OCT 11, 2017 7:30 AM PDT

Keynote Presentation: Targeting Molecular Chaperones in Cancer: Lessons Learned from HSP90

Speaker

Abstract

The first small molecule inhibitor of the molecular chaperone Heat Shock Protein 90 (HSP90) was identified more than 20 years ago. Upon determination of the drug binding site and clarification of its mechanism of action, HSP90 was validated as an anti-cancer molecular target, robust preclinical activity was demonstrated, and the first clinical trials of an HSP90 inhibitor in cancer patients were initiated several years later. Since then, additional natural product and synthetic HSP90 inhibitors have been identified and many have been clinically evaluated. As a class, these inhibitors are ATP-competitive and inhibit the ATPase driven HSP90 chaperone cycle, causing degradation of HSP90-dependent proteins (termed clients), including many oncogenes, via the proteasome. While numerous clinical trials have been performed with HSP90 inhibitors and encouraging data have been obtained, no HSP90 inhibitor has yet received FDA approval. One consequence of HSP90 inhibition is upregulation of the cytoprotective heat shock response, a broad transcriptional response to proteotoxic stress that is regulated by the transcription factor Heat Shock Factor 1 (HSF1). HSF1 also mediates a cancer-specific transcriptional program. HSP90 is proposed to sequester HSF1 in unstressed cells, but there is little evidence to support this model. A better mechanistic understanding of the role of HSP90 in modulating HSF1 may facilitate improved clinical activity of HSP90 inhibitors. We recently showed that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both constitutive and heat-induced HSF1 transcriptional activity. Not only do these suggest a role for HSP90 in feedback regulation of the proteotoxic stress response, but this characteristic of current HSP90 inhibitors likely contributes to lack of robust clinical response and we are currently evaluating several strategies that target HSP90 inhibitor effects on HSF1 without impacting HSP90 inhibitor-mediated degradation of oncogenic clients. Finally, a consistent property of HSP90 inhibitors to concentrate in tumors and to remain for an extended time period compared to normal tissues has prompted the use of HSP90 inhibitors as intracellular delivery vehicles to direct and concentrate conjugated cytotoxic agents in tumor while sparing normal tissues. This strategy extends the potential clinical utility of HSP90 inhibitors in cancer and a Phase 1 trial of such an HSP90-drug conjugate is underway.


Show Resources
You May Also Like
MAY 11, 2021 10:00 AM PDT
C.E. CREDITS
MAY 11, 2021 10:00 AM PDT
Date: May 11, 2021 Time: 10:00zm PDT Your samples are some of the most valuable assets in the laboratory. After spending countless hours on extraction and preparation, your conclusions could...
SEP 14, 2021 7:00 AM PDT
C.E. CREDITS
SEP 14, 2021 7:00 AM PDT
Date: September 14, 2021 Time: 7am PDT, 10am EDT, 4pm CEST A conventional thermal cycler has long been a commodity product in the lab and end-point PCR techniques can be completed almost wit...
JUN 09, 2021 7:00 AM PDT
C.E. CREDITS
JUN 09, 2021 7:00 AM PDT
Date: June 9, 2021 Time: 09 June 2021, 7am PDT, 10am EDT, 4pm CEST cells with dramatic implications on the validity of past cell culture related research. The fact that at least 509 cell lin...
APR 01, 2021 8:00 AM PDT
C.E. CREDITS
APR 01, 2021 8:00 AM PDT
Date: April 01, 2021 Time: 8:00am (PST), 11:00am (EST) Generating therapeutic antibodies is far more challenging than obtaining antibodies that merely recognize their targets. Engineering po...
JUL 15, 2021 9:00 AM PDT
JUL 15, 2021 9:00 AM PDT
Date: July 15, 2021 Time: 9:00am (PDT), 12:00pm (EDT) The Pisces workflow robust, easy-to-use, end-to-end multi-omics solution for highly multiplexed targeted Spatial RNA analysis. VeranomeB...
APR 21, 2021 5:00 PM CEST
APR 21, 2021 5:00 PM CEST
Date: April 21, 2021 Time: 8:00am (PDT), 11:00am (EDT), 5:00pm (CEST) Spatial Answers Trilogy - Spatial Answers in Immunology Immunology Researchers share their Spatial Discoveries in SARS-C...
OCT 11, 2017 7:30 AM PDT

Keynote Presentation: Targeting Molecular Chaperones in Cancer: Lessons Learned from HSP90


Specialty

Cancer

Health

Research And Development

Personalized Medicine

T-Cells

Earth Science

University

Analytical Chemistry

Disease

Research

Biochemistry

Wellness

Geography

Asia67%

North America33%

Registration Source

Website Visitors100%

Job Title

Medical Laboratory Technician100%

Organization

Medical Center33%

Ambulatory Care33%

Manufacturer - Other33%


Show Resources
Loading Comments...
Show Resources