The search for new cancer treatments is slow – fewer drugs for cancer reach the clinic than for other diseases. The high failure rate is due to the paucity of effective experimental models for selecting the most promising drugs for clinical trials. The models are particularly poor for prostate cancer, one of the most common cancers in Australia, yet also one of the most difficult to grow in the laboratory. To address these challenges, we established a new collection of patient-derived xenografts (PDXs) of prostate cancer and used them to identify effective combination treatments.
The Melbourne Urological Research Alliance collection of PDXs currently includes 58 tumours spanning the clinical, pathological, and genomic spectrum of prostate cancer, from treatment-naïve primary tumours to metastases from men who failed current systemic therapies. The PDXs have diverse mechanisms of resistance to androgen receptor (AR)-directed therapies, including mutations, amplifications, and structural rearrangements of the AR gene, expression of AR variants, and transformation into aggressive AR-null phenotypes. To identify new therapies for these heterogeneous tumours, we treated PDXs with different combinations of compounds targeting the DNA damage repair pathway. This showed that the combination of talazoparib, a PARP inhibitor, and CX-5461, a small molecule inhibitor of RNA polymerase I, synergistically inhibits the growth of PDXs with diverse phenotypes of advanced prostate cancer. A Phase 1 trial of this combination therapy will commence in 2021 for men with metastatic castration-resistant prostate cancer.
In summary, our collection of contemporary preclinical models provides diverse tumours for testing new treatments for prostate cancer, such as the combination of talazoparib and CX-5461. This highlights the potential of patient-derived models to prioritise treatment strategies for clinical translation.