Chemical Biology Program
The Gabriela Chiosis Lab
The goal of my program is to investigate stressor maladaptation mechanisms such as they occur in several diseases. Our approach takes advantage of the way nature has evolved to control such stressors, and that is by a unique usage of the chaperome, referred here as the epichaperome. The epichaperome, which we discovered, is structurally, dynamically and functionally distinct from the housekeeping chaperome, and my lab has pioneered an approach to take advantage of such features. By using innovative methods, we develop small molecule chemical toolsets specifically targeted to the epichaperome; these act as “sensors” of the epichaperome, and in turn, of the chronic stressor-associated proteome-wide malfunctions. By the use of these unique toolsets we aim to understand, diagnose and treat cellular processes associated with chronic stressors. 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 toolsets, we go beyond investigation; we identify, measure and quantify, i.e. we can diagnose. By attacking the epichaperome specifically, we perturb the disease-causing proteome, and in turn revert or slow the disease phenotype, i.e. we can treat.
To summarize, we use a unique chemical biology approach to understand, diagnose and treat cellular processes associated with chronic cellular stress. My 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 disease 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 diagnostics and therapeutics.
To successfully function in such diverse research interests, the lab relies on the services and input of several dedicated facilities available through the Tri-institutional program (MSKCC, Weill Cornell Medicine, Rockefeller U). It has also established a strong interdisciplinary and synergistic network of collaborations to facilitate the translation of our findings from bench to bedside, in both cancer and Alzheimer’s disease. Through my dual appointment in the Department of Medicine and the Program in Chemical Biology, I have direct contact with and play a bridging role between the basic scientists and clinicians involved in these interdisciplinary efforts.
The epichaperome is an integrated chaperome network that facilitates tumour survival. Rodina A, Wang T, Yan P, Gomes ED, Dunphy MP, Pillarsetty N, Koren J, Gerecitano JF, Taldone T, Zong H, Caldas-Lopes E, Alpaugh M, Corben A, Riolo M, Beattie B, Pressl C, Peter RI, Xu C, Trondl R, Patel HJ, Shimizu F, Bolaender A, Yang C, Panchal P, Farooq MF, Kishinevsky S, Modi S, Lin O, Chu F, Patil S, Erdjument-Bromage H, Zanzonico P, Hudis C, Studer L, Roboz GJ, Cesarman E, Cerchietti L, Levine R, Melnick A, Larson SM, Lewis JS, Guzman ML, Chiosis G. Nature. 2016 Oct 5. doi: 10.1038/nature19807.
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]
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.
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.
Gabriela Chiosis, PhD
- The Chiosis lab uses a unique chemical biology approach to understand, diagnose, and treat cellular processes associated with chronic molecular stress, with the ultimate goal of developing novel therapeutic options for use in the clinic.
- PhD, Columbia University
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
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Doctors and faculty members often work with pharmaceutical, device, biotechnology, and life sciences companies, and other organizations outside of MSK, to find safe and effective cancer treatments, to improve patient care, and to educate the health care community.
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Gabriela Chiosis discloses the following relationships and financial interests:
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