Cancer - understanding its evolution and targeting its dependencies
University of Colorado Anschutz Medical Campus, Department of Medicine
The student should have passion and curiosity for biology and research. Prior coursework should include classes in biochemistry and molecular biology.
Our lab seeks to understand how carcinogenic conditions promote cancer evolution and to discover pathway dependencies in cancers that can be exploited therapeutically.
How cancer shapes evolution, and how evolution shapes cancer: For the former, we have developed an evolutionary based model for cancer development, Adaptive Oncogenesis. In this model, mutations (including oncogenic mutations) face fitness landscapes that vary with age or following carcinogen exposure. We propose that long-lived multicellular organisms have evolved stem cell populations with high fitness, not only as a means of efficiently maintaining a tissue, but also because high fitness in a cell population will oppose somatic evolution. Highly effective competition in a young healthy stem cell population serves to maintain the status quo, preventing somatic evolution. But in stem cell pools damaged by aging, irradiation or other insults, the fitness landscape will be dramatically altered. The fitness of the stem cell pool will be reduced, promoting selection for mutations and epigenetic events that improve fitness. Using mouse models, human samples and computational modeling, we are currently exploring how reduced progenitor cell fitness resulting from irradiation, inadequate diet, smoking or aging can select for adaptive oncogenic events and thereby promote the expansion and fixation of oncogenically initiated cells.
Discovering and targeting cancer dependencies: These studies in the DeGregori lab are geared towards the development of novel therapeutic strategies to treat leukemias and non-small cell lung cancers (NSCLC). We perform genome-wide screens using novel genetic methods to identify genes whose inhibition will synergize with current targeted therapeutics to eliminate cancer cells. Our screens have identified a number of genes that synergistically inhibit leukemia (including CML and AML) and NSCLC cells, in combination with clinically used targeted inhibitors, and these genes have been validated as therapeutic targets by using both pharmacological and genetic approaches. These studies could lead to discovery of adjuvants to current therapies that will more effectively treat or possibly even cure these devastating cancers.
Students will participate with others in the lab and at lab meetings. He/She will work under the guidance of a senior graduate student or a postdoctoral fellow in the lab. He/She will work with samples from mice or humans, mostly using cell culture models. He/She will present experimental results to the lab and the Cancer Center poster session.