Abstract 4504: Targeting cMYC in metastatic castration resistant and neuroendocrine prostate cancer

Prostate cancer is the most common cancer in men and the second leading cause of cancer death among men in the United States according to the National Cancer Institute. Current treatment modalities involve prostatectomy, androgen receptor blockade and supportive/palliative care. Despite these treatment options, metastatic castration resistant prostate cancer and neuroendocrine prostate cancer still have very dismal clinical outcomes. Therefore, there is a need to understand the biology of the aggressive prostate cancer subtypes to identify novel targetable molecules. The castration resistant prostate cancer, neuroendocrine prostate cancer and the metastatic prostate cancers that recur have c-MYC amplification. These cancers are not responsive to androgen blockade or deprivation therapy. Attempts to target c-MYC have been difficult due to the intrinsic disordered nature of c-MYC. Various approaches have been attempted to control c-MYC; namely RNAi which has high off target effects, anti-sense oligonucleotides (ASO) which have low cellular penetrance and needs phosphorothioate modification, G-quadruplex inhibitors which are unspecific as they block POLII, the BRD4 and CDK inhibitors which are indirect inhibitors of c-MYC. Only OmoMyc a bHLH domain mutant with enhanced leucine zipper dimerization is in phase 1 trials with limited bioavailability. To explore the possibility of targeting c-MYC in these difficult-to-treat prostate cancers, we transfected C4-2B, a cellular model of metastatic castration resistant prostate cancer, with engineered destabilized 3‘UTR AU rich element of c-MYC. We found that we degraded c-MYC transcript and protein and killed the cancer cells. Taken together, we offer preliminary evidence that we can directly target c-MYC and inhibit these difficult-to-treat cancers. In vivo studies to validate these findings are ongoing.

Citation Format: Chidiebere U. Awah, Olorunseun O. Ogunwobi. Targeting cMYC in metastatic castration resistant and neuroendocrine prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4504.