Department Affiliation: Primary: Oncology
Degree: M.D., Ph.D., University of Chicago
Rank: Associate Professor
Telephone Number: 410-502-0678
Fax Number: 410-502-0677
E-mail Address: rudin@jhmi.edu
School of Medicine Address: Cancer Research Building I, Room 334, Baltimore, MD 21231
Molecular mechanisms of apoptosis, roles of apoptosis in carcinogenesis and therapeutic resistance, novel therapeutic development in animal models of cancer
My laboratory has focused on the roles of apoptotic regulation in carcinogenesis and therapeutic resistance. One approach we have taken is to study cell death pathways in a simpler system, the yeast S. cerevisiae. Through a genetic screen to identify factors in yeast that could be functionally replaced by human Bcl-xL, we identified a yeast gene, SVF1, which promotes yeast cell survival in response to a variety of cellular stressors. We are currently working on several aspects of SVF1 function in yeast and its potential parallels in mammalian apoptotic control.
In a screen for changes in apoptotic pathways following genotoxic exposure in mammalian cells, we found that transcription of the retrotransposable element Alu is markedly induced by multiple DNA-damaging agents. Alu elements comprise over 10% of the genome. We demonstrated that genotoxic exposure is associated with not only transcription but also with retrotransposition of Alu elements. This is the first demonstration of active Alu retrotransposition in an experimental model, and has general implications for understanding a fundamental aspect of genome structure.
We have been interested in the role of glycolytic regulation in apoptotic regulation: a consistent finding in response to DNA damaging agents is a marked inhibition of key regulators of glucose uptake and glycolytic metabolism. The same pathways, in fact, appear to be affected by multiple cell death triggers. We recently found that Akt and the downstream factor mTOR play a particularly key role in resistance to certain classes of chemotherapeutic agents, and have defined a feedback loop by which mTOR influences Akt activity.
Finally, we are interested in translating laboratory observations into novel cancer treatment. Among other agents, we are investigating a novel small molecule inhibitor of Bcl-2, which we have shown has single agent activity against small cell lung cancer xenografts. We are now testing this agent, as well as other novel therapeutics, in a series of lung cancer heterotransplants. These heterotransplants are lung tumors that have been directly transferred from patients to mice without intervening cell culture, an innovative model that we think may better reflect cancer growth in vivo. Clinical translation of several of these novel therapeutics is being pursued.
Representative Publications:
- Vander Heiden, M.G., Choy, J.S., Brace, J.L., Vander Weele, D.J., Harris, M.H., Prange, B., Kron, S.J., Thompson, C.B., and Rudin, C.M. Bcl-xL complements Saccharomyces cerevisiae genes that facilitate the switch from glycolytic to oxidative metabolism, J. Biol. Chem. 277:44870-44876, 2002. Pub Med Reference
- Karnauskas, R., Niu, Q., Talapatra, S., Plas, D., Greene, M., Crispido, J., and Rudin, C.M. Bcl-xL and Akt cooperate to promote leukemogenesis in vivo, Oncogene 22:688-698, 2003. Pub Med Reference
- Rudin, C.M., Yang, Z., Schumaker, L., Egorin, M.J., Zuhowski, E.G., and Cullen, K.J. Inhibition of glutathione synthesis reverses Bcl-2-mediated cisplatin resistance, Cancer Res. 63:312-318, 2003. Pub Med Reference
- Hagan, C.R., Sheffield, R., and Rudin, C.M. Human Alu retrotransposition in murine cells, Natl. Genet. 35:219-220, 2003. Pub Med Reference
- Elstrom, R.L., Bauer, D.E., Buzzai, M., Karnauskas, R., Harris, M.H., Plas, D.R., Zhuang, H., Cinalli, R.M., Alavi, A., Rudin, C.M., and Thompson, C.B. Akt stimulates aerobic glycolysis in cancer cells, Cancer Res. 64:3892-3899, 2004. Pub Med Reference
- Vander Weele, D.J., Zhou, R., and Rudin, C.M. Akt upregulation increases resistance to microtubule-directed chemotherapeutic agents through mTOR, Mol. Cancer Ther. 3:1605-1613, 2004. Pub Med Reference
- Brace, J.L., Vander Weele, D.J., and Rudin, C.M. Svf1 inhibits reactive oxygen species generation and promotes survival under conditions of oxidative stress in Saccharomyces cerevisiae, Yeast 22:641-652, 2005. Pub Med Reference
Other graduate programs in which Dr. Rudin participates:
