Home | News | Directories | Calendar | Maps | Contact Us | Webmail
Perelman School of Medicine at the University of Pennsylvania Advanced Search

Constantinos (Costas) Koumenis, Ph.D.

Constantinos (Costas) Koumenis, Ph.D.

faculty photo
Professor of Radiation Oncology
Department: Radiation Oncology
Graduate Group Affiliations

Contact information
University of Pennsylvania, Perelman School of Medicine
3400 Civic Center Blvd., Bldg 421
Smilow Center for Translational Research, Room 8-124
Philadelphia, PA 19104-5156
Office: 215-898-0076
Fax: 215-898-0090
Lab: 215-898-0078
Education:
BS (Pharmacy with honors)
Aristotle University, Thessaloniki, Greece, 1989.
PhD (Biochemistry)
University of Houston, Houston, Texas, 1994.
Permanent link
 
Perelman School of Medicine > Faculty > Search

Description of Research Expertise

KEYWORDS:
Tumor Microenvironment, Tumor Metabolism, Integrated Stress Response, drug screens, radiosensitizers.

RESEARCH INTERESTS:
Delineation of mechanisms of resistance to tumor microenvironmental stress, with emphasis on the Unfolded Protein Response in cancer. Development of small molecule agents to target these mechanisms as novel targeted modalities. Development of novel radiosensitizers.

My laboratory is primarily interested in two broad areas:

1. 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.

2. To increase the therapeutic effectiveness of ionizing radiation (IR) by either employing existing compounds with relatively safe toxicity profiles or employ screening strategies to identify novel and potent radiation sensitizers. We are also interested in developing novel delivery approaches for such compounds, such as biocompatible nanoparticles.

CONTRIBUTION TO SCIENCE:
1. My group was the first to demonstrate that hypoxia activates a translational control program known as the Integrated Stress Response (ISR), which adapts cells to endoplasmic reticulum (ER) and nutrient stress. We first identified that the ER resident kinase PERK is activated under hypoxia and phosphorylates the translation initiation factor eIF2. We then demonstrated that inactivation of ISR signaling by mutations/deletions in the ER kinase PERK and cytoplasmic kinase GCN2 impair cell survival under hypoxia or nutrient deprivation and result in reduced tumor growth in animal models, including sarcomas and colorectal tumors.
(a) Koumenis C*, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, Koromilas A, Wouters BG. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol. 2002 Nov;22(21):7405-16. PubMed PMID: 12370288; PubMed Central PMCID: PMC135664. * Corresponding Author
(b) Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 2005 Oct 5;24(19):3470-81. PubMed PMID: 16148948; PubMed Central PMCID: PMC1276162.
(c) Fels DR, Ye J, Segan AT, Kridel SJ, Spiotto M, Olson, M, Koong, A and Koumenis, C. Preferential cytotoxicity of bortezomib toward hypoxic tumor cells via overactivation of endoplasmic reticulum stress pathways. Cancer Res. 2008 Nov 15;68(22):9323-30. PubMed PMID: 19010906; PubMed Central PMCID: PMC3617567.
(d) Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN, Bobrovnikova-Marjon E, Diehl A, Ron, D, Koumenis C. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 2010 Jun 16;29(12):2082-96. PubMed PMID: 20473272; PubMed Central PMCID: PMC2892366.

2. More recently, we also demonstrated that c-Myc can induce cell-autonomous ER stress and that lymphomas with activated Myc rely on active UPR for survival. Moreover, in collaboration with Dr. Amaravadi’s group we showed that BRAF inhibitors activate cytoprotective autophagy via UPR activation, and targeting the PERK arm of the UPR with small molecule inhibitors overcomes resistance to BRAFi.
(a) Chitnis NS, Pytel D, Bobrovnikova-Marjon E, Pant D, Zheng H, Maas N, Frederick B, Kushner J, Chodosh L, Koumenis C, Fuchs SY, Diehl, A. miR-211 is a prosurvival microRNA that regulates chop expression in a PERK-dependent manner. Mol Cell. 2012 Nov 9;48(3):353-64. PubMed PMID: 23022383; PubMed Central PMCID: PMC3496065.
(b) Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, Qiu B, Zhang H, Cerniglia G, Bi M, Li Y, Gao Y, Liu H, Li C, Maity A, Thomas-Tikhonenko A, Perl AE, Koong A, Fuchs SY, Diehl JA, Mills IG, Ruggero D, Koumenis C. ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest. 2012 Dec;122(12):4621-34. PubMed PMID: 23143306; PubMed Central PMCID: PMC3533536.
(c) Dey S, Tameire F, Koumenis C. PERK-ing up autophagy during MYC-induced tumorigenesis. Autophagy. 2013 Apr;9(4):612-4. PubMed PMID: 23328692; PubMed Central PMCID: PMC3627677.
(d) Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, Lazova R, Klump V, Pawelek JM, Xu X, Xu W, Schuchter LM, Davies MA, Herlyn M, Winkler J, Koumenis C, Amaravadi RK. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest. 2014 Mar;124(3):1406-17. PubMed PMID: 24569374; PubMed Central PMCID: PMC3934165.

