A new study suggests that a new type of cancer drug called PARP inhibitors, including a new drug called olaparib that is currently showing promising results in trials as a targeted treatment for inherited forms of breast and ovarian cancer, may also be effective against other cancers.
The study was led by scientists from the Breakthrough Breast Cancer Research Centre at the Institute for Cancer Research in London, UK, and is published in the 16 September issue of EMBO Molecular Medicine.
PARP inhibitors are an exciting new avenue in cancer therapy called “synthetic lethality”. They are showing promising results in early stage clinical trials of patients with inherited forms of advanced breast, ovarian and prostate cancers caused by faulty BRCA1 and BRCA2 genes. BRCA tumors account for about 5 per cent of breast cancer cases.
Results from a recently published Phase I clinical trial showed that despite having already received many standard therapies, more than 50 per cent of the patients’ tumors shrank or did not grow further, with one of the first patients to receive the treatment still in remission two years later, according to information from the Institute for Cancer Research.
The researchers report they have now discovered that cells with a faulty PTEN gene are up to 25 times more sensitive to PARP inhibitors than cells that do not have the faulty gene, and suggest that these drugs may also be effective as a targeted treatment for many cancers where faulty PTEN plays a key role.
PTEN (phosphatase and tensin homolog) is a tumor suppressor gene and is one of the most commonly mutated genes in human cancers; recent studies also suggest it is important for keeping the genome stable.
Faults in PTEN are common in a range of cancers, and may account for between 30 and 80 per cent of breast, prostate, melanoma (a deadly form of skin cancer), endometrial (womb) and colon cancers, said the researchers.
They argue that like cells with faulty BRCA1 and BRCA2 genes, cells with faulty PTEN genes rely on the enzyme PARP (short for Poly(ADP-ribose) polymerase) to keep their DNA intact. But PARP inhibitors block the PARP enzyme, which when combined with faulty PTEN should deliver a double blow to the cancer cell and force cell suicide or apoptosis.
They suggest that such an event should cause tumors to stop growing or even shrink, and because the drug works in a targeted way, it only affects cancer cells and not healthy cells, so the result should be fewer side effects.
The researchers recommend that:
“The clinical assessment of PARP inhibitors should be extended beyond those with BRCA mutations to a larger group of patients with PTEN mutant tumours.”
Professor Alan Ashworth, Director of the Breakthrough Breast Cancer Research Centre at the ICR, told the press:
“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,” said Ashworth.
“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,” he added.
Dr Chris Lord, also of the Breakthrough Breast Cancer Research Centre and who led the research with Ashworth 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.”
“Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors (p NA).”
Ana M. Mendes-Pereira, Sarah A. Martin, Rachel Brough, Afshan McCarthy, Jessica R. Taylor, Jung-Sik Kim, Todd Waldman, Christopher J. Lord, Alan Ashworth.
EMBO Molecular Medicine, Published Online: Sep 16 2009.
Source: Institute of Cancer Research.
Written by: Catharine Paddock, PhD