PARP Inhibitors are opening new doors in cancer treatment by targeting vulnerabilities in cancer that researchers are beginning to understand better.
Can a vulnerability be changed into an advantage? The answer is clearly yes when it comes to cancer therapies. The number of examples is growing exponentially, as predicted when studies of the basic biology of cancer revealed mutations and other changes in the genes of cancer cells and further research deepened the understanding of the consequences of these alterations.
In this issue of CURE®, you will read about an example of this concept that is still evolving: the expanding number of ways that a class of drugs known as PARP inhibitors can help patients with ovarian cancer.
It has long been known that breast and ovarian cancers run in some families, and this ultimately led to the discovery of several inherited mutations that predispose people to specific cancers. Among the first of these were the BRCA 1 and 2 genes; it was found that individuals carrying mutated copies of these genes, which are involved in DNA repair, had up to an 80% lifetime risk of breast cancer and a 30% risk of ovarian cancer.
This knowledge allowed testing of patients with strong family histories of these cancers or who had received a diagnosis at a young age — and prompted recommendations that those with BRCA mutations undergo enhanced screening and preventive surgeries to minimize the associated risks. However, it took scientists several years to develop treatments specific to patients with BRCA mutation-associated cancers.
A key discovery was that drugs inhibiting a DNA repair enzyme called poly (ADP-ribose) polymerase (PARP) exhibited what is known as a synthetic-lethal effect in cells that had defective BRCA 1 or 2 genes. For ovarian cancer, in which BRCA mutations are most prevalent, this means that cancer cells that already cannot repair their own DNA because of a BRCA mutation are incapacitated and killed with the addition of PARP inhibitors, which block a different DNA-repair pathway.
PARP inhibitors were initially approved for patients with advanced ovarian cancers and BRCA defects after standard chemotherapy was no longer effective. More recently, these agents have been approved in the maintenance setting — they help prevent disease progression or relapse after the cancer has responded to chemotherapy. These drugs can also help patients who have normal BRCA genes but other impairments in the DNA repair process.
Even more exciting: combinations that hit cancer cells with a double whammy. Pairing PARP inhibitors with immunotherapy or antiangiogenic (tumor blood vessel-blocking) drugs shows significant promise.
Because all this treatment involves identifying the unique biology of specific cancers and then tailoring treatments and “synergistic” combinations to them, this story illustrates the great promise of personalized cancer therapy.