A Novel Oral Drug For Ovarian Cancer Patients
Olaparid is being tested in a high risk hereditary patients
Jul 1, 2009
Ovarian cancer is the sixth leading cause of cancer-related deaths in the occidental world and the second most common gynecological cancer after breast cancer. It is a leading cause of death from gynecological malignancies accounting for 4% of all cancers among women from industrialized countries. Largely asymptomatic, early detection of ovarian cancer is rare and screening programs in the general population have for the most part been unsuccessful. Over 70% of patients with ovarian cancer are diagnosed at an advanced stage of the disease when the disease has already spread in the body.
BRCA1 and BRCA2 Genes
Risk factors of ovarian cancer are not well known. Age, low parity, and inherited genetic mutations in particular cancer predisposition genes are all associated with an increase risk of developing ovarian cancers. Several genes have been linked to ovarian cancer but the most predominant are BRCA1 and BRCA2 genes. Ovarian cancer due to inherited BRCA1 and BRCA2 gene mutations account for only 5 to 10% of all ovarian cancer, but the risk of developing an ovarian cancer is 40 to 50%. See also this article about BRCA and ovarian cancer.
Breast and ovarian cancer are the most common cancer in patients with BRCA1 or BRCA2 gene mutation. However an increased risk of other cancers, such as prostate cancer and pancreatic cancer has also been observed. See this article for a recent report on BRCA2 mutation and risk of pancreatic and prostate cancer.
Genome Surveillance and DNA Repair
BRCA1 and BRCA2 are also considered as tumour suppressors since the normal expression of those genes prevents cells from becoming cancerous. The proteins encoded by these two genes are also named BRCA1 and BRCA2, and are involved in genome surveillance. When cells divide DNA is copied, or replicated, allowing the daughter cell to have an exact DNA copy of the mother cell. Although sometimes mistakes occur, the process is under surveillance by proteins that will repair these mistakes. This is called genome surveillance.
PolyADP-ribose Polymerase
The protein PARP, or polyADP-ribose polymerase, is also an enzyme involved in DNA repair. This protein produces polymers of ADP-ribose, which will modify other specific proteins recruited at the site of DNA damage. Over the last 20 years inhibitors of PARP have been investigated, but were active at high concentrations only. High concentration of a drug is often toxic to normal cells. More recently, inhibitors of PARP have been considerably improved and have entered clinical trials.
PARP Inhibitors For Ovarian Cancer
In 2005, Bryant and colleagues as well as Farmer and colleagues have shown, in their publications in volume 434 of the scientific journal Nature (Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase, pp 913-917; Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, pp 917-921, 2005), the efficiency of PARP in BRCA mutant cells. Since then PARP inhibitors have attracted attention of scientists for chemotherapeutic application in hereditary breast and ovarian cancer.
In the last American Society of Clinical Oncology (ASCO) meeting, Dr. William Audeh and colleagues presented a new inhibitor named olaparib. Olaparib has been tested on 57 ovarian cancer patients with BRCA mutation and who were resistant to standard chemotherapy. Not only were the patients responding to the treatment and showing reduced symptoms of cancer but also the novel drug showed a low toxicity. The study is published in the Journal of Clinical Oncology (27:15s, 2009).
Although the new drug needs to be further tested in larger cohort of patients, this is a major breakthrough in the treatment of BRCA mutant patients, when they become resistant to standard chemotherapy and for whom no other treatment is currently available.
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