Low-Dose Hsp90 Inhibitor Selectively Radiosensitizes HNSCC and Pancreatic Xenografts.

Abstract

PURPOSE:

Treatment approaches using Hsp90 inhibitors at their maximum tolerated doses (MTDs) have not produced selective tumor toxicity. Inhibition of Hsp90 activity causes degradation of client proteins including those involved in recognizing and repairing DNA lesions. We hypothesized that if DNA repair proteins were degraded by concentrations of an Hsp90 inhibitor below those required to cause nonspecific cytotoxicity, significant tumor-selective radiosensitization might be achieved.

EXPERIMENTAL DESIGN:

Tandem mass tagged-mass spectrometry was performed to determine the effect of a subcytotoxic concentration of the Hsp90 inhibitor, AT13387 (onalespib), on global protein abundance. The effect of AT13387 on in vitro radiosensitization was assessed using a clonogenic assay. Pharmacokinetics profiling was performed in mice bearing xenografts. Finally, the effect of low-dose AT13387 on the radiosensitization of three tumor models was assessed.

RESULTS:

A subcytotoxic concentration of AT13387 reduced levels of DNA repair proteins, without affecting the majority of Hsp90 clients. The pharmacokinetics study using one-third of the MTD showed 40-fold higher levels of AT13387 in tumors compared with plasma. This low dose enhanced Hsp70 expression in peripheral blood mononuclear cells (PBMCs), which is a biomarker of Hsp90 inhibition. Low dose monotherapy was ineffective, but when combined with radiotherapy, produced significant tumor growth inhibition.

CONCLUSIONS:

This study shows that a significant therapeutic ratio can be achieved by a low dose of Hsp90 inhibitor in combination with radiotherapy. Hsp90 inhibition, even at a low dose, can be monitored by measuring Hsp70 expression in PBMCs in human studies.

• Authors: Ranjit K Mehta, Sanjima Pal, Koushik Kondapi, Merna Sitto, Cuyler Dewar, Theresa Devasia, Matthew J Schipper, Dafydd G Thomas, Venkatesha Basrur, Manjunath P Pai, Yoshihiro Morishima, Yoichi Osawa, William B Pratt, Theodore S Lawrence, Mukesh K Nyati
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 19 Pg. 5246-5257 (10 01 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32718999 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Benzamides
• HSP90 Heat-Shock Proteins
• Isoindoles
• Radiation-Sensitizing Agents
• (2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone

Topics

• Animals
• Benzamides (pharmacology)
• DNA Repair (drug effects, radiation effects)
• Dose-Response Relationship, Drug
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics)
• Heterografts
• Humans
• Isoindoles (pharmacology)
• Leukocytes, Mononuclear (drug effects)
• Mice
• Proteolysis (drug effects, radiation effects)
• Radiation Tolerance (drug effects, genetics)
• Radiation-Sensitizing Agents (administration & dosage, adverse effects)
• Squamous Cell Carcinoma of Head and Neck (drug therapy, genetics, pathology, radiotherapy)