Novel patient-derived 3D culture models to guide clinical decision-making in prostate cancer

Castration-resistant prostate cancer remains an incurable disease. The unmet clinical need to optimally select individual treatment options, and thereby maximize survival benefit, can be addressed by patient-specific preclinical models. Patient-derived organoids preserve original tumor characteristics and have shown potential for high-throughput assessments and coclinical drug testing, as highlighted for several cancer types in this review. This new patient-derived 3D culture technique and its downstream applications are the subjects of intense investigation in prostate cancer. Although challenges are not trivial, we expect a major impact on prostate cancer research, with a window of opportunities for early bench-to-bedside translation of new drug discoveries and guidance of patient-tailored disease management

Darolutamide added to docetaxel augments antitumor effect in models of prostate cancer through cell cycle arrest at the G1-S transition

Resistance to taxane chemotherapy is frequently observed in metastatic prostate cancer. The androgen receptor (AR) is a major driver of prostate cancer and a key regulator of the G1-S cell cycle checkpoint, promoting cancer cell proliferation by irreversible passage to the S-phase. We hypothesized that AR signaling inhibitor (ARSi) darolutamide in combination with docetaxel could augment antitumor effect by impeding the proliferation of taxane-resistant cancer cells. We monitored cell viability in organoids, tumor volume and PSA secretion in patient-derived xenografts (PDXs) and analyzed cell cycle and signaling pathway alterations. Combination treatment increased anti-tumor effect in androgen-sensitive, AR-positive prostate cancer organoids and PDXs. Equally beneficial effects of darolutamide added to docetaxel were observed in a castration-resistant model, progressive on docetaxel, enzalutamide and cabazitaxel. In vitro studies showed that docetaxel treatment with simultaneous darolutamide resulted in a reduction of cells entering the S-phase in contrast to only docetaxel. Molecular analysis in the prostate cancer cell line LNCaP revealed an upregulation of Cyclin Dependent Kinase inhibitor p21, supporting blockade of S-phase entry and cell proliferation. Our results provide a preclinical support for combining taxanes and darolutamide as a multimodal treatment strategy in metastatic prostate cancer patients progressive on ARSi and taxane chemotherapy.</p