U.K. Researchers Launch Clinical Trial of Mercaptopurine (6-MP) In Women with Hereditary Breast and Ovarian Cancer

A Cancer Research UK-funded clinical trial of a new drug for patients with advanced breast or ovarian cancer due to inherited BRCA gene mutations has been launched at the Experimental Cancer Medicine Centre at the University of Oxford.

A Cancer Research UK-funded trial of a new drug for patients with advanced breast or ovarian cancer due to inherited BRCA gene faults has been launched at the Experimental Cancer Medicine Centre at the University of Oxford (OxFord ECMC).

Mutations in the BRCA 1 (BReast CAncer-1) and BRCA 2 genes are thought to account for around 2-5 percent of all breast cancer cases. Women carrying the BRCA1 and BRCA2 mutation have a 45-65 percent chance of developing breast cancer, and a 20-45 percent chance of developing ovarian cancer, by the age of 70. Genetic testing for faulty BRCA genes is available for women with a very strong family history.

DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day. A special enzyme (shown above in color), encircles the double helix to repair a broken strand of DNA. Without molecules that can mend DNA single strand and double strand breaks, cells can malfunction, die, or become cancerous. (Photo: Courtesy of Tom Ellenberger, Washington University School of Medicine in St. Louis)

Cells lacking a properly functioning BRCA1 or BRCA2 gene  are less able to repair DNA damage. These defective cells are more sensitive to (i) platinum-based chemotherapy drugs such as cisplatin – which work by causing double-stranded DNA breaks, and (ii) PARP inhibitors, a newer class of drugs which prevent cells lacking a properly functioning BRCA gene from being able to repair damaged DNA. PARP inhibitors have shown promise in clinical trials but, as with most drugs, resistance can develop meaning some women can stop responding.

This trial, led by a team based at the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, is looking at a drug called “6MP” (a/k/a mercaptopurine; brand name: Purinethol), which is already used to treat leukemia and is often given in combination with another chemotherapy drug called “methotrexate.”

Earlier studies involving cells grown in the laboratory suggest that a class of drugs called “thiopurines,” which includes 6MP, are effective at killing cancer cells lacking BRCA – a gene which significantly increases the risk of breast and ovarian cancer – even after they have developed resistance to treatments like PARP inhibitors and cisplatin.

This trial is one of a growing number looking at matching patients to the most appropriate treatment based on their genetic makeup and that of their cancer – an approach known as “personalized medicine.”

If successful, the results will pave the way for a larger Phase 3 clinical trial, which could lead to an additional treatment option for the 15 out of every 100 women with breast and ovarian cancers, which are caused by faults in the BRCA1 or BRCA2 gene.

Trial leader Dr. Shibani Nicum, a gynecology specialist based at the Oxford ECMC, and a researcher in Oxford University’s Department of Oncology, said: “PARP inhibitors are a powerful new class of drugs developed specifically to target tumors caused by BRCA 1 and BRCA2 faults, but drug resistance remains a problem. We hope that the very encouraging results we have seen in early laboratory studies involving 6MP will lead to increased treatment options for these patients in the future.”

U.K. trial participant Suzanne Cole, 54, from Newbury, has a strong history of ovarian cancer in her family, with her sister, mother and grandmother all having been diagnosed with suspected cases of the disease at a relatively young age. But, it was not until many years later, after she herself was diagnosed with cancer, that doctors were able to trace the cause of this back to a BRCA1 mutation in her family.

Suzanne Cole said: “I was diagnosed in 2009 and initially had surgery then chemotherapy. I was then told about the trial and I went away and studied the information. The doctors were able to answer all my questions and then I agreed to sign up. I’m happy to be a part of this work as it could help others by moving treatments forward.”

Professor Mark Middleton, director of the Oxford ECMC, said: “It’s exciting to see drugs being developed for specific groups of patients who share the same underlying genetic faults in their cancer. Targeted treatments are at the cutting edge of cancer care and we’re proud to be involved in bringing such drugs a step closer to the clinic.”

Dr. Sally Burtles, Cancer Research UK’s director of the ECMC Network, said: “This study helps demonstrate the value of being able to pool subsets of patients who share specific rare faults in their tumor from a UK-wide network of Experimental Cancer Medicine Centres. This will be crucial as we move towards a new era of personalized medicine with treatments targeted according to the individual biological profile of a patient’s cancer.”

For more information on the trial, please visit www.cancerhelp.org.uk, or call the Cancer Research UK cancer information nurses on 0808-800-4040.

Sources:

  • Researchers trial new drug for women with hereditary breast and ovarian cancer, Press Release, Cancer Research UK, August 17, 2011.
  • Issaeva N, et al. 6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance. Cancer Res. 2010 Aug 1;70(15):6268-76. Epub 2010 Jul 14. PubMed PMID: 20631063; PubMed PMCID: PMC2913123.

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