Dr. Timothy J. McDonnell
The University of Texas MD Anderson Cancer Center
Department of Hematopathology
- Cell death
My laboratory is interested in defining the molecular genetic alterations that cumulatively result in transformation and tumor progression. We are particularly interested in how the products of oncogenes and tumor suppressor genes regulate apoptotic cell death. Much of the research in my lab is devoted to mechanistic studies focused on clinically relevant issues in cancer biology, for example, the therapeutic resistance of prostate cancer. A variety of approaches are employed varying from histopathology to molecular biology, and more recently biochemistry. Our research involves the use of patient material as well as established cell lines and genetically engineered strains of mice, some of which we generate in our laboratory. My lab was the first to document bcl-2 gene deregulation was not limited to lymphoid malignancies but occurred at high frequency in specific types of solid tumors. My laboratory is interested in the pathogenesis of cancer and the role of apoptosis resistance as a contributor to disease progression and therapeutic resistance. We have demonstrated that bcl-2 is an important contributor to these processes in human tissue samples in vitro, and in vivo using xenografts and a transgenic mouse model. The latter utilizes a probasin promoter to target bcl-2 expression specifically to the prostatic glandular epithelium in transgenic mice. This model provides the most convincing evidence that bcl-2 directly confers resistance to cell death induction by androgen ablation and can contribute to in vivo multistep prostate carcinogenesis. These studies have provided the necessary preclinical information for ongoing clinical trials at several cancer centers targeting bcl-2 in patients with advanced cancer. In order to study the coordinate regulation of cell death, cell division, and differentiation my laboratory has focused on the epidermal keratinocyte as a model system. More recently we have become involved with interdisciplinary efforts to apply selective cell death induction strategies in patients with advanced-stage cancers. These strategies are based on defining resistance mechanisms and developing therapies to sensitize, otherwise resistant, tumor cells to cell death induction. Ongoing studies are focused on several issues including defining signaling events mediated by sonic hedgehog relevant for multistep carcinogenesis, defining the basis of Ha-ras and bcl-2 complementation during multistep carcinogenesis in vivo, defining the mechanistic basis of bcl-2 inhibition of p53-mediated cell death, developing strategies to optimize cell death induction in cancer, use of high throughput expression profiling and tissue microarrays to characterize genomewide alterations in cancer and other tumor types to enable rational stratification of patients with cancer.
Office: MDA Y5.6006 (Unit 89)
Ph.D. - University of North Dakota - 1982
M.D. - Washington University - 1986