.tmb-propic-md.jpg?Culture=en&sfvrsn=c25d2b2f_9 "Professor Louis Chesler (Profile pic)")
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Up to two in five advanced prostate cancer patients could be treated with a combination of two targeted drugs, according to new research.
Findings by a team of scientists at The Institute of Cancer Research, London showed that the drugs not only slowed tumour growth, but they killed cancer cells – which may better prevent the development of resistance to treatment.
The two drugs are in development or already in use for the treatment of other cancers, so the researchers hope clinical trials of this combination can begin soon for prostate cancer patients.
Around 55,000 men in the UK are diagnosed with prostate cancer each year. Once resistance to hormone therapy develops, effective treatments are limited and the prognosis for these patients is poor. Scientists are therefore searching for new ways to treat the disease.
Targeting two proteins
Researchers at The Institute of Cancer Research (ICR), funded by The Wellcome Trust, Prostate Cancer Foundation, Prostate Cancer UK, and The Cancer Research UK Convergence Science Centre, tested a number of drugs which are either approved or in clinical trials for other cancers. They tested combinations of these drugs in prostate cancer cells that had become resistant to hormone therapy.
MCL1 is a protein that promotes cancer cell survival. Similarly, AKT plays a key role in a mechanism that many cancer cells rely on to survive, grow and resist treatment.
The research, published in the journal Nature Communications, found that inhibiting MCL1 and AKT at the same time triggered prostate cancer cell death.
Drugs are already in trials or approved for use to treat cancer
In humans, drugs to inhibit MCL1 have had limited success in the past, due to toxic side-effects. The team therefore targeted MCL1 indirectly, by inhibiting CDK9 – a protein that regulates MCL1 levels – using the drug fadraciclib.
Fadraciclib was jointly discovered by scientists in the Centre for Cancer Drug Discovery at the ICR, in collaboration with the company Cyclacel. It is currently in clinical trials for blood cancers.
The team inhibited AKT using either a drug called ipasertib, or capivasertib. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Pharmaceuticals (and its collaboration with the ICR and Cancer Research Technology Limited).
In studies in the lab, they found that combining fadraciclib with either capivasertib or ipatasertib also triggered prostate cancer cell death.
Finding the right patients for the drugs
The team then explored which patients might respond best to the combination. They tested the drugs in prostate cancer cells with different molecular and genetic make-up.
Prostate cancer cells which were PTEN-loss/PI3K-activated – a tumour type which up to 40 per cent of patients with advanced prostate cancer have – responded the best to the combination of CDK9 ad AKT inhibitors.
In mice with this tumour type, the combination of drugs significantly slowed tumour growth, while using either drug alone had no effect on tumour growth. In just 10 days, untreated tumours grew, on average, more than six times in size. The combination of drugs kept tumours from doubling in size in that time.
An enzyme involved in programmed cell death was activated, indicating that the drug combination had killed the cancer cells, in addition to slowing their growth.
The researchers are currently seeking funding to progress the drug combination into clinical trials for prostate cancer.
The team screened lots of drugs that could be used to treat advanced prostate cancer, to find the right combination, for the right patients. They found that one specific tumour type, with high levels of MCL1 – accounting for around 16 per cent of treatment-resistant prostate cancers – responded best to MCL1 inhibition alone.
The researchers hope that CDK9 inhibitors, such as fadraciclib, could be used to treat these patients.
The approach may prevent resistance occurring
Dr Adam Sharp, Leader of the Translational Therapeutics Group at The Institute of Cancer Research, London, said:
"For men with advanced prostate cancer, once hormone therapies stop working, the outcomes are bleak. Researchers are constantly searching for new treatment options, but discovering and developing a new drug from scratch is a lengthy process.
“In this work, we screened a large number of drugs that are in development, or already being used to treat cancers. We identified a particularly promising pairing that could help patients with advanced prostate cancer, and our data suggests that up to 40 per cent of people with this disease could benefit. Excitingly, we found that the treatment doesn’t just slow tumour growth – it actually kills cancer cells. We’re cautiously optimistic that this approach may better prevent resistance to treatment from occurring.
“The work of Dr. Juan Jimenez-Vacas and Dr. Daniel Westaby, alongside our collaborative teams, was instrumental to this research, in uncovering the role of the MCL1 protein in advanced prostate cancer and identifying optimal ways to target it to treat the disease.”
Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, said:
“Showing that this combination works in the laboratory is just the first step. I hope that, since capivasertib is approved for use, and both fadraciclib and ipatasertib are in clinical trials to treat other cancers, we can soon begin to test this combination in people with advanced prostate cancer.”
The ICR's role in the discovery and development of the drugs
Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said:
“Finding new ways to overcome treatment resistance is a key priority in cancer research. This study highlights how progress can come from re-assessing existing drugs in innovative ways. By identifying the most effective combinations – and, crucially, the patients most likely to benefit – we hope to halt cancer’s progression and give patients more time with their loved ones.
“The ICR has an unrivalled track record in academic drug discovery and development. I am proud of the role we have played in the discovery and development of fadracliclib and capivasertib, through partnerships between academics, clinicians and the pharmaceutical industry. It’s exciting to see the potential benefit of using these drugs to treat prostate cancer patients whose hormone therapy has stopped working, and I look forward to seeing the next stages of this important research.”