Abstract Metastatic prostate cancer (PCa) represents an unmet treatment need, with a 5-year survival rate of only 30%. MicroRNAs (miRNAs) are small noncoding RNAs that hold therapeutic promise for PCa and act as important tumor suppressors and pro-oncogenic factors in the prostate. The Kerscher lab identified the miR-888 cluster as preferentially enriched in human metastatic PCa cell lines and prostatic fluids from patients with high-grade PCa compared to low-grade or non-cancer patients. We showed that cluster members promoted prostate growth and aggressiveness in vitro, particularly miR-888 and miR-891a, and these miRNAs accelerated tumor load in mice. Reciprocally, inactivation of miR-888 and miR-891a using antisense oligos reversed these effects, highlighting their potential as antimiR targets for PCa. AntimiRs are valuable tools for inhibiting miRNA function, but current antimiR therapies require high dosage and suffer from poor tissue specificity. To address these shortcomings, the Kerscher lab collaborated with Dr. Raman Bahal’s group to test the efficacy of their acid-sensing peptide pHLIP (pH low insertion peptide) as a novel prostate tumor delivery reagent conjugated to peptide nucleic acids (PNAs) designed to inhibit miR-888 or miR-891a. We hypothesized that pHLIP-PNA-antimiRs against miR-888/-891a would allow efficient delivery to prostate tumors (with inherently acidic microenvironments) and inhibit progression to lethal disease. We also predicted more pronounced effects in castration-resistant PCa. Indeed, when endogenous miR-888/891a levels were analyzed by qRT-PCR across a panel of human PCa cell lines representing the spectrum of this disease, we noted that miR-888 Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2053.
Cain et al. (Fri,) studied this question.