Abstract 3050: Targeting SREBP-driven transcriptional programs in metastatic prostate cancer

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among men in the United States. Metastasis is the major cause of mortality associated with prostate cancer, and despite the availability of targeted therapeutic agents, metastatic prostate cancer remains a lethal disease. Therefore, there is a significant unmet need to identify new drug targets and develop novel targeted therapeutic agents. Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors, comprising SREBP-1 and SREBP-2, that govern lipid homeostasis by regulating the expression of numerous enzymes involved in fatty acid and cholesterol synthesis (lipogenesis). The role of SREBPs in regulating non-lipogenic transcriptional programs is beginning to be elucidated. Published findings associate perturbation of SREBP-dependent transcriptional programs in the development, progression, and metastasis of various cancers, including PCa. Our analysis of publicly available patient datasets revealed increased gene expression for SREBPs in prostate tumors compared to normal prostate. Further, we discovered significantly higher gene expression for SREBPs in metastatic samples compared to primary prostate tumors. Moreover, we found significantly elevated levels of SREBPs in more invasive PC3M and C4-2B compared to the less invasive PC3 and LNCaP prostate cancer cell lines. Hence, we hypothesized that pharmacological inhibition of SREBPs might be an effective therapeutic strategy against metastatic prostate cancer. We have developed a novel boron-containing compound, BF175, which inhibits the expression and transcriptional activity of SREBPs, but the information on the anticancer action of BF175 in various cancers, including prostate cancer, is very limited. In this study, we investigated the SREBP-mediated anticancer activity of BF175 in prostate cancer. We found that BF175 inhibited the viability, proliferation, and metastatic potential as well as induced apoptosis in all prostate cancer cell lines tested. We also confirmed that BF175 inhibited the expression of SREBPs in the tested prostate cancer cell lines. Of note, BF175 exhibited significantly higher potency as an anticancer agent in more invasive prostate cancer cell lines compared to their less invasive counterparts. Taken together, our results demonstrate that BF175 shows promise as a novel anticancer agent that may improve outcomes in lethal metastatic prostate cancer. Citation Format: Prashanth Parupathi, Lakshmi Sirisha Devarakonda, Enkiel Francois, Bhaskar C Das, Avinash Kumar. Targeting SREBP-driven transcriptional programs in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3050.