Related Experiment Video
Updated: Jun 15, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Previously unrecognized and potentially consequential challenges facing Hsp90 inhibitors in cancer clinical trials
Cheng Chang1, Xin Tang1, David T Woodley1
1Department of Dermatology and USC-Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, CA 90033, USA.
Abstract:
Targeting the heat shock protein-90 (Hsp90) chaperone machinery in various cancers with 200 monotherapy or combined-therapy clinical trials since 1999 has not yielded any success of food and drug administration approval. Blames for the failures were unanimously directed at the Hsp90 inhibitors or tumors or both. However, analyses of recent cellular and genetic studies together with the Hsp90 data from the Human Protein Atlas database suggest that the vast variations in Hsp90 expression among different organs in patients might have been the actual cause. It is evident now that Hsp90β is the root of dose-limiting toxicity (DLT), whereas Hsp90α is a buffer of penetrated Hsp90 inhibitors. The more Hsp90α, the safer Hsp90β, and the lower DLT are for the host. Unfortunately, the dramatic variations of Hsp90, from total absence in the eye, muscle, pancreas, and heart to abundance in reproduction organs, lung, liver, and gastrointestinal track, would cause the selection of any fair toxicity biomarker and an effective maximum tolerable dose (MTD) of Hsp90 inhibitor extremely challenging. In theory, a safe MTD for the organs with high Hsp90 could harm the organs with low Hsp90. In reverse, a safe MTD for organs with low or undetectable Hsp90 would have little impact on the tumors, whose cells exhibit average 3-7% Hsp90 over the average 2-3% Hsp90 in normal cells. Moreover, not all tumor cell lines tested follow the "inhibitor binding-client protein degradation" paradigm. It is likely why the oral Hsp90 inhibitor TAS-116 (Pimitespib), which bypasses blood circulation and other organs, showed some beneficiary efficacy by conveniently hitting tumors along the gastrointestinal track. The critical question is what the next step will be for the Hsp90 chaperone as a cancer therapeutic target.
Insights
Heat shock protein-90 (Hsp90) inhibitors failed in cancer trials due to organ-specific expression variations. Hsp90α acts as a toxicity buffer, while Hsp90β drives dose-limiting toxicity, making a safe maximum tolerable dose challenging.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Heat shock protein-90 (Hsp90) chaperone inhibition has been extensively explored in cancer therapy, with over 200 clinical trials since 1999 failing to achieve FDA approval.
- Previous failures were attributed to Hsp90 inhibitors, tumors, or both, overlooking significant inter-organ expression variability of Hsp90 in patients.
Purpose of the Study:
- To investigate the role of Hsp90 expression heterogeneity across different organs as a potential cause for the lack of success in Hsp90-targeted cancer therapies.
- To elucidate the distinct roles of Hsp90α and Hsp90β isoforms in mediating drug toxicity and efficacy.
Main Methods:
- Analysis of cellular and genetic studies.
- Examination of Hsp90 expression data from the Human Protein Atlas database.
- Review of clinical trial outcomes for Hsp90 inhibitors.
Main Results:
- Hsp90β is identified as the primary driver of dose-limiting toxicity (DLT), whereas Hsp90α acts as a buffer against inhibitor-induced toxicity.
- Significant variations in Hsp90 expression exist across organs (e.g., absent in the eye, abundant in the liver), complicating the establishment of a safe maximum tolerable dose (MTD).
- Some tumor cell lines do not adhere to the expected inhibitor binding-client protein degradation pathway, and oral inhibitors like TAS-116 show efficacy by targeting gastrointestinal tumors.
Conclusions:
- Organ-specific Hsp90 expression variability is a critical factor hindering the development of effective Hsp90 inhibitors for cancer treatment.
- Understanding the differential roles of Hsp90α and Hsp90β is crucial for designing safer and more effective Hsp90-targeted therapies.
- Future strategies may need to consider targeted delivery or focus on specific Hsp90 isoforms or expression patterns to overcome toxicity and efficacy challenges.
More Related Videos
07:57Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
09:39Exploring Biomolecular Interaction Between the Molecular Chaperone Hsp90 and Its Client Protein Kinase Cdc37 using Field-Effect Biosensing Technology
Published on: March 31, 2022
Related Concept Videos
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...