This project addresses the use of Hsp90 molecular chaperone -inhibitors to promote cancer cell death. The studies are focused on the mechanisms by which Hsp90 inhibitors synergize when combined with specific protein kinase inhibitors to promote apoptosis. Benzoquinoid ansamycins, including geldanamyin (GA), are compounds that inhibit Hsp90's ATPase activity and promote degradation of client kinases and transcription factors via the ubiquitin/proteasome system. Recent clinical trials with a derivative of GA, 17-AAG, showed that it is well tolerated. Furthermore, 17-AAG appears to be especially effective in promoting death of tumor cells compared with cells from healthy tissue. Hsp90 represents only one of many proteins that have been identified in a new wave of 'targeted'chemotherapeutics. Others include protein kinases (the prototype of targeted therapy), histone deacetyltransferases, the proteasome and anti-apoptotic proteins. In addition, there are many examples where combining therapies towards two targets promotes synergistic cancer cell killing. The mechanisms underlying this synergy likely reflects the way signaling pathways in general are organized into networks, whose robust character can withstand loss of a single component. Since Hsp90 has a general role in buffering signaling pathways, it could provide a basis for chemosensitizing cells to other drugs. Our studies are based on this rationale. In the first aim we will determine the specificity with which casein kinase II (CK2) and Hsp90 inhibitors promote apoptosis in cancer cells, based on preliminary studies. We will characterize the mechanisms of this effect by investigating pathways where CK2 and Hsp90 have a convergent function in cell survival.
In aim 2, we will identify additional protein kinases whose loss of function promotes apoptosis in the presence of Hsp90 inhibitors and characterize their roles in cell survival. Finally, we will examine how Akt sensitivity to Hsp90 inhibitors is modulated by cellular environment and how mutation in B-Raf affects its chaperone-dependence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA132378-02
Application #
7693676
Study Section
Special Emphasis Panel (ZCA1-SRRB-K (O1))
Program Officer
Wali, Anil
Project Start
2008-09-26
Project End
2013-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$1,630,014
Indirect Cost
Name
City College of New York
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
603503991
City
New York
State
NY
Country
United States
Zip Code
10031
Kodama, Hiroshi; Vroomen, Laurien G; Ueshima, Eisuke et al. (2018) Catheter-based endobronchial electroporation is feasible for the focal treatment of peribronchial tumors. J Thorac Cardiovasc Surg 155:2150-2159.e3
Nicolas, Laura; Cols, Montserrat; Choi, Jee Eun et al. (2018) Generating and repairing genetically programmed DNA breaks during immunoglobulin class switch recombination. F1000Res 7:458
Juarez, Michelle T; Kenet, Chloe M (2018) Translating Research as an Approach to Enhance Science Engagement. Int J Environ Res Public Health 15:
Zheng, Simin; Kusnadi, Anthony; Choi, Jee Eun et al. (2018) NME proteins regulate class switch recombination. FEBS Lett :
Palaniappan, Latha; Garg, Arun; Enas, Enas et al. (2018) South Asian Cardiovascular Disease & Cancer Risk: Genetics & Pathophysiology. J Community Health 43:1100-1114
Srimathveeravalli, Govindarajan; Abdel-Atti, Dalya; PĂ©rez-Medina, Carlos et al. (2018) Reversible Electroporation-Mediated Liposomal Doxorubicin Delivery to Tumors Can Be Monitored With 89Zr-Labeled Reporter Nanoparticles. Mol Imaging 17:1536012117749726
Del Ferraro, Gino; Moreno, Andrea; Min, Byungjoon et al. (2018) Finding influential nodes for integration in brain networks using optimal percolation theory. Nat Commun 9:2274
Eguchi, Takashi; Bains, Sarina; Lee, Ming-Ching et al. (2017) Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Patients With Stage I Non-Small-Cell Lung Cancer: A Competing Risks Analysis. J Clin Oncol 35:281-290
Gany, Francesca; Bari, Sehrish; Prasad, Lakshmi et al. (2017) Perception and reality of particulate matter exposure in New York City taxi drivers. J Expo Sci Environ Epidemiol 27:221-226
Fried, Eric S; Li, Yue-Ming; Gilchrist, M Lane (2017) Phase Composition Control in Microsphere-Supported Biomembrane Systems. Langmuir 33:3028-3039

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