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Updated: Sep 23, 2026
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder
Helga Weber1,2, José R Valbuena3, Mustafa A Barbhuiya4
1Center of Excellence in Traslational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile.
Abstract:
Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.
Insights
Heat shock protein 90 (HSP90) inhibitors, like 17-AAG, show promise in treating gallbladder cancer (GBC). Preclinical studies demonstrate significant tumor reduction and apoptosis, suggesting HSP90 is a viable therapeutic target for GBC.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Gallbladder cancer (GBC) is an aggressive malignancy with limited treatment options and poor patient outcomes.
- Current therapies like chemotherapy and radiotherapy show poor response rates in GBC patients.
- Novel therapeutic strategies targeting molecular pathways are urgently needed to improve GBC treatment efficacy.
Purpose of the Study:
- To identify effective small molecule inhibitors against GBC cell lines.
- To evaluate the preclinical efficacy of HSP90 inhibitors in GBC models.
- To assess HSP90 expression in human GBC tumors to determine its therapeutic relevance.
Main Methods:
- Screening of 130 small molecule inhibitors on seven GBC cell lines.
- In vitro and in vivo evaluation of 17-AAG and geldanamycin (GA) in GBC models.
- Immunohistochemical analysis of HSP90 expression in 209 human GBC tissue samples.
Main Results:
- 17-AAG was identified as a potent inhibitor across multiple GBC cell lines.
- 17-AAG and GA reduced HSP90 target proteins (EGFR, AKT, ERK), inhibited cell viability and migration, and induced cell cycle arrest and apoptosis.
- In vivo, 17-AAG significantly reduced tumor size by 69.6% in a preclinical GBC model.
- HSP90 was expressed in 87% of human GBC tumors, with strong expression in 33%.
Conclusions:
- HSP90 inhibition represents a promising therapeutic strategy for gallbladder cancer.
- 17-AAG demonstrates significant preclinical antitumor activity against GBC.
- Targeting HSP90 may offer a new avenue for GBC treatment, especially with emerging HSP90 inhibitors.
