Charles M. Rudin

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 2 Room 544, 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-x_L, 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:

• Ross. H.J., Hart, L.L., Swanson, P.M., Rarick, M.U., Figlin, R.A., Jacobs, A.D., McCune, D.E., Rosenberg, A.H., Baron, A.D., Grove, L.E., Thorn, M.D., Miller, D.M., Drachman, J.G., Rudin, C.M.  A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma. Lung Cancer 54:69-77, 2006.  Pub Med Reference
  
• Hann, C.L., Rudin, C.M.  Fast, hungry, and unstable: finding the Achilles’ heel of small-cell lung cancer.  Trends Mol Med. 13:150-157, 2007.  Pub Med Reference

• Brace, J.L., Lester, R.L., Dickson, R.C., Rudin, C.M.  SVF1 regulates cell survival by affecting sphingolipid metabolism in Saccharomyces cerevisiae. Genetics. 175:65-76, 2007. Pub Med Reference

• Hagan, C.R., Rudin, C.M.  DNA cleavage and Trp53 differentially affect SINE transcription. Genes Chromosomes Cancer 46:248-260, 2007.  Pub Med Reference

• Azzoli, C.G., Krug, L.M., Miller, V.A., Rizivi, N.A., Kris, M.G., Dunne, M., Farmer, A., Pizzo, B., Tyson, L., Seeger, T., Coleman, B., Moore, E., Lastinger, L., Venkatraman, E., Rudin, C.M.   A Phase II tolerability study of cisplatin plus docetaxel as adjuvant chemotherapy for resected non-small cell lung cancer.  J. Thorac. Oncol. 2:638-644, 2007.  Pub Med Reference

• Reddy, P.S., Burroughs, K.D., Hales, L.M., Ganesh, S., Hay, C., Jones, B.H., Li, S., Skele, K.L., Vasko, A.-J., Yang, J., Watkins, D.N., Rudin, C.M., Hallenbeck, P.L.  Seneca Valley Virus: a systemically deliverable oncolytic picornavirus, and the treatment of neuroendocrine cancers.  J. Natl. Cancer Inst. 99:1623-1633, 2007.  Pub Med Reference

• Rudin, C.M., Salgia, R., Wang, X., Hodgson, L., Masters, G.A., Green, M., Vokes, E.E.  A randomized phase II study of carboplatin and etoposide with or without oblimersen, antisense bcl-2, for extensive stage small cell lung cancer. J Clin Oncol. 26:870-876, 2008.  Pub Med Reference

• Rudin, C.M., Liu, W., Desai, A., Karrison, T., Jiang, X., Janisch, L., Das, S., Ramirez, J., Fackenthal, D.L., Chen, P., Armstrong, D.K., Brahmer, J.R., Fleming, G.F., Vokes, E.E., Carducci, M.A., Ratain, M.J.   Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity.  J. Clin. Oncol. 26: 1119-11127, 2008.  Pub Med Reference

• Hann, C.L., Daniel, V.C., Hierman, J., Sugar, E., Cope, L., Lin, M., Watkins, D.N., Rudin, C.M.  Therapeutic efficacy of ABT-737, a selective inhibitor of Bcl-2, in small cell lung cancer.  Cancer Res. 68:2321-2328, 2008.  Pub Med Reference

• Riely, G.J., Rizvi, N.A., Kris, M.G., Milton, D.T., Solit, D.B., Rosen, N., Senturk, E., Azzoli, C.G., Brahmer, J.R., Seshan, V.E., Fogle, M., Ginsberg, M., Miller, V.A., Rudin, C.M.  Randomized phase 2 study of pulse erlotinib before or after carboplatin and paclitaxel in current or former smokers with stage IIIB or IV non-small cell lung cancer. J. Clin. Oncol. 27:264-270, 2009.   Pub Med Reference

• Daniel, V.C., Marchionni, L., Hierman, J.S., Rhodes, J.T., Devereux, W.L., Rudin, C.M., Yung, R., Dorsch, M., Parmigiani, G., Peacock, C., Watkins, D.N.  A primary xenograft model of small cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res. 69:3364-3373, 2009.  Pub Med Reference

• Rudin, C.M., Avila-Tang E, Samet JM.  Lung cancer in never smokers: a call to action. Clin. Cancer Res.  15:5622-5625, 2009.  Pub Med Reference

• Samet, J.M,. Avila-Tang, E., Boffetta, P., Hannan, L.M., Olivo-Marston, S., Thun, M.J., Rudin, C.M.  Lung cancer in never smokers: clinical epidemiology and environmental risk factors. Clin. Cancer Res. 15: 5626-5645, 2009.  Pub Med Reference

• Rudin, C.M., Avila-Tang, E., Harris, C.C., Herman, J.G., Hirsch, F.R., Pao, W., Schwartz, A.G., Vahakangas, K.H., Samet, J.M.  Lung cancer in never smokers: molecular profiles and therapeutic implications. Clin. Cancer Res.  15:5646-5661, 2009.  Pub Med Reference

• Von Hoff, D.D., LoRusso, P.M., Rudin, C.M., Reddy, J.C., Yauch, R.L., Tibes, R., Weiss, G.J., Borad, M.J., Hann, C.L., Brahmer, J.R., Mackey, H.M., Lum, B.L., Darbonne, W.C., Marsters, J.C., de Sauvage, F.J., Low, J.A.  Inhibition of the Hedgehog pathway in advanced basal cell carcinoma. New Engl. J. Med. 361:1164-1172, 2009.  Pub Med Reference

• Rudin, C.M., Hann, C.L., Laterra, J., Yauch, R.L., Callahan, C.A., Fu, L., Holcomb, T., Stinson, J., Gould, S.E., Coleman, B., LoRusso, P.M., Von Hoff, D., de Sauvage, F.J., Low, J.A.  Treatment of medulloblastoma with Hedgehog pathway inhibitor GDC-0449.  New Engl. J. Med. 361:1173-1178, 2009.  Pub Med Reference

• Yauch, R.L., Dijkgraaf, G.J.P., Alicke, B., Januario, T., Ahn, C.P., Holcomb, T., Pujara, K., Stinson, J., Callahan, A., Tang, T., Bazan, J.F., Kan, Z., Seshagiri, S., Hann, C.L., Gould, S.E., Low, J.A., Rudin, C.M., de Sauvage, F.J.  Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma.  Science 2009 (Epub ahead of print).  Pub Med Reference

Other graduate programs in which Dr. Rudin participates:

Anti-Cancer Drug Development Program