Scientists have identified the BCL2 protein as a potential drug target for an aggressive form of prostate cancer that is resistant to hormone therapy. The research, published in the Journal of Clinical Investigation, indicates that elevated levels of BCL2 are linked to poorer outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC).
The study, conducted by researchers at The Institute of Cancer Research, London, examined biopsies from 245 patients with mCRPC across two independent cohorts. The findings revealed that patients with higher BCL2 levels had a significantly shorter overall survival, with a median of 20.4 months compared to 53.0 months for those with lower levels.
BCL2 Levels Impact Hormone Therapy Response
Further analysis showed a marked difference in response to hormone therapies based on BCL2 expression. In patients with high BCL2 levels, only 12.5% experienced a PSA level reduction of more than 50% following hormone therapy, compared to 47.6% of patients with lower BCL2 expression. Overall survival from the start of hormone therapy was also significantly shorter in the high-BCL2 group (9.7 months) compared to the low-BCL2 group (24.3 months).
Docetaxel as a Potential Alternative
Interestingly, the study found no significant difference in overall survival or PSA response when patients were treated with the chemotherapy drug docetaxel, regardless of BCL2 levels. This suggests that docetaxel could be a more effective treatment option than hormone therapy for patients with high BCL2 expression.
Targeting BCL2 for Treatment
Based on these findings, a clinical trial is currently underway to assess the efficacy of venetoclax, a BCL2 inhibitor already approved for certain types of leukemia, in combination with the hormone therapy enzalutamide for prostate cancer.
In laboratory experiments, researchers found that targeting the entire BCL2 family of proteins—BCL2, BCLXL, and MCL1—yielded the most promising anti-tumor response. However, they noted that safely targeting these three proteins in humans would likely require advanced drug delivery technologies, such as antibody-drug conjugates, to specifically target cancer cells and minimize harm to healthy tissue.
Expert Commentary
Dr. Adam Sharp, Leader of the Translational Therapeutics Group at The Institute of Cancer Research, London, stated, "Our results have shown that there’s a large disparity in outcomes for people whose cancers have high levels of the BCL2 protein, and that their cancers respond less well to hormone therapies than others. Further research could provide evidence for more personalised treatment plans, as these cancers may respond better to docetaxel than enzalutamide or abiraterone."
Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, added, "BCL2 is a protein that promotes cell survival, and we have shown that cancers with higher levels of the protein cause significantly worse outcomes for patients. If targeting BCL2 proves effective in clinical trials, patients with advanced prostate cancer will be able to look forward to better, personalised treatments."
