My research goals are centered on several overarching themes:
How do the constellations of mutations present within each tumor influence its behavior? In particular, what are the functional consequences of specific tumor-associated mutations, in isolation or in combination with other genetic alterations, including germline variation? How do environmental factors and comorbidities modulate these genetic phenotypes?
Does the order in which mutations are acquired influence the characteristics of a tumor? How can we reconcile the observation of frequent somatic mutant clonal expansions in phenotypically normal tissues? Can we manipulate which mutant clones are expanded, allowing them to outcompete tumorigenic clones?
How can we efficiently leverage real-world clinicogenomics to reveal clinically relevant insights from cancer genomes? Can serial ctDNA sampling serve as a "naturally-occurring" functional genomic screen for mutations affecting therapeutic responses?
What are the molecular mechanisms underlying tumor plasticity (e.g. transdifferentiation and dedifferentiation)? Can tumor plasticity act as a key driver of immune evasion? How can we block the ability of tumors to utilize these strategies and thereby evolve resistance against therapies?
Why are the genetic factors that promote resistance to T cell killing in vitro so rarely identified in patient cohorts undergoing immunotherapy? From better understanding this disconnect, can we rationally design new therapeutic approaches to increase the proportion of patients that respond to immunotherapy?