HSP90-Specific nIR Probe Identifies Aggressive Prostate Cancers: Translation from Preclinical Models to a Human Phase...

Area of Science:

• Oncology
• Biochemistry
• Molecular Imaging

Background:

• Prostate cancer requires methods to distinguish indolent from lethal forms, improving treatment strategies and reducing overtreatment.
• Heat shock protein 90 (Hsp90) is a critical chaperone for oncogenic drivers, including the androgen receptor, making it a potential target for cancer detection.

Purpose of the Study:

• To develop and evaluate a novel noninvasive probe for detecting aggressive prostate cancer by targeting Hsp90.
• To assess the sensitivity and specificity of the probe in preclinical models and a phase I human study.

Main Methods:

• A near-infrared fluorescing molecule (HS196) was developed by linking a fluorescent dye to an Hsp90-binding drug.
• HS196 uptake was evaluated in prostate cancer cell lines and in human prostatectomy specimens from a phase I study.
• Single-cell RNA sequencing was used to characterize HS196-positive cells.

Main Results:

• The HS196 probe demonstrated high sensitivity and specificity for detecting prostate cancer cell lines, with greater uptake in more aggressive subtypes.
• In human subjects, systemically administered HS196 was detected in malignant prostate cancer nodules.
• Single-cell RNA sequencing confirmed HS196 uptake by malignant prostate epithelium, including neuroendocrine cells associated with therapeutic resistance.

Conclusions:

• The Hsp90-targeting probe HS196 shows potential as a noninvasive diagnostic tool for aggressive prostate cancer.
• This approach may aid in differentiating indolent from lethal prostate cancers, guiding clinical treatment decisions.
• A theranostic version of HS196 is currently under clinical investigation.