The tumor transforms, changes its nature, and sometimes from adenocarcinoma it becomes neuroendocrine carcinoma, a more serious and aggressive form of prostate cancer, resistant to hormonal treatments and capable of shortening the life of patients who are affected by it. Now, a study published on Clinical Cancer Research, identified a molecular mechanism underlying this transformation, and also identified a possible countermeasure: inhibitors of BET proteins. But let’s go in order.
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What are we talking about
Prostate cancer accounts for about 20% of all cancers diagnosed among men over 50: in our country alone, there are 37,000 new cases every year. Among the treatment options – in addition to surgery, radiation therapy, chemotherapy and watchful waiting – is hormone therapy, the first-line treatment for metastatic disease. Today, among the hormone therapy drugs we have new and very effective androgen receptor inhibitors available, such as enzalutamide, apalutamide, darolutamide and abiraterone, for example. Which is a really good thing. But some studies have recently shown that in patients treated with these powerful antiandrogens, the incidence of neuroendocrine carcinoma of the prostate is 17%, while in other patients it does not reach 1%. “A fact that strongly suggests that interfering with androgen receptor function contributes to an increase in the number of prostatic neuroendocrine tumors,” reflects Joshi J. Alumkal, of Rogel Cancer Center, Department of Internal Medicine at the University of Michigan and author principal of the study.
Questions and answers
But how do prostate cancers become neuroendocrine? How do drugs that block the androgen receptor interfere with the transformation process? And finally (and above all), how can this process be stopped? Using cell cultures and biopsies from patients with prostate cancer, the authors observed that in resistant cells the DNA is organized in such a way as to favor the transition to the neuroendocrine form when the androgen receptor is blocked by drugs. “We discovered – added Alumkal – that E2F1, a transcription factor involved in cell differentiation, plays an important role in this process, ie in the change of identity of the cells towards the more aggressive form. In this process – the authors have always observed – E2F1 does not act alone, but is helped by a particular type of protein, the bromodomine BET proteins.
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The research team then discovered that by blocking the action of these proteins with BET inhibitor drugs (molecules discovered in the 1990s, but whose anticancer activity began to be studied in the last decade) the transformation can be interrupted. “When we went to treat cultured neuroendocrine carcinoma cells, including those derived from patients, with BET inhibitors, we greatly reduced the viability of these tumors,” Alumkal said.
A promising way
Prior to this study, Alumkal and his colleagues had done another one, a clinical one, on patients with prostate cancer. The authors found that a BET inhibitor, ZEN-3694, gave better results on more aggressive tumors. “We then went back – says Alumkal – and we saw that several of those patients were suffering from neuroendocrine carcinoma of the prostate which depended on the treatment”. Those who had the best results with ZEN-3694 were those who expressed the most E2F1 and the BET bromodomain proteins, and least the androgen receptor.
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The next step? A larger, international and randomized clinical trial is already planned, which will focus in particular on evaluating the efficacy of ZEN-3694 in men who respond poorly to androgen receptor inhibitors. We’ll see. But a road has opened, and it looks promising.
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