Harvard Catalyst Profiles

While therapies for cancer have improved dramatically over the past three decades, many patients will eventually stop responding to therapy as their cancers develop resistance and relapse. Identifying new approaches to overcome resistance is thus a major unmet medical need. At the same time, cytotoxic therapies introduce significant stress on normal tissues, such as the hematopoietic system driving the expansion of mutant clones and the development of therapy related leukemias. Understanding how this evolution occurs could help us prevent this devastating consequence of cancer therapy. My lab focuses on understanding how therapy exposure shapes the evolution of both malignant and native hematopoietic cells and how we can intervene to alter these process using a combination of human genetic studies, functional genomics, mouse models and detailed understanding of drug pharmacodynamics. Ongoing projects in my lab that would be amenable to student participation include: 1) Mechanistic studies of resistance to thalidomide analogs. This project utilizes whole genome CRISRP/Cas9 screens to identify novel pathways involved in mediating resistance to this class of drugs in multiple myeloma cells. Work is now focusing on understanding the role of the retinoic acid receptor in mediating thalidomide analog resistance. 2) Understanding the role of the DNA damage response in mediating clonal outgrowth in therapy related MDS and AML. This project combines insights from a genetically defined cohort of patients with therapy related MDS/AML with whole genome CRISPR/Cas9 screens to identify the pathways that when mutated allow for clonal expansion during treatment with cytotoxic therapy. Students would ideally have some experience with basic wet lab work such as molecular biology, tissue culture, etc.