Research we fund

Our research program’s goal is to identify therapeutically actionable pathways in pre-leukemic and leukemic stem cells in myeloid malignancies. We specifically dissect molecular circuits governing stem cell self-renewal and differentiation, how these change during aging, and contribute to leukemic stem cell evolution and maintenance. Accomplishing this work will enable the rational design of curative intervention and perhaps even prevention strategies for patients with myeloid malignancies.

The goal of this project is to investigate the role of the epigenetic regulator Eleven-Nineteen-Leukemia (ENL) and its cancer mutations in acute myeloid leukemia (AML). Our studies leverage the expertise in chromatin biology, functional genomics, and AML modeling, as well as unique chemical compounds and mouse models. Results from this project will provide novel biological insights into our understanding of AML pathogenesis and facilitate the development of novel epigenetic therapies.

My lab is focused on understanding the pathogenic interplay between oncogenic mutations, chronic inflammation and aberrant metabolism as a driver of the evolutionary processes that culminate in lethal myeloid malignancies. We leverage mouse models and human patient samples to establish modalities for targeting this interplay throughout disease pathogenesis. My long-term goal is to improve patient outcomes by establishing therapies that prevent and/or delay evolution to acute leukemia.

Our research seeks to understand how ordered acquisition of oncogenic mutations transforms human hematopoietic stem cells into myeloid malignancies. We leverage patient-derived induced pluripotent stem cells and primary normal and malignant stem cells to study how mutation cooperation drives leukemic progression in vitro and in vivo. Our long-term goal is to identify disease mechanisms and develop targeted therapies to eradicate malignant stem cells.

The focus of my research is to understand the causes and early-life origins of acute lymphoblastic leukemia (ALL). We use a two-pronged approach: 1) conducting epidemiological studies of ALL in susceptible populations to understand genetic predisposition, and 2) investigating the in utero origins of ALL across subtypes. Our goals are to identify children at the highest risk of developing ALL through genetic screening and to lay the groundwork for precision prevention strategies.

Pediatric acute lymphoblastic leukemia (ALL) that is resistant to standard therapy is a challenge that has been partially overcome by T-cell therapy, yet relapse still occurs in up to 50%. We are conducting two clinical trials that test a next-generation T-cell therapy and the first incorporation of T-cell therapy into initial therapy. These trials will inform future development and the optimal place for this therapy with the goal of improving cure rates for children with very high risk ALL.

I aim to identify drivers of pediatric and adolescent/young adult lymphoma disparities so that targeted health equity interventions can be developed. Integration of large datasets, systematic collection of social determinants data in clinical trials, and collaboration with patient advocates will: a) create new population-based resources to study lymphoma outcomes; b) establish a novel framework for equity research in lymphoma clinical trials; and c) identify real-world targets for intervention.

The genomic architecture of residual CLL and molecular determinants of disease progression after targeted combination therapy are unknown. In a phase 2 study of zanubrutinib and venetoclax in CLL, I will investigate the depth of response and genomic changes using cellular and circulating tumor DNA. Data generated from this proposal will provide foundational evidence to develop genomic markers for non-invasive monitoring of treatment response and precise prediction of outcome.

In June 2023, LLS made an equity investment in Rgenta Therapeutics to "Support development of RNA-targeting molecules for blood cancers." 

Rgenta Therapeutics is developing a pipeline of oral, small-molecule RNA-targeting medicines with an initial focus on oncology and neurological disorders. Rgenta has a proprietary platform to mine the massive genomics data to identify targetable RNA processing events and to design small-molecule glues to modulate the interactions among the spliceosome, regulatory proteins, and RNAs. 

Rgenta is working closely with LLS TAP to further develop RNA-targeting molecules by supporting preclinical studies with the goal of moving towards clinical development in hematological malignancies. 

In November 2022, LLS made an equity investment in Dren Bio to "Support Clinical Development of the DR-01 Program for Rare Leukemia & Lymphoma Indications Including Large Granular Lymphocyte Leukemia (LGLL) and Cytotoxic Lymphomas."

Dren Bio is a clinical-stage biopharmaceutical company focused on developing therapeutic antibodies for the treatment of cancer, autoimmune and other serious diseases. Dren Bio’s pipeline encompasses two distinct programs, the first focusing on the engineering of antibodies with enhanced antibody-dependent cellular cytotoxicity (ADCC) capabilities and the second revolving around its proprietary Targeted Myeloid Engager and Phagocytosis Platform.

DR-01 is a novel antibody targeting CD94 which is known to be upregulated on LGLL cells. DR-01 functions through depletion of target cells via ADCC by means of fratricide, a method in which the same cell type induces ADCC on each other. A Phase 1/2 trial is ongoing to assess the safety and efficacy of DR-01 in previously treated LGLL patients and cytotoxic lymphomas (NCT05475925).

DR-0201 is a first-in-class bispecific antibody capable of engaging tissue-resident and trafficking myeloid cells to induce deep B cell depletion via targeted phagocytosis. DR-0201 is currently being evaluated in a Phase 1 study in B-NHL patients (NCT06392477).