Constantinos Koumenis, Ph.D.
Associate Professor

University of Pennsylvania School of Medicine
Department of Radiation Oncology
185 John Morgan Building
3620 Hamilton Walk
Philadelphia, PA 19104-6072
Office: (215) 898-0076
Lab: (215) 898-0078
Fax: (215)-898-0090
koumenis@xrt.upenn.edu

Publications
Koumenis Lab
Costas Koumenis CV

Research Interests

My laboratory is primarily interested in two broad areas:
A. To understand the mechanisms by which components of the microenvironment (e.g. hypoxia, low nutrient availability) interact with cellular survival/apoptotic pathways to produce a more resistant tumor phenotype. Once we understand the regulation and function of these survival pathways, we then design cell-based and assays to screen small molecule libraries for compounds that inhibit these processes and test them alone or in combination with genotoxic agents in several animal tumor models
B. To increase the therapeutic effectiveness of ionizing radiation (IR) by either employing existing compounds with relatively safe toxicity profiles or employt screening strategies to identify novel and potent radiation sensitizers.

A. Tumor hypoxia, low nutrient availability and their role in tumor progression and radio/chemoresistance. Areas of low oxygen tension (hypoxia), develop via multiple intrinsic and extrinsic mechanisms during tumor progression. In addition to being an impediment to radiotherapy and chemotherapy, tumor hypoxia acts as a selective pressure towards a more aggressive tumor phenotype, and is an independent prognostic factor that predicts for poorer overall patient survival irrespective of therapeutic modality. We are focusing our efforts in understanding how hypoxia regulates protein translation, since it is the most energy-expensive cellular process. We have shown that cells under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the Integrated Stress Response (ISR), which adapts cells to endoplasmic reticulum (ER) stress. Inactivation of ISR signaling by mutations in the ER kinase PERK and the translation initiation factor eIF2alpha, impair cell survival under hypoxia. Tumors derived from these mutant cell lines are smaller and exhibit higher levels of apoptosis in hypoxic areas compared to tumors with an intact ISR. Moreover, expression of ISR target proteins ATF4 and CHOP was noted in hypoxic areas of human tumor biopsy samples. We also have recently shown that inhibition of the ISR target ATF4 leads to inhibition of survival and proliferation in several tumor cells without other external stresses. These cells initially activate cytoprotective autophagy but succumb to the effects of low amino-acid availability, particularly asparagine, an amino acid involved in key energy metabolism pathways. Collectively, these findings demonstrate that activation of the ISR is required for tumor cell adaptation to tumor stresses suggest that this pathway is an attractive target for anti-tumor modalities. We are currently analyzing the role(s) of ATF4 in hypoxic and metabolic cell adaptation and the effect of pharmacological activators of ER stress as potential hypoxic cells cytotoxic agents.

Some relevant publications:

Ye J, Koumenis C. (2009) ATF4, an ER stress and hypoxia-inducible transcription factor and its potential role in hypoxia tolerance and tumorigenesis. Curr Mol Med. 9:411-6

Fels, D., Ye, J., Segan, AT., Kridel, S., Spiotto, M., Olson, M., Koong, A.C. and Koumenis, C (2008). Preferential cytotoxicity of bortezomib towards hypoxic tumor cells via overactivation of ER stress pathways. Cancer Res., 68:9323-30.

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., 8;25(5):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.

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.

Koumenis C., Naczki, C., Koritzinsky, M., Rastani, S., Diehl, A., Sonenberg, N. , Koromilas, A., and G. Wouters, BG. (2002) Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2. Mol. Cell Biol., 22: 7405-16


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 my lab is to target molecular pathways known to be implicated in chemo/radioresistance (e.g., oncogene activation, increased oxidative stress) using novel compounds with minimal or low toxicity against normal, untransformed cells, and thus have a good probability of entering the clinic. We are following a 3-pronged approach to this problem. The first approach use of naturally-occurring compounds (e.g., Curcumin, Vitamin D analogs) with established safety profiles through many years of use in complementary and alternative medicine. The second entails a gene therapy-based approach by delivery of an adenoviral protein (E4orf6) known to inhibit DNA double strand break repair to radiosensitize brain tumor cells. The third strategy involves an unbiased screening of chemical compound libraries for novel, tumor-specific radiosensitizers. Two compounds with desirable pharmacologic profiles with potent tumor-specific radiosensitizing properties have already been identified and in vivo studies have been initiated.

Some relevant publications:

Javvadi P., Segan A.T., Tuttle, S.W., and Koumenis, C. (2008) The chemopreventive agent curcumin is a potent radiosensitizer of human cervical tumor cells via increased ROS production and overactivation of the MAPK pathway. Mol. Pharmacol., 73:1491-501.

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., 67:8791-9.

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.

Hart, L., Yannone, S., Ornelles, D. and Koumenis, C. (2005) The Adenovirus E4orf6 protein inhibits double strand break repair and radiosensitizes human tumor cells in an E1B-55K-independent manner. J. Biol. Chem., 280: 1474–81.

Dunlap, N., Schwartz, G. G., Eads, D., Cramer, S. D., Sherk, A., John, V., Koumenis, C. (2003) 1alpha,25-dihydroxyvitamin D3 (Calcitriol) and its analogue, 19-nor-1alpha,25(OH)2D2, potentiate the effects of ionizing radiation on human prostate cancer cells. Br. J. Cancer, 89:46-53.

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