Research Abstract
Our group is broadly interested in how genetic abnormalities within cancer cells influence their biology, and how that biology can in turn be exploited to therapeutic advantage. We address these questions through basic research studies of key tumor cell signaling pathways, complemented by genetic analysis of patient tumor samples conducted through our companion laboratory, the MGH Translational Research Laboratory (TRL). Our ability to work at the interface of basic tumor biology and therapeutic application is strongly supported by our network of collaborators and by the research and clinical infrastructure of the MGH Cancer Center.
The p53 Network in Cancer Biology and Therapy
The p53 tumor suppressor functions as a key nodal point for integrating cellular responses to DNA damage. As such, p53 regulates genes involved in diverse cellular processes including cell cycle progression, apoptosis, and angiogenesis. Our recent work has defined roles for the p53-related transcription factors p63 and p73 in breast, ovarian, and squamous cancers, including the refractory “triple-negative†breast cancer subtype which occurs commonly in BRCA1 mutation carriers. Our success in defining novel functional interactions within the p53 family provides new therapeutic possibilities for these treatment-refractory malignancies.
TOR Signaling and the p53-Regulated Stress Response
One gene to emerge from our efforts to identify new pathways regulated by p53 family members is REDD1, a critical negative regulator of the TOR kinase that modulates the activity of the Tuberous Sclerosis tumor suppressor complex. Most human tumors exhibit abnormalities of p53 and/or TOR signaling, and indeed our biochemical and in vivo studies have demonstrated that REDD1 itself functions in a novel tumor suppressor pathway. We are currently using animal models, in vitro studies and biochemical approaches to understand the mechanisms of REDD1-mediated tumor suppression.
Tumor Genotyping to Drive Personalized Cancer Therapy
Activation of diverse oncogenes (e.g. RAS, RAF, EGFR) through somatic mutation not only causes cancer, but is now known to be an important determinant of the clinical response to targeted therapeutics. Until recently, identifying such abnormalities was restricted to research settings, as the technologies required for routine, high-performance tumor genotyping were not available. At the MGH TRL we have developed and validated high-throughput clinical diagnostic platforms for broad-based tumor genetic analysis. The availability of tumor genotyping for our large cancer patient population is accelerating the clinical trials process and is providing remarkable new opportunities for translational research.
