Abstract Prostate cancer is a predominant cause of cancer related death in men and in most cases, it is difficult to diagnose and adequately monitor. Cancer cells entail targets for effective therapy; however, non-malignant cells do not because they are not expressed in the same way in a cancer cell as in normal cells. RalBP1 functions as a crucial mercapturic acid transporter, playing an essential role in cancer cell survival and therapy resistance. RalBP1 has been identified as the key to radiation and chemotherapy resistance as it is an overexpressed, multi-specific ATP-dependent transporter. Therefore, we investigated its involvement in modulating critical signaling proteins that influence upstream survival pathways and mechanisms responsible for chemo-radiotherapy resistance in prostate cancer. Evidence from in vitro cell cultures and in vivo tumor models suggests that cancer cell survival depends on RalBP1, as its inhibition or depletion results in selective toxicity toward malignant cells. By generating glutathione-electrophile conjugates (GS-Es) within cells, RalBP1 induces apoptosis in cancer cells. In vivo studies revealed that treatment of DU145 prostate cancer xenograft-bearing mice with RalBP1-directed agents; antibodies, siRNA, or antisense oligonucleotides that led to a marked suppression of tumor growth, even in already established subcutaneous tumors, and did so without signs of systemic toxicity. Interestingly, both RalBP1 antibodies, which block RalBP1-mediated transport function, and gene-silencing approaches such as siRNA and antisense, which diminish RalBP1 expression, demonstrate nearly equivalent tumor-regressive effects. This equivalence suggests that disrupting RalBP1 transport function at the cell membrane is sufficient to elicit an anticancer response. Collectively, these findings uncover a novel therapeutic potential for RalBP1 inhibition or depletion in prostate cancer and underscore its promise as a target for new treatment strategies. (This work was supported in part by the Department of Defense grant HT9425-25-1-0500. Funding from the Beckman Research Institute of City of Hope is also acknowledged). Citation Format: Sharad S. Singhal, Madhu Krishna, Prakash Kulkarni, David Horne, Ravi Salgia. RalBP1 inhibition: A novel therapy for prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7127.
Singhal et al. (Fri,) studied this question.