Gut Bacteria May Fuel P Ca Tt Resistance

Dear All,

In a Recent study by Nicolo Pernigoni, Johann de Bono et al, 2021, Science, 374 (Issue 6564 Oct 8th) on ‘Commensal Bacteria Promote Endocrine Resistance in Prostate Cancer through Androgen Biosynthesis’ has opened a new avenue in our understanding of ‘ADT Resistance’ of P Ca. This study was funded by the Prostate Cancer Foundation, Movember, Prostate Cancer UK, Cancer Research UK and The John Black Charitable Foundation.

The study revealed how gut bacteria contribute to the progression of advanced prostate cancers and their resistance to hormone therapy -- by providing an alternative source of growth-promoting androgens, or male hormones.

P Ca is driven by Androgens and ADT either by Surgery or Pharmaceutical Agents form the standard of care especially in its advanced stages. After an Initial response, hsP Ca usually Progresses to CRPC owing to various mechanisms that include altered AR Signaling and Intratumour accumulation of Androgens even during ADT.

Nicolo Pernigoni, Johann de Bono et al showed that Gut Commensal Bacteria are able to synthesize Dehydroepiandrosterone (DHEA) and Testosterone in Patients (Experimentally mice) with CRPC and prevent complete suppression of Androgens during ADT.

They also analysed microbial genetic material from the stool of men with prostate cancer and identified a specific bacterium - Ruminococcus - that may play a major role in the development of resistance. In contrast, the bacterium Prevotella Stercorea was associated with favourable clinical outcomes.

Researchers incubated mini-tumours called Organoids derived from prostate cancer patients with different gut bacteria and attempted to treat them in the lab. This helped them identify favourable and unfavourable bacterial 'fingerprints' linked to prostate cancer outcome, which could help identify men who could benefit from strategies to manipulate the microbiome. de Bono mentioned that findings reveal that the initiation of hormone therapy for prostate cancer can trigger 'gut bugs' to start producing androgen hormones. These androgens can then sustain prostate cancer's growth and drive resistance to hormone therapy -- worsening men's survival outcomes.

The next step will be to further explore how we apply these signatures in patients, with the aim of devising tests to pick out men who would benefit from. The next aim would be to Develop Antibiotic Therapies and other strategies to manipulate the Microbiomes. In the long-term, the aim would be produce a 'yoghurt' enriched with favourable bacteria to prevent resistance to treatment.

Though this study is still in the Initial stages, much thoughts on this would soon emerge making it possible for prolongation of Progress of P Ca.

Studies have recently found that the Newer ADTs now available induce Drug Resistance earlier than the conventional ADTs we were using till recently. This study may also help us in the Upfront ‘Triplet therapy’ that has been introduced for mP Ca in PEACE 1 Trial, which has shown progression free survival and Radiographic Progression Free survival. Median overall survival in these patients was 5.1 years with the triplet therapy compared to just 3.5 years without Abiraterone. Adding Abiraterone to ADT plus Docetaxel resulted in a 50% improvement in radiographic progression-free survival, with a median rPFS of 4.5 years for the triplet combination compared to just 2.0 years for ADT plus Docetaxel alone.

The story of P Ca is never ending with new concepts emerging every now and then making it difficult as to how Advanced P Ca’s should be treated. Each advances that emerge are aimed to provide more insights into our understanding.

With warm regards,



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