An advanced understanding of cancer biology comes of age 41 Specific targeting of DNA repair mechanisms

In recent years one successful targeted approach has been to exploit the vulnerability of tumors with an impaired DNA damage repair mechanism by inhibiting a second DNA repair pathway and as such commit the cancer cell to die. This concept of synthetic lethality has been most successfully demonstrated in patients bearing tumors with BRCA-1/-2 mutations where homologous recombination (HR) mechanisms are already known to be inadequate. This hypothesis has reactivated the development of poly (ADP-ribose) polymerase (PARP) inhibitors. PARP is an enzyme that is crucial in the base excision repair pathway. When this repair mechanism is inhibited in the presence of pre-existing impaired HR then efficient

DNA repair is prevented and apoptosis occurs. Following pre-clinical and more recently proof of concept clinical trials in patients with BRCA mutated breast and ovarian carcinoma, the PARP inhibitor olaparib has demonstrated significant activity [46]. Whilst it is hoped that the application of these agents may broaden to include sporadic tumours in which mutations in DNA pathways may also be found, there has also been considerable interest in other tumours types where these mutations may be found. The inherited BRCA-2 mutation is associated with a 20% lifetime risk of developing prostate cancer that often occurs before 65 years of age. The subsequent tumors are often of high Gleason score, more advanced stage at diagnosis and patients have a shorter survival than patients with sporadic prostate cancers [47]. One of three prostate cancer patients with germ-line BRCA variant had a prolonged response to olaparib in a phase 1 trial [48]. In addition to BRCA mutated cancers, pre-clinical evidence has also demonstrated a sensitivity of tumours with phosphatase and tensin homolog (PTEN) deficiency to PARP inhibition [49]. This is one of the most commonly mutated genes in human cancers where it has a role in genome stability. PTEN deficiency is associated with an HR defect that sensitizes tumours cells to PARP inhibition using the same mechanism as BRCA mutated cancers.

At present, the clinical development of olaparib has been focused on breast and ovarian cancer. Studies in prostate cancer are underway with the PARP inhibitor veliparib (or ABT888) in combination with temozolamide in a phase I study recruiting patients with metastatic prostate cancer. In addition a phase I study using the Merck PARP inhibitor - MK4827 is currently recruiting to a prostate cancer enriched second stage following encouraging phase I study data in advanced solid malignancies [50].

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment