Ganetespib and HSP90: Translating Preclinical Hypotheses into Clinical Promise

As with many physiologic processes that become subverted during tumorigenesis, the chaperoning activity of heat shock protein 90 (HSP90) is often exploited by cancer cells to confer aberrant proliferative, survival, and/or metastatic potential. Functional inhibition of HSP90 results in the degradati...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2014-03, Vol.74 (5), p.1294-1300
Main Authors: PROIA, David A, BATES, Richard C
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Drug Evaluation, Preclinical
HSP90 Heat-Shock Proteins - antagonists & inhibitors
HSP90 Heat-Shock Proteins - metabolism
Humans
Medical sciences
Neoplasms - drug therapy
Neoplasms - metabolism
Pharmacology. Drug treatments
Triazoles - pharmacology
Triazoles - therapeutic use
Tumors
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Summary:As with many physiologic processes that become subverted during tumorigenesis, the chaperoning activity of heat shock protein 90 (HSP90) is often exploited by cancer cells to confer aberrant proliferative, survival, and/or metastatic potential. Functional inhibition of HSP90 results in the degradation of its client proteins, in turn providing a means to concomitantly disrupt multiple oncogenic signaling cascades through one molecular target. Pharmacologic blockade of HSP90 has, therefore, emerged as an innovative and multifaceted approach for the development of new antineoplastic agents. However, no HSP90 inhibitors are currently approved for cancer therapy and the full promise of this class of agents is yet to be realized. This review focuses on the preclinical activity profile of ganetespib, a potent small-molecule inhibitor of HSP90, the characterization of which has provided important frameworks for the optimal design and application of HSP90 inhibitor-based strategies in a variety of cancer types. Beyond client protein-driven tumors, ganetespib can also potentiate the effects of other molecularly targeted and standard-of-care therapeutics while simultaneously overcoming drug resistance in multiple tumor types, thereby positioning this compound as the leading HSP90 inhibitor currently under clinical development.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-13-3263