3. We have also been interested in basic mechanisms of radiation resistance and DNA repair and the interactions between virtal proteins and the DNA repair machinery.
(a) Dunlap N, Schwartz GG, Eads D, Cramer SD, Sherk AB, John V, Koumenis C. 1alpha,25-dihydroxyvitamin D(3) (calcitriol) and its analogue, 19-nor-1alpha,25(OH)(2)D(2), potentiate the effects of ionising radiation on human prostate cancer cells. Br J Cancer. 2003 Aug 18;89(4):746-53. PubMed PMID: 12915889; PubMed Central PMCID: PMC2376931.
(b) Hart LS, Yannone SM, Naczki C, Orlando JS, Waters SB, Akman SA, Chen DJ, Ornelles D, Koumenis C. The adenovirus E4orf6 protein inhibits DNA double strand break repair and radiosensitizes human tumor cells in an E1B-55K-independent manner. J Biol Chem. 2005 Jan 14;280(2):1474-81. PubMed PMID: 15507430.
(c) Hart LS, Ornelles D, Koumenis C. The adenoviral E4orf6 protein induces atypical apoptosis in response to DNA damage. J Biol Chem. 2007 Mar 2;282(9):6061-7. PubMed PMID: 17172468.
(d) Stewart RD, Yu VK, Georgakilas AG, Koumenis C, Park JH, Carlson DJ. Effects of radiation quality and oxygen on clustered DNA lesions and cell death. Radiat Res. 2011 Nov;176(5):587-602. PubMed PMID: 21823972.


ROTATION PROJECTS:
Currently the lab is accepting 2 new rotation students.

Selected Publications

Lehman SL, Cerniglia GJ, Johannes G, Ryeom S, Koumenis C: Translational upregulation of an individual p21Cip1 transcript variant by GCN2 regulates cell proliferation and survival under nutrient stress. PLoS Genet in press 2015.

Dey S, Sayers CM, Lehmans S, Cheng Y, Cerniglia G, Tuttle S, Feldman M, Zhang P, Fuchs S, Diehl AJ, Koumenis C: ATF4 regulates promotes metastasis via cooperative upregulation of Heme Oxygenase-1 with Nrf2. J Clin Invest in press 2015.

Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, Lazova R, Klump V, Pawelek JM, Xu X, Xu W, Schuchter LM, Davies MA, Herlyn M, Winkler J, Koumenis C, Amaravadi RK.: Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest 124(3): 1406-17, Mar 2014.

Guttmann D, Hart L, Du K, Seletsky A, Koumenis C: Inhibition of Hsp27 radiosensitizers head and neck cancer by modulating DNA repair. Intl. J. Radiat Oncol Biol Phys 87(1): 168-75, Sep 2013 Notes: granted supported.

Sayers CM, Papandreou I, Guttmann DM, Maas NL, Diehl JA, Witze ES, Koong AC, Koumenis C: Identification and characterization of a potent activator of p53-independent cellular senescence via a small-molecule screen for modifiers of the integrated stress response. Mol Pharmacol 83(3): 594-604, Mar 2013.

Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, Qiu B, Zhang H, Cerniglia G, Bi M, Li Y, Gao Y, Liu H, Li C, Maity A, Thomas-Tikhonenko A, Perl AE, Koong A, Fuchs SY, Diehl JA, Mills IG, Ruggero D, Koumenis C: ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest 122(12): 4621-34, Dec 2012.

Marotta D, Karar J, Jenkins WT, Kumanova M, Jenkins KW, Tobias JW, Baldwin D, Hatzigeorgiou A, Alexiou P, Evans SM, Alarcon R, Maity A, Koch C, Koumenis C: In vivo profiling of hypoxic gene expression in gliomas using the hypoxia marker EF5 and laser-capture microdissection. Cancer Res 71(3): 779-89, Feb 2011.

Chitnis NS, Pytel D, Bobrovnikova-Marjon E, Pant D, Zheng H, Maas NL, Frederick B, Kushner JA, Chodosh LA, Koumenis C, Fuchs SY, Diehl JA: miR-211 is a pro-survival micro-RNA that regulates chop expression in a PERK-dependent manner. Mol Cell 48(3): 353-64, Nov 2012.

Ye J, Kumanova M, Hart SL, Sloane K, Zhang H, De Panis DN, Bobrovnikova-Marjon E, Diehl A, Ron D, Koumenis C: The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBOJ 29(12): 2082-96, Jun 2010.

Bi M, Hu N, Blais J, Fels D, Koritzinsky M, Naczki C, Harding H, Novoa I, Kaufman R, Ron D, Bell J, Wouters BG, Koumenis C: ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 24(19): 3470-81, Oct 2005.

back to top
Last updated: 05/21/2015
The Trustees of the University of Pennsylvania