Today’s session titled PARP Inhibitors, DNA Repair, and Beyond: Theory Meets Reality in the Clinic was chaired by Michal Kastan, who covered updates from his lab and worldwide, on two potential pathways to target—ATM and P53. His talk was followed by talks by Judy Garber and Elisabeth Plummer.
Kastan began by discussing ATM (Ataxia-Telangiectasia Mutated), citing it as a good target for radiosensitization. Kastan is responsible for the identification and characterization of a novel ATM kinase reversible inhibitor called CP-466722. His group has also developed a high-throughput assay for ATM inhibition in order to attempt to find other ATM inhibitors. He stated that some potential applications of ATM are as kinase inhibitors, radiosensitizers (either external beam or brachytherapy including antibody conjugates), and stated that there should also be synthetic or combination lethality with the loss of other DNA damage response and repair genes. He ended his discussion by pointing out that ATM inhibitors may have anti-tumor activity on their own.
Kastan postulated that “down the road we will have the ability to make very potent and selective combinations for therapy,” saying that for example in cases of hypoxic BRCA2 breast or ovarian cancers, clinicians could use PARP inhibitors, ATM inhibitors, and XRT, “in specific combinations and taking advantage of the tumor microenvironment.”
In his discussion of P53, Kastan pointed out that downregulation of P53 protects cells—enables them to live, and that if you keep a cell alive this is a way to protect normal tissues from chemotherapy and radiotherapy; protect tissues from accidental exposure (an interest of the Department of Defense), and protect organs from significant tissue damage during hypoxia-reperfusion injury. Kastan noted that blocking apoptosis could also allow us to reduce neuronal cell death in neurodegenerative states, and that it’s a useful research tool since it will help us grow cells that are difficult to grow in culture, such as stem cells.
He finished his discussion by listing the ways in which targeting DNA repair pathways will find clinical use: In settings where synthetic lethality can be exploited, ie PARP, ATM, Chk1, as sensitizers for chemotherapy or radiation therapy (ATM); as protectors of normal tissue (P53), and in combination therapies, with each other and with cytotoxic agents.
Judy Garber: Status of Clinical Development of PARP Inhibitors
The second speaker of the session, Judy Garber, discussed the status of clinical development of PARP inhibitors. She stated that some possible roles of PARP inhibitors in cancer treatment include, synthetic lethality; to potentiate specific cytotoxic drugs; and to potentiate radiation therapy.
She discussed olaparib, Astra Zeneca’s orally active PARP inhibitor which is being used in breast and ovarian cancers in BRCA carriers, and also mentioned iniparib, saying that at this meeting there will be a presentation of an oral abstract by M. Birrer, showing the results of a Phase II trial of iniparib in combination with gemcitabine(Drug information on gemcitabine)/carboplatin in patients with platinum-resistant recurrent ovarian cancer.
Garber cited recent evidence relating to the efficacy of iniparib in BRCA-2 associated pancreatic cancer and mentioned that a recent paper explores whether PTEN deficiency is a good predictor for PARP inhibitor activity. She said that PARP inhibitors may also be significant in PTEN-deficient endometrial cancer as well as prostate cancer.
Garber noted that there are six PARP inhibitors currently in development, however “it’s a challenge to figure out which will go forward as single agents, which will be developed, in what settings, which are the most active, which will have the most toxicity, and how will the companies strategize to move these drugs forward.” She also stated that there are 18 ovarian and 17 breast studies for PARP inhibitors currently underway.
Elisabeth Plummer: Development of PARP Inhibitors and Their Potential Roles in Chemo-Potentiation
Elizabeth Plummer was the last speaker of the session and discussed the development of PARP inhibitors and their potential roles in chemo-potentiation, saying that this is a “fascinating area with enormous potential.” The data from their Phase II study will be presented at this meeting, and is called “Phase II trial of the PARP Inhibitor AG-014699 in BRCA 1 and 2-mutated, advanced ovarian and/or locally advanced or metastatic breast cancer;” she stated that this is the first-in-class study with AG-014699. The abstract states that AG-014699 resulted in significant PARP inhibition, was well tolerated, and resulted in a clinical benefit rate of 32%. Plummer added that one patient with a rapidly growing melanoma had complete response and he remains in remission after 14 cycles in total. A second patient had partial response in an inoperable desmoids tumor; he also remains in complete remission. She added “I think you’re seeing that in the melanoma world, some patients do very well.”
She stated that her group went straight into a Phase II study in metastiatic melanoma; the study contained 46 patients with metastatic disease in 6 UK centers, and that more myelosupporsesssion was observed than in the phase 1 study, 40% had dose reduction, and 17% had response rates, with disease control for more than six months in 40% of patients, with increased overall survival.
Plummer noted that there are currently 57 PARP inhibitor trials listed, and that 29 are open to recruitment, with a mix of combinations. At this meeting, there are more than 20 PARP presentations showing 15 clinical trials.