New drug target discovered for aggressive form of prostate cancer

Scientists have discovered that a protein linked to prostate cancer is associated with more aggressive disease. It could provide a new target for treatment and help predict who will develop resistance to hormone therapy.

In a new study published in Journal of Clinical InvestigationsA team from the Institute of Cancer Research in London was able to show that the protein BCL2 is present in large quantities in a subtype of advanced prostate cancer that no longer responds to hormone therapy. The researchers estimate that around 10% of people with prostate cancer have high levels of this protein.

The team proposed a new treatment strategy targeting BCL2 – a protein responsible for preventing cell death. A clinical trial for prostate cancer testing the BCL2 inhibitor venetoclax – a drug approved for types of leukemia – with the hormone therapy enzalutamide has already begun.

Patients with high BCL2 levels have a shorter overall survival

Metastatic castration-resistant prostate cancer (mCRPC) is an advanced cancer that remains fatal and urgently requires new treatments. In one of the largest studies of its kind, researchers examined 427 biopsies from 245 patients with mCRPC in two independent cohorts.

They found that patients with higher BCL2 levels had a significantly shorter overall survival of 20.4 months compared to 53.0 months from the time of mCRPC diagnosis.

In the second cohort, they found a significant difference in response to common hormone therapies depending on the cancer's BCL2 level. PSA levels – a marker for prostate cancer – fell by more than 50% in only 12.5% ​​of patients with higher BCL2 levels, compared to 47.6% of patients with lower BCL2 expression. Overall survival from the start of therapy was also significantly different: it was 9.7 months for patients with higher BCL2 levels compared to 24.3 months.

Discovery of possible alternative treatment methods

However, the researchers found no difference in overall survival or PSA response when the cancers were treated with the chemotherapy drug docetaxel, suggesting that this treatment may be more beneficial than hormone therapy for patients with high BCL2 levels.

In the lab, the team tried to attack BCL2. They found that the best anti-tumor response in cells was achieved when they targeted the BCL2 family of proteins – BCL2, BCLXL and MCL1 – together, which is due to the interactions between these proteins in the body. The researchers suspect that in humans, drug delivery technologies – such as antibody-drug conjugates – that specifically target cancer cells and spare healthy tissue would be needed to safely target these three proteins together.

“Big differences in the results”

Dr Adam Sharp, Head of the Translational Therapeutics Group at the Institute of Cancer Research in London and Honorary Medical Oncologist at the Royal Marsden NHS Foundation Trust, said: “We urgently need new treatments to improve the quality and duration of life of patients with advanced prostate cancer.”

“Our results have shown that there are large differences in outcomes for people whose cancers have high levels of BCL2, and that their cancers respond less well to hormone therapies than others. Further research could provide evidence for more personalized treatment plans, as these cancers may respond better to docetaxel than to enzalutamide or abiraterone.

“Researchers Daniel Westaby, Juan Jiminez-Vacas and Ines Figueiredo played a crucial role in understanding the link between the BCL2 protein and this subtype of prostate cancer, as well as in uncovering the regulatory mechanisms of the protein.”

Professor Johann de Bono, Professor of Experimental Cancer Medicine at the Institute of Cancer Research in London and Consultant Medical Oncologist at the Royal Marsden NHS Foundation Trust, said: “BCL2 is a protein that promotes cell survival and we have shown that cancers with higher levels of this protein lead to significantly worse outcomes for patients.

“If targeting BCL2 proves effective in clinical trials, patients with advanced prostate cancer can look forward to better, personalized treatments. Our research has also suggested a combination therapy strategy that should be investigated and may prove even more effective than targeting BCL2 alone.”

“Finding ways to combat therapy resistance is crucial”

Professor Kristian Helin, chief executive of the Institute of Cancer Research in London, said: “We know that while a drug may keep one person's cancer at bay for a long time, it can unfortunately quickly lose its effect in another person. Finding ways to combat treatment resistance – and providing alternatives sooner – is vital.”

“This research has helped identify a subgroup of patients who may respond better to alternatives to hormone therapy and who may benefit even more from a BCL2 inhibitor. I look forward to trials identifying these patients and am confident that these findings will lead to new treatment strategies for patients with advanced prostate cancer.”