Researchers Report “Exciting” Results of PARP Inhibitors for Treating Mesothelioma and Other Cancers
Two years ago researchers reported that PARP inhibitors could be the key to defeating mesothelioma resistance to cisplatin, a common chemotherapy agent. Now, in a recent study, researchers have found this new class of drugs “shows early promise” for mesothelioma and many other cancer patients.
According to an April 21 press release from American Association for Cancer Research, researchers set out to test the efficacy and safety of a combination of drugs, olaparib and the investigational agent AZD5363. The therapy targeted clinical trial patients with ovarian cancer and the BRCA1/2 mutations. The investigators were excited to find that the combination treatment was safe and yielded responses in patients with a variety of cancer types, including breast, ovarian, and mesothelioma, regardless of BRCA1/2 mutation status.
“Here, we are reporting results from the dose-escalation portion of the trial, which showed that it was indeed possible to combine these drugs safely,” said Timothy Yap, MD, PhD, NIHR BRC clinician-scientