Project 1: Combined Suppression of MYC as therapy for CRPC: the COSMYC trial

PROJECT 1 – PROJECT SUMMARY Prostate cancer cells (PCa) are highly adaptable in response to the tumor microenvironment. In response to chronic exposure to a low testosterone environment, Androgen Ablation Therapy (AAT)-resistant PCa cells adaptively autoregulate androgen receptor (AR) levels through overexpression and gene amplification to

sufficient levels to resume AR signaling. Under increasing pressure of androgen deprivation these AAT resistant cells become even more resistant to additional hormone therapy through overexpression of AR and other oncologic drivers such as MYC. Paradoxically, laboratory and clinical studies have demonstrated that AAT-

resistant cells with high AR are often growth inhibited following exposure to supraphysiologic levels of androgen (SPA). Additionally, AAT-resistant cells exposed to SPA adaptively decrease expression of AR leading to renewed sensitivity to androgen ablative therapies like enzalutamide (Enza). Based on these results, we

performed clinical studies evaluating the safety and efficacy of high dose T in men with asymptomatic metastatic AAT-resistant PCa. We termed this therapy “Bipolar Androgen Therapy” (BAT) to reflect rapid cycling between the polar extremes of supraphysiologic to near castrate levels of serum T over a treatment cycle. In summary,

in these trials we demonstrated that high dose T could be given safely to asymptomatic men with AAT-resistant PCa. Across the studies, we observed PSA50 and objective response in ~30% of men. Time to clinical/radiographic progression to BAT in this study and others is ~ 6 months. In the TRANSFORMER study,

195 men with AAT-resistant PCa progressing on Abi were randomized to receive BAT or Enza with subsequent crossover to the opposite arm. Remarkably, the median time to PSA progression and PSA50 response for patients receiving Enza after Abi was 3.8 months and 25% but was 10.9 months and 78% respectively for

patients who had BAT before Enza. These results confirm that BAT can increase the duration of response to AAT such as Enza. Preclinical models and analysis of tumor biopsies from patients pre-BAT from patients progressing on androgen receptor inhibitors demonstrate that AR inhibitor resistance is correlated with high AR

and MYC expression. These analyses further demonstrate that high pre-treatment AR activity predicts response to BAT. BAT also induces a rapid downregulation of the MYC oncogene that is associated with response. However, over time an adaptive decrease in AR and increase in MYC-expression is observed which drives

resistance to BAT. In PCa models, co-administration of BET bromodomain inhibitors with BAT produces profound decrease/loss of MYC expression that is associated with enhanced cell killing, even in cells that have developed resistance to BAT. Based on these results, our primary hypothesis is that the combination of BAT

with the bromodomain inhibitor ZEN-3694 will enhance cell killing due to rapid increase in AR and decrease in MYC signaling. Additionally, the combination of BAT + BET inhibitor will downregulate AR levels and inhibit MYC expression leading to enhanced response to Enza in AAT-resistant patients.