CHIOSIS LAB MSKCC 

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A unique chemical biology approach to understand, diagnose, and treat cellular processes associated with chronic stress, with the ultimate goal of developing novel therapeutic options for use in the clinic.
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Experimental Drug Targets Misbehaving Proteins in Brain Cancer and Alzheimer’s Disease

Our team is developing drugs that target epichaperomes and restore normal cell functions. These drugs are in clinical trials for Alzheimer’s disease and different types of cancer.

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New paper published in Nature Communications

Read in Nature Communications on the challenges of discovering the epichaperome drug PU-AD in clinical evaluation in alzheimers and glioblastoma.

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On how a sugar changes a chaperone from a folding to a scaffolding protein and how that leads to interactome network alterations and disease

Our study reveals how a protein called GRP94, which is normally a “good guy” in the cell, turns bad when it has a sugar molecule added to it.

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Paper published in Cell Reports

Yan et al. show how N-glycosylation transforms a chaperone from a folding to a scaffolding protein that remodels protein connectivity, with the end result of proteome-wide dysfunction. This specific modification, exploited by cancer cells for enhanced fitness, is an actionable target in disease.

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Our Nat comm is featured in Neurology Today, the official news source of the American Academy of Neurology (AAN) andis chosen by the Editor for  Editor's Pick Podcast

Working in PS19 mice, which carry a transgenic mutant tau gene, researchers observed abundant epichaperome formation at three months in the hippocampus, amygdala, and other brain structures implicated in Alzheimer's disease, which preceded the appearance of tau pathology.
 

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News: Our paper features news from ALZFORUM

A new study reveals a sticky web of protein-protein interactions, centered on heat shock protein 90 (HSP90) and other chaperones, in the brains of people with AD. This network, not found in healthy tissue, appears to entangle a host of proteins that are normally involved in synaptic connectivity, learning, and memory. An HSP90 inhibitor called PU-AD, currently in early clinical trials for AD, breaks up the party, normalizing HSP90’s connections and improving synaptic function and cognition in mouse models of tauopathy or AD. The paper, from Gabriela Chiosis, Memorial Sloan Kettering Cancer Center, and Wenjie Luo, Weill Cornell Medical College, both in New York, appeared in Nature Communications on January 16.  

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New paper published in Nature Communications

Inda MC, Joshi S, Wang T, et al. The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction. Nat Commun. 2020;11(1):319. Published 2020 Jan 16. doi:10.1038/s41467-019-14082-5  

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NIH Featured Research: Faulty protein connections short-circuit brain in Alzheimer's disease

Stress-induced changes in protein connections in the brain contribute to the cognitive decline seen in Alzheimer’s disease. In mice, this malfunctioning protein network and its associated cognitive decline were reversed by an experimental drug, according to a recent study supported in part by NIA. The findings suggest a new way to look at how Alzheimer’s develops in the brain by focusing on protein networks.
 

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News: Study Reveals a New Way That Stress and Aging Lead to Alzheimer’s

Researchers find that a targeted approach being developed to treat certain cancers also appears to help rewire brain circuitry in Alzheimer’s disease.  

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News: Bull’s-Eye: Imaging Technology Could Confirm When a Drug Is Going to the Right Place

By combining an imaging agent with a targeted therapy, MSK researchers can determine which tumors are likely to respond to the drug and then confirm that the drug is reaching the tumor.  

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Our latest article was featured on the cover of the journal of Cancer Cell

Pillarsetty N, Jhaveri K, Taldone T, et al. Paradigms for Precision Medicine in Epichaperome Cancer Therapy. Cancer Cell. 2019;36(5):559–573.e7. doi:10.1016/j.ccell.2019.09.007