Drug Resistance is a Major Drawback to Targeted Therapies
Targeted therapies, like the Bruton's tyrosine kinase inhibitor ibrutinib, have shown remarkable efficacy as cancer treatments. For example, approximately 90% of patients with chronic lymphocytic leukemia respond to treatment with ibrutinib. However, in ~60% of these cases, the therapy eventually fails.
Quantifying the Response of Lymphoma Cells to Therapy
To understand drug resistance in lymphoma, the James lab collects primary samples from subjects with lymphoma treated with ibrutinib and other targeted agents. We are using mass spectrometry-based proteomics and sequencing to determine how signaling is altered in lymphoma cells from patients on therapy.
Modeling the Effects of Mutation on Therapy Resistance
Using primary human B cells, we developed a murine model for non-Hodgkin's lymphoma. We use gene editing to introduce putative resistance-associated genetic variants into this lymphoma model. We measure the effects of these variants on B cell differentiation, lymphoma initiation, and response to drugs.
Identifying New Therapies That Target Drug Resistance
We employ screening and targeted testing (CRISPR and small molecule) to ask which genes and pathways are required in B cells and primary lymphoma cells for resistance to lymphoma drugs. The overall goal is to identify new drugs that will prevent or mitigate resistance to current lymphoma therapies.
