HSP90 specific nIR probe identifies aggressive prostate cancers: a translational study from preclinical models to a human pilot study

Current screening modalities for prostate cancer rely on serologic testing for PSA and transrectal biopsy; however, many prostate cancers behave indolently.Because aggressively growing tumors depend on oncogenic drivers, we hypothesized that we could identify early, but aggressive prostate cancer,by an imaging modality targeting Hsp90, a chaperone for many molecules involved in oncogenic signaling. Previously we observedgreater avidity ofa probe,consisting of a near infrared dye tethered to an Hsp90 inhibitor,for cancers with greatermetastatic potential. We now report that an Hsp90 inhibitor-linked near infrared dye with greater tissue penetration could detect prostate cancers in preclinical models and in a phase I human clinical trial. These data, demonstrating specific uptake into aggressive tumors, in conjunction with our prior observations on photodynamic therapy guided by Hsp90 expression support a theranostic approach todetect and treatearly aggressive prostatecancers. Overall design: The uptake of anear infrared (nIR)probe-linked to an HSP90 binding drug (designated HS196)was assessed in preclinical models of prostate cancerwith various biologic behaviors. A human phase I study assessed the safety and uptake of HS196 in prostate cancers of patients undergoing prostatectomy. Tumors were removed following treatment with probe and HS196+/neg cells from the tumor were sorted and analyzed by single cell RNAseq to identify the cell types taking up the probe.