Chemical Biology and Translational Research

The goal of my program is to investigate the nature of chronic stress as it occurs in numerous diseases and aging. Our approach takes advantage of the way nature has evolved to control such stresses, and that is by a unique usage of the chaperome, referred to here as the chronic stress chaperome (CSC). The CSC is epigenetically and thermodynamically distinct from the housekeeping chaperome, and my lab has pioneered an approach to take advantage of such feature. By using innovative methods, we develop small molecule chemical tool sets specifically targeted to the CSC; these act as “sensors” of the CSC and, in turn, of the chronic stress-associated proteome. By the use of these unique tool sets we aim to understand, diagnose, and treat cellular processes associated with chronic stress. We address multiple mechanistic and biochemical questions less amenable to approaches that treat the chaperome as monolithic entity (i.e., the classical biochemical and genetic tools). We investigate in endogenous systems, both at the cellular and the organismal level, the inherent proteome changes and mechanisms that lead to disease, i.e., we can understand. By sensing disease states through the chemical tool set, we go beyond investigation; we identify, measure, and quantify, i.e., we can diagnose. By attacking specifically the CSC, we perturb the disease-causing proteome, and thus revert or slow the disease phenotype, i.e., we can treat. To summarize, we use a unique chemical biology approach targeted to the CSC to understand, diagnose, and treat cellular processes associated with chronic stress. The research group is interdisciplinary and functions with the understanding that we are able to discover and synthesize pharmacological agents, determine their mechanisms of action and significance in disease treatment, and ultimately develop rational strategies for their use in clinic. Soon after joining the lab, trainees are exposed to views from colleagues with diverse backgrounds and start to see problems from a new perspective, developing their understanding of cancer and of ways to combat it. They also learn to approach projects in a collaborative and interdisciplinary manner, which we believe are key to our success in the discovery and translation of novel therapeutic options. To successfully function in such diverse research interests, the lab relies on the services and input of several dedicated facilities available at MSK. We also rely on the expertise of numerous collaborators. Through my dual appointment in the Department of Medicine and the Program in Molecular Pharmacology, I have direct contact with and play a bridging role between the basic scientists and clinicians involved in these interdisciplinary efforts.

Publications

Identification of an allosteric pocket on human hsp70 reveals a mode of inhibition of this therapeutically important protein. Rodina A, Patel PD, Kang Y, Patel Y, Baaklini I, Wong MJ, Taldone T, Yan P, Yang C, Maharaj R, Gozman A, Patel MR, Patel HJ, Chirico W, Erdjument-Bromage H, Talele TT, Young JC, Chiosis G. Chem Biol. 2013 Dec 19;20(12):1469-80. doi: 10.1016/j.chembiol.2013.10.008. Epub 2013 Nov 14.

Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Patel PD, Yan P, Seidler PM, Patel HJ, Sun W, Yang C, Que NS, Taldone T, Finotti P, Stephani RA, Gewirth DT, Chiosis G. Nat Chem Biol. 2013 Sep 1. doi: 10.1038/nchembio.1335. [Epub ahead of print]

Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DaGama EM, Caldas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, Chiosis G. Nat Chem Biol. 2011 Sep 25;7(11):818-26. doi: 10.1038/nchembio.670.

Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo Y, Wu N, de Stanchina E, White J, Gross SS, Ma Y, Varticovski L, Melnick A, Chiosis G. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8368-73. doi: 10.1073/pnas.0903392106. Epub 2009 May 5.

Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Rodina A, Vilenchik M, Moulick K, Aguirre J, Kim J, Chiang A, Litz J, Clement CC, Kang Y, She Y, Wu N, Felts S, Wipf P, Massague J, Jiang X, Brodsky JL, Krystal GW, Chiosis G. Nat Chem Biol. 2007 Aug;3(8):498-507. Epub 2007 Jul 1.

Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90. He H, Zatorska D, Kim J, Aguirre J, Llauger L, She Y, Wu N, Immormino RM, Gewirth DT, Chiosis G. J Med Chem. 2006 Jan 12;49(1):381-90.

Office phone:
646-888-2235
Office fax:
646-422-0416
Laboratory phone:
646-888-2216/2238
Selected Achievements

AACR – Cancer Research and Prevention Career Development Award in Translational Lung Cancer Research, in Memory of Duffy Wall

Susan G. Komen Breast Cancer Translational Research Award

Frederick R. Adler Chair for Junior Faculty

Award for Drug Discovery Research for Frontotemporal Dementia

Top 5 percent cited author in Biology and Biochemistry 2010 (analysis by Thomson Reuters)

Translated from bench-to-bedside the Hsp90 inhibitor PU-H71 and the non-invasive companion diagnostic 124I-PU-H71 PET assay