A Cercek

A Grothey

A Thiel

AN Tse

BR Hirsch

C Moser

CL Kline

D Zhou

DA Proia

David A. Proia

Donald L. Smith

DS Rocha da

DV Catenacci

GP Nagaraju

H Machida

J Acquaviva

J Bartek

J Sang

J Trepel

JC Friedland

Jim Sang

JS Russell

JW Goldman

KH Lee

KS Bisht

L Neckers

L Whitesell

LC Cummings

M Meyers

M Taipale

M Zouhairi El

MA Socinski

Manuel Sequeira

N Gandhi

R Siegel

Richard C. Bates

S Aparo

S He

S Pakneshan

Suqin He

T Segawa

T Shimamura

T Taldone

TT Koll

U Banerji

W Xu

W Ying

X Yin

Y Li

Z Saridaki

SummaryThe integration of targeted agents to standard cytotoxic regimens has improved outcomes for patients with colorectal cancer (CRC) over recent years; however this malignancy remains the second leading cause of cancer mortality in industrialized countries. Small molecule inhibitors of heat shock protein 90 (HSP90) are one of the most actively pursued classes of compounds for the development of new cancer therapies. Here we evaluated the activity of ganetespib, a second-generation HSP90 inhibitor, in models of CRC. Ganetespib reduced cell viability in a panel of CRC cell lines in vitro with low nanomolar potency. Mechanistically, drug treatment exerted concomitant effects on multiple oncogenic signaling pathways, cell cycle regulation, and DNA damage repair capacity to promote apoptosis. Combinations of ganetespib and low-dose ionizing radiation enhanced the radiosensitivity of HCT 116 cells and resulted in superior cytotoxic activity over either treatment alone. In vivo, the single-agent activity of ganetespib was relatively modest, suppressing HCT 116 xenograft tumor growth by approximately half. However, ganetespib significantly potentiated the antitumor efficacy of the 5-Fluorouracil (5-FU) prodrug capecitabine in HCT 116 xenografts, causing tumor regressions in a model that is intrinsically resistant to fluoropyrimidine therapy. This demonstration of combinatorial benefit afforded by an HSP90 inhibitor to a standard CRC adjuvant regimen provides an attractive new framework for the potential application of ganetespib as an investigational agent in this disease.</jats:p

Crossref

Investigational New Drugs

The HSP90 inhibitor ganetespib has chemosensitizer and radiosensitizer activity in colorectal cancer

https://link.springer.com/content/pdf/10.1007%2Fs10637-014-0095-4.pdf

The HSP90 inhibitor ganetespib has chemosensitizer and radiosensitizer activity in colorectal cancer

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