Ok, time for another science entry. This is a report from ASCO News about a presentation re PARP Inhibitors, another targeted therapy that has been studied for some years in other cancers and is now also being explored for breast cancer. It is clear that the growing edge of cancer research is targeted therapies, and that is great news--suggests that people will be more likely to receive treatments that will help their particular cancer and the rest of us will be spared side effects from something that wouldn't help much. As in, the sledge hammer approach is gradually being edited by something more gentle and more effective.
Synergies in therapy gained from targeting DNA repair pathways were the focus of Saturday's Education Session "PARP Inhibitors, DNA Repair, and Beyond: Theory Meets Reality in the Clinic."
Session Chair Michael B. Kastan, MD, PhD, of St. Jude Children's Research Hospital, presented an overview of future approaches for exploiting DNA repair pathways.
Many tumors exhibit mutations in one or more DNA repair genes, and it is likely that those mutations are the source of the development of the tumor itself. In addition, tumors having a defect in one repair pathway are particularly sensitive to inhibition of a different repair pathway, presumably because that second repair pathway compensates for the loss of function associated with the first mutation.
These mutations potentially serve as an Achilles' heel that can be exploited for clinical benefit. Inhibition of a DNA repair pathway in cells lacking a complementary pathway results in what is known as synthetic lethality.
Two likely candidates for drug development are inhibitors of ataxia telangiectasia mutated (ATM) and oligonucleotides. ATM, Judy E. Garber, MD, MPH, noted that
which is required for response to DNA damage and to maintain genome stability, is perhaps the most important cell cycle checkpoint kinase.
BRCA1 tumors have increased sensitivity to DNA-damaging agents and are resistant to microtubule inhibitors.
Oligonucleotides are small molecules that protect normal cells by blocking p53 translation, whether the damage is due to chemotherapy or radiotherapy, to accidental exposure to radiation, or to hypoxia-reperfusion injury associated with myocardial infarction and stroke.
PARP inhibitors are case studies for the concept of synergies in therapy gained from targeting DNA repair pathways and the challenges of utilizing these compounds in the clinic. Through research with PARP inhibitors, the family of PARPs has been identified as the mediator of base excision repair of single-strand DNA breaks, the main safeguard against endogenous DNA damage.
A complementary DNA repair pathway, for error-free repair of double-strand DNA breaks, is homologous recombination, which has been found to be defective in many forms of cancer. PARP inhibitors have helped elucidate the process of normal DNA repair; their therapeutic use for cancers that lack complementary pathways for DNA repair results in synthetic lethality, and they function as radiation and chemotherapy sensitizers. Some have even shown activity as single agents.
Theoretically, another clinical benefit of PARP inhibitors is that they should be less toxic to normal tissues with intact complementary pathways of DNA repair. With such an appealing therapeutic index, this novel class of targeted therapy has generated a great deal of interest.
Judy E. Garber, MD, MPH, of Dana-Farber Cancer Institute, discussed the current status of the clinical development of PARP inhibitors in the context of hereditary breast cancer. She noted that BRCA1 tumors have increased sensitivity to DNA-damaging agents like cisplatin and are resistant to microtubule inhibitors like paclitaxel.
Work with cisplatin has shown promise, but identifying biomarkers that are discriminatory for response has been elusive. In view of the difficulties in establishing effective treatments for different patient profiles, PARP inhibitors have great potential roles, especially as chemopotentiators.
PARP inhibitors that are far enough along in development to have names (e.g., olaparib, iniparib, and veliparib) have shown promise, but the variability in responses suggests that the mechanism of activity of these compounds is not yet fully understood. They are being studied in a wide range of tumors including breast, ovarian, pancreatic, and prostate.
Elizabeth R. Plummer, MD, DPhil, of the Northern Centre for Cancer Care, United Kingdom, reviewed the early development of PARP inhibitors as chemopotentiators and described some of the challenges presented by thesestudies. Citing the 23 years between the first description of in vitro chemopotentiation with a PARP inhibitor and the first phase I clinical trial of intravenous AG014699 combined with temozolomide, Dr. Plummer noted that the road was long
and required a team effort to take the concept from the laboratory to the clinic.1
Nonetheless, the first-in-class study demonstrated target enzyme inhibition and no PARP inhibitor-specific toxicity. A phase II study of the combination enrolled 46 patients with metastatic melanoma.
Toxicity was observed in this study, with dose reduction necessary for 40% of the patients due to myelosuppression. The response rate was 17%, with disease control for 6 months or longer for 40% of the patients. Overall survival and progression-free survival were prolonged compared with historical controls.
Today there are at least nine PARP inhibitors at the clinical trial stage. Currently clinicaltrials.gov lists 57 trials, 29 of which are open to recruitment. Most are chemopotentiation protocols, although single-agent studies are being conducted with olaparib, MK4827, PF0367338, and CEP-9722.
PARP inhibitors that are far enough along in development to have names have shown promise, but the variability in responses suggests that the mechanism of activity of these compounds is not yet fully understood.
Dr. Plummer noted that it is not yet known how much PARP has to be inhibited to achieve therapeutic activity.
The possibilities for PARP inhibitors are exciting, but the question remains whether enough has been learned about these DNA repair pathways to manipulate them for clinical benefit.
1. Durkacz BW, Omidiji O, Gray DA, et al. (ADP-ribose)n participates in DNA excision repair. Nature. 1980;283:593- 596.