Tumors try to ‘escape’ from molecularly target therapies in many ways: cells ‘reprogram’ themselves in response to treatment by modifying their structure or functionality. Studying adaptive responses of cancer cells is therefore important to identify new drug combinations that can overcome cancer defenses: thanks to this type of analysis, the Gianni Bonadonna Foundation has developed a protocol for the evaluation of p38 inhibitors in localized prostate cancer in combination with enzalutamide and with or without abiraterone. We talk about it with the study chair Diego Tosi, scientific coordinator of the Foundation and head of the Early Clinical Trial Unit – Department of Medical Oncology of the Montpellier Cancer Institute in France.
«It has been recently demonstrated that extensive profiling of functional adaptive responses might provide a rational base to combine targeted treatments», Tosi says. «We recently studied the effects of hormonotherapy agents such as enzalutamide on tumor transcriptome and phosphokinome, demonstrating that MAPK p38 could constitute a rescue pathway in human prostate cancer cells treated with enzalutamide, and we hypothesized that a combination of enzalutamide and an inhibitor of p38 could have synergistic inhibitory effects on tumor cells. The data collected in vitro and in vivo indicate that enzalutamide and abiraterone (another hormonotherapy agent) when used alone induce the phosphorylation of p38, and that the addition of a kinase inhibitor can partially reverse the resistance in the cells; the three drugs combination is synergistic even in preclinical models of hormonotherapy-resistant prostate cancer».
The protocol of the phase 1b TARMAK study developed by Tosi for Gianni Bonadonna Foundation provides for the enrollment of patients with localized prostate cancer, to be treated with enzalutamide and a p38 inhibitor with or without abiraterone. «Our analyses have shown that the combination of hormonotherapy agents and p38 inhibitor is highly synergistic; the goal of the study, which we hope to start in the near future, is to verify it in humans given the very promising preclinical data», Tosi concludes.