Cancer Biology Program

Address

185 John Morgan Building
3620 Hamilton Walk
Philadelphia, PA 19104-4268

Office tel.: 215-898-0076
Lab tel.: 215-898-0078
Fax: 215-898-0090
E-mail: koumenis@xrt.upenn.edu

Education

Aristotle University, Greece, BS (Honors), Pharmacy. 1989

University of Houston, TX, Ph.D. Biochemistry, 1994.

Stanford Univ. School of Medicine, CA, Postdoctoral Training, Cancer Biology, 1999.

Research Interests

• Tumor hypoxia, Unfolded Protein Response, translational regulation of gene expression.

Key words: Tumor hypoxia, translation, apoptosis, angiogenesis, radiation, chemotherapy

Search PubMed for articles

Description of Research

A. Tumor hypoxia and its role in tumor progression. Hypoxia is a dynamic feature of the tumor microenvironment that contributes to cancer progression. We are trying to understand the molecular mechanisms that lead to adaptation of tumor cells to hypoxic stress and to develop strategies for targeting and inhibiting these adaptive processes in order to achieve better therapeutic outcomes in patients with solid tumors. Recent evidence from our lab and others indicates that hypoxia activates components of the Unfolded Protein Response (UPR), a coordinated program that integrates translational regulation of gene expression and cellular adaptive responses to cellular adaptation to increased levels of unfolded proteins in the endoplasmic reticulum. We have shown that tumor cells with compromised UPR signaling are more sensitive to hypoxic stress in vitro and form tumors that grow slower in vivo. We are currently investigating the role of specific UPR targets, such as ATF4 and Chop in hypoxia resistance and whether clinically approved agents that induce ER stress are preferentially cytotoxic to hypoxic cells.

B. Development of novel chemo/radiosensitizers. The development of chemoresistance and radioresistance in solid tumors is a major reason for tumor recurrence and treatment failure. Another goal of our lab is to target molecular pathways implicated in chemo/radioresistance using novel modalities, by either screening chemical libraries consisting of small molecule compounds with good pharmacophore scores or employing gene therapy approaches combined with targeted radiation delivery modalities, in order to increase the effectiveness of radiotherapy on solid tumors.

Recent Publications

Bi, M., Hu, N., Blais, J., Fels, D., Koritzinsky, M., Naczki, C., Harding, H., Novoa, I., Kaufman, R., Ron, D., Bell, J., Wouters B. G., and Koumenis, C. (2005). ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 24:3470-81.

Koritzinsky. M., Dostie, J., Pyronnet, S. Jaime J., Bell, J., Lambin, P., Pettersen, E.O., Koumenis, C., Sonenberg N., and Wouters, B.G. (2006). Hypoxia inhibits cap-dependent mRNA translation through eIF4F. EMBO J. 25:1114-25.

Maxwell, P. and Koumenis, C. (2006). Low Oxygen stimulates the Intellect: Meeting report of Keystone Symposium on “Hypoxia and Development, Physiology and Disease”, in Breckenridge, CO. EMBO Rep., 7:679-684.

Hart L.S., Ornelles D.O., Koumenis C. (2007). The adenoviral E4ORF6 protein induces atypical apoptosis in response to DNA damage. J Biol Chem. 282:6061-7.

Lally B.E., Geiger G.A., Kridel S., Arcury-Quandt A.E., Robbins M.E., Kock N.E, Wheeler K., Peddi P., Georgakilas A., Kao, G.D. and Koumenis C (2007) . Identification and biological evaluation of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library. Cancer Res., in press.

Lab

• Our lab and others have shown that components of the Unfolded Protein Response (UPR) contribute to tumor cell survival under stress and contribute to tumor growth (see Bi et al., 2005, Fels and Koumenis, 2006). Using a combination of genetic and biochemical approaches, we'd like to determine the role of the UPR component ATF6 in resistance to tumor hypoxia. This will determine whether this protein is a valid target for anti-tumor approaches and consequently a valid target for screening for inhibitors of its activity.
• Using a high-throughput screening assay, we identified a class of novel and potent small molecule radiation sensitizers which increase the cytotoxic potency of ionizing radiation without themselves exhibiting significant cytotoxicity (Lally et al, Cancer Res., in press). A rotation project is available to further analyze the mechanism of action of these compounds which are hypothesized to act as inhibitors of the double-stranded DNA repair machinery in cancer cells