An Unexpected Antitumor Activity of Enzalutamide in Prostate Cancer
Almost all prostate cancer patients respond to androgen deprivation therapy initially. However, lethal disease, castration-resistant prostate cancer (CRPC), eventually occurs. It has become overwhelmingly clear that the residual androgens remaining after castration, along with the androgen receptor (AR), remain crucial for CRPC; this has led to second-generation antiandrogen therapies, such as abiraterone (ABI) and enzalutamide (ENZ). ABI inhibits CYP17A1, an enzyme required for androgen synthesis, whereas ENZ is a potent AR antagonist. Both prolong survival for patients with CRPC. However, some retrospective meta-analysis clinical studies suggest that ENZ is superior to ABI in both 1st and 2nd line treatment of CRPC. Recently, synergizing their effects by concurrently combining them or using one after the other has been proposed to maximize the clinical benefit. Nevertheless, several clinical trials suggest that a concurrent combination of ENZ and ABI offers no advantage over ENZ alone. In contrast, multiple prospective and retrospective clinical studies support the preferential use of ABI as first-line therapy, followed by ENZ. The biological mechanisms underlying these clinical observations remain unclear. In this project, we found an unexpected off-target effect of ENZ, which enhances its efficacy to battle prostate cancer. Follow-up work is ongoing to determine the mechanisms and develop more potent drugs that can cotarget AR and another promising protein we identified to tackle prostate cancer.
The Combination of Enzalutamide and PARP Inhibitor in Prostate Cancer
Poly(ADP-ribose) polymerase inhibitors (PARPis) target homologous recombination repair mutations
(HRRm) (especially, BRAC1 or 2 mutations) tumors by trapping PARP at sites of DNA damage, leading to replication fork collapse and cell death. However, recent clinical trials combining ENZ with the PARPi talazoparib demonstrated improved outcomes in patients lacking HRRm, suggesting additional mechanisms that remain unclear. Utilizing HRRm-free prostate cancer cell models, we show that PARPis suppress basal AR transcriptional activity, whereas ENZ primarily inhibits androgen-induced AR signaling. Combined ENZ and PARPi treatment further suppresses AR activity and decreases cell viability compared to either agent alone. Notably, knockout or overexpression of PARP1, PARP2, and PARP7 does not attenuate PARPi-mediated AR suppression, indicating that this effect occurs independently of PARP inhibition or trapping. While PARP1 loss shifts the IC 50 values for PARPis, the combination treatments remain effective. Collectively, these findings demonstrate that PARPis modulate AR signaling through PARP-independent mechanisms that complement AR inhibition by ENZ. These data further provide mechanistic insight into the clinical efficacy of ENZ and PARPis combination beyond patients harboring HRRm. In this project, we aim to identify the mechanism underlying the complementary effect of ENZ and PARPi on suppressing prostate cancer progression.
Alternative Molecules for Bipolar Androgen Therapy in Prostate Cancer Treatment
Another very exciting project we are working on is bipolar androgen therapy (BAT, AKA SPA, supraphysiological androgen) in prostate cancer treatment. Although most efforts in developing treatment strategies to tackle prostate cancer focus on inhibiting AR signaling, with treatments such as abiraterone and enzalutamide, abundant emerging evidence in both preclinical models and patients suggests that SPT (supraphysiological testosterone) treatment can cause regression of prostate cancer via cell-cycle arrest, DNA damage, etc., making SPA an alternative strategy for treating prostate cancer patients. However, SPT profoundly disrupts endocrine and cardiovascular homeostasis, leading to hypertension, fluid retention, thromboembolic risk, and metabolic abnormalities, which collectively restrict BAT to carefully selected patients and preclude its broader use. Moreover, despite promising clinical responses, resistance to BAT emerges in a substantial subset of prostate cancer patients, limiting the durability of benefit and posing a significant challenge in routine clinical practice. Therefore, treatment strategies that circumvent the systemic toxicity and resistance of SPT remain unmet needs. In this project, we aim to identify alternative molecules to replace testosterone to perform the BAT in prostate cancer, which can address the unmet needs of the treatment strategy.