Scientists at the Institute of Oncology Research (IOR, affiliated to USI) and The Institute of Cancer Research, London, in collaboration with researchers from the University of Padova, have made a very important discovery about mechanisms in the human intestine that could in the future change the therapeutic approach in cases of prostate cancer that has become resistant to castration. The study is published in the prestigious journal Science.
Castration-resistant prostate cancer (CRPC) is usually treated with androgen deprivation therapy (ADT), a therapy that decreases circulating androgen levels the main drivers of prostate cancer growth. However, after an initial response, tumors develop different mechanisms of resistance to ADT, often resulting in an unfavorable prognosis. Scientists at IOR in Switzerland and The Institute of Cancer Research, London (UK), have now identified a new mechanism of resistance that involve the gut microbiota. The human gastrointestinal tract harbours a complex and dynamic population of trillion of microorganisms, the gut microbiota, which exert a marked influence on the human body during homeostasis and diseases including cancer.
The intestinal microbiota of mice and patients developing CRPC is enriched in specific bacterial species. This is the discovery of the researchers of the Molecular Oncology group, directed by Prof. Andrea Alimonti, MD (Institute of Oncology Research, IOR, affiliated to USI). "These species – explains Prof Alimonti – are able to produce androgens from their metabolic precursors". In this way bacteria can fuel tumor growth even if patients are under ADT. In men androgens are normally produced by the testicles and the adrenal glands. Thus, the discovery that bacteria can contribute to a significant amount of circulating androgens is groundbreaking.
"Microbiota elimination through broad-spectrum antibiotic therapy can delay CRPC emergence", explain the two first authors of the study Nicolò Pernigoni, PhD candidate and Elena Zagato, PhD - both at the IOR. "On the contrary – continues Arianna Calcinotto, group leader at the IOR – fecal microbiota transplantation from CR individuals accelerates CRPC progression, as it enriches androgen-producing bacterial species in the hosts".
Through metagenomic analyses in patients, researchers did also identify a "favourable" bacterial signature, associated with a better prognosis, and an "unfavorable" bacterial signature, associated with poor clinical outcome. "Our discoveries pave the way to adjuvant therapeutic strategies that, through microbiota manipulations, counteract the expansion of androgen-producing bacterial species", explains Prof Alimonti. "These can include, for example, antibiotic therapy, probiotic administration, or fecal microbiota transplantation interventions. Our dream would be one day to produce a 'yogurt' enriched with favorable bacteria that can prevent the occurrence of CRPC. We are looking to industrial partners that are willing to fulfill this dream", concludes Prof Alimonti. The stratification of patients according to the "favorable" or "unfavorable" bacterial signature will be instrumental to test the efficacy of these treatments. Future work from this consortium will investigate these translational and clinical implications.
Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis is the title of the study conducted at the IOR in collaboration with the Institute of Cancer Research, London (UK) and the University of Padova (Italy).
The full version is available online at >> www.science.org