Scientists uncover new potential for targeted cancer treatment

PARP inhibitors, including the new drug, olaparib, which Breakthrough Breast Cancer and Institute of Cancer Research (ICR) scientists helped develop, are already showing considerable promise in clinical trials for cancer linked to BRCA mutations, including some breast and ovarian cancers.

Scientists from the Breakthrough Breast Cancer Research Centre at the ICR have now shown that PARP inhibitors can also kill cancer cells with a faulty PTEN gene. Results published today in the journal EMBO Molecular Medicine showed that cells with faulty PTEN genes were up to 25 times more sensitive to PARP inhibitors than cells with normal PTEN.

Faults in the PTEN gene are common in a range of cancers, accounting for between 30 and 80 percent of breast, prostate, melanoma (skin), endometrial (womb) and colon cancers. Nearly 46,000 women are diagnosed with breast cancer in the UK each year, with just under 12,000 women dying of the disease.

Professor Alan Ashworth, Director of the Breakthrough Breast Cancer Research Centre at the ICR, said: “These results are exciting because they show that PARP inhibitors are potentially a powerful targeted treatment with few side effects which may help a broad range of cancer patients.

“Clinical trials have already shown the potential of PARP inhibitors for patients with tumours caused by faulty BRCA genes. We now need to test whether the promising results from this study can be matched in the much larger group of patients with PTEN-related tumours.”

The use of PARP inhibitors is part of a novel approach to cancer therapy called synthetic lethality. A cell with a PTEN fault relies on a protein called PARP to keep its DNA undamaged. PARP inhibitors work by blocking PARP, and when combined with defective PTEN, causes the cancer cell to die. This means the tumour should either stop growing or get smaller. Due to the drug working in a targeted way, it kills cancer cells while leaving healthy cells relatively unaffected, which means fewer side effects for patients.

Patients with inherited forms of advanced breast, ovarian and prostate cancers - caused by faulty BRCA1 and BRCA2 genes - have already benefited from PARP inhibitors in a recently published Phase I clinical trial. Despite having previously received many standard therapies, more than half of the patients’ tumours shrank or stabilised, with one of the first patients to be given the treatment still in remission after two years. BRCA-related tumours make up about 5 percent of breast cancer cases.

Dr Chris Lord, who led the research with Prof Ashworth at the Breakthrough Breast Cancer Research Centre at the ICR, said: “This new class of drugs could potentially make a big difference for many thousands of cancer patients, including some with very limited treatment options.  It shows Breakthrough’s focus on turning lab research into patient benefit as quickly as possible is having an impact.”

Professor Peter Rigby, Chief Executive of the ICR, said: “This is an exciting development in the use of PARP inhibitors, showing that they could benefit far more patients than previously believed. The ICR is proud to have been involved in all stages of the development of these drugs and we look forward to further clinical trials and to identifying patients with other types of cancers who could benefit.”