My research program has a long standing interest in using mouse models to address the cellular, molecular, and genetic mechanisms of tumor progression. The functions of oncogenes and tumor suppressor genes are remarkably conserved between mice and humans and mouse models have and will continue to provide fundamental insights into the causes, prevention, and treatment of human cancer.
We use a range of inbred mouse strains as well as genetically engineered mice (GEM) as models to address the genetic basis of cancer. However cancer is more than a genetic disease and the environment plays a major role in human cancer. To address the interaction between environmental exposure and genetic predisposition, which ultimately dictates cancer risk, our laboratory has pioneered the combined use of carcinogen induced cancer models with genetic models of cancer. For example, these studies revealed a major role for p53 in inhibiting chemical and radiation induced cancer, identified the first example of tumor suppressor gene haploinsufficiency (e.g. p27/Kip1), a concept that is now widely accepted, and identified the epigenetic regulator CTCF as a tumor suppressor gene.
My lab continues to focus on the p53 pathway in tumor suppression, with published studies addressing the role of upstream regulators Atm (ataxia telangiectasia mutated), DNA-PK (DNA-dependent protein kinase), and p19Arf (alternative reading frame) in p53 activation, apoptosis, and tumor suppression. Collectively, these in vivo mouse model studies implicate oncogene signaling through Arf as the major upstream regulator of p53’s tumor suppressor activity and implicate this signaling pathway in cancer metastasis. Recently we, in collaboration with Dr. Galina Filippova used mouse models to demonstrate that the DNA binding protein CTCF (CCCTC binding factor) is a haploinsufficient tumor suppressor gene for multiple cancer types. As mutation or hemizygous loss of CTCF occurs in over 50% of human breast and endometrial cancers, our findings establish a major role for CTCF and epigenetic deregulation in human cancer. Other ongoing projects in my lab on the epigenetic basis of cancer include examining the transgenerational epigenetic effects of ionizing radiation on lung cancer.
With the realization that mouse models could be more effectively used in translational cancer research, my lab took on a central role in pioneering the use of mouse models in biomarker research for early detection of cancer. These studies overcame several technical and experimental bottlenecks for proteomic analysis of plasma and identified tumor specific signatures that are currently being tested in human samples for use as early detection biomarkers.
Targeted therapies represent the future of oncology treatment, yet most cancers still lack effective treatments. My lab is applying functional genetic RNA interference screening approaches to discover new cancer drug targets. Using arrayed well-based siRNA high throughput screens, we are identifying, genome wide, the entire set of druggable genes that are required for survival of cancer cells that carry defined mutations, but not normal cells. Through a process of prioritization involving bioinformatic approaches and the latest TCGA data followed by validation in preclinical models, we will are identifying novel targets for drug development.
In summary, my laboratory continues to generate fundamental insights into cancer causation and progression, we are advancing biomarker science to discover and validate biomarker for early detection of cancer, and we are leading a new initiative to discover and develop novel drug targets. Our team is optimistic that these efforts will lead to more effective treatments that are tailored to the patient’s genetic profile.