A multi-institutional group of researchers and clinicians have developed a quicker and more accurate way of testing new prostate cancer treatments. The findings were recently published in European Urology.
Typically, new cancer treatments undergo pre-clinical testing on oversimplified cancer cells artificially grown in a lab, rather than on live tumors (as they are incredibly difficult to keep alive once they have been removed from the patient’s body).
Now a collaborative team has developed a new way to grow tumors in the lab, derived from donor patient tumors. These new lab-grown tumors are as complex as the tumors they are derived from, yet are able to be kept alive in the lab, enabling researchers to test the efficacy of a variety of drug combinations more quickly and efficiently than ever before.
Four new patient-derived xenografts (PDXs) were established from independent metastases of two patients and characterized using integrative genomics. A panel of rationally selected drugs was tested using an innovative ex vivo PDX culture system.
“The lab-grown tumors will accelerate cancer research so that scientific discoveries benefit patients sooner,” explained Gail Risbridger from Monash University (Melbourne, Australia).
The following drugs were evaluated: androgen receptor signalling inhibitors (enzalutamide and galeterone), a PARP inhibitor (talazoparib), a chemotherapeutic (cisplatin), a CDK4/6 inhibitor (ribociclib), bromodomain and extraterminal (BET) protein inhibitors (iBET151 and JQ1), and inhibitors of ribosome biogenesis/function (RNA polymerase I inhibitor CX-5461 and pan-PIM kinase inhibitor CX-6258).
Drug efficacy in ex vivo cultures of PDX tissues was evaluated using immunohistochemistry for Ki67 and cleaved caspase-3 levels. Candidate drugs were also tested for antitumor efficacy in vivo, with tumour volume being the primary endpoint.
Integrative genomics revealed that the new PDXs exhibited heterogeneous mechanisms of resistance, including known and novel androgen receptor mutations, genomic structural rearrangements of the androgen receptor gene, and a neuroendocrine-like AR-null phenotype. Despite their heterogeneity, all models were sensitive to the combination of ribosome-targeting agents CX-5461 and CX-6258.
“These pre-clinical tests can rapidly determine which drugs should be trialed in patients,” Risbridger added.
This study demonstrates that ribosome-targeting drugs may be effective against diverse castration-resistant prostate cancer subtypes including androgen receptor-null disease, and highlights the potential of contemporary patient-derived models to prioritize treatment strategies for clinical translation
To share these unique lab-grown tumors with researchers around the world, the team established the collaborative platform Melbourne Urology Research Alliance (MURAL), which is a consortium of scientists, urologists, oncologists, pathologists, computer scientists and patient representatives. Housing the largest collection of lab-grown prostate cancer tumors, MURAL provides scientists globally with the best tools to test new drugs to fight prostate cancer.
Sources: Lawrence MG, Obinata D, Shahneen S et al. Patient-derived models of abiraterone- and enzalutamide-resistant prostate cancer reveal sensitivity to ribosome-directed therapy Eur. Urol. doi:https://doi.org/10.1016/j.eururo.2018.06.020 (2018)(Epub ahead of print); www.eurekalert.org/pub_releases/2018-07/mu-ebt072418.php