HSP90-Specific nIR Probe Identifies Aggressive Prostate Cancers: Translation from Preclinical Models to a Human Phase I Study
Abstract
A noninvasive test to discriminate indolent prostate cancers from lethal ones would focus treatment where necessary while reducing overtreatment. We exploited the known activity of heat shock protein 90 (Hsp90) as a chaperone critical for the function of numerous oncogenic drivers, including the androgen receptor and its variants, to detect aggressive prostate cancer. We linked a near-infrared fluorescing molecule to an HSP90 binding drug and demonstrated that this probe (designated HS196) was highly sensitive and specific for detecting implanted prostate cancer cell lines with greater uptake by more aggressive subtypes. In a phase I human study, systemically administered HS196 could be detected in malignant nodules within prostatectomy specimens. Single-cell RNA sequencing identified uptake of HS196 by malignant prostate epithelium from the peripheral zone (AMACR+ERG+EPCAM+ cells), including SYP+ neuroendocrine cells that are associated with therapeutic resistance and metastatic progression. A theranostic version of this molecule is under clinical testing.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 21, 2021
- Source ID
- 10.1158/1535-7163.mct-21-0334
Entities
People
- Amy Hobeika
- André Rogatko
- Chaitanya Acharya
- Erika J Crosby
- Herbert Kim Lyerly
- Ivan Spasojevic
- Jiaoti Huang
- Joshua D Ginzel
- Joshua Snyder
- Kensuke Kaneko
- Leonard M. Neckers
- Michael A. Morse
- Philip F. Hughes
- Rendon C. Nelson
- Takuya Osada
- Thomas J. Polascik
- Timothy Haystead
- Xiao-yi Yang
- Zachary C Hartman
Organizations
- Duke Cancer Institute
- Duke University
- Duke University Hospital
- National Cancer Institute
- United States Department of Defense