. We thus propose studies to determine how RSK1 contributes to CMML pathogenesis, and to evaluate the therapeutic potential of RSK1 inhibition for CMML patients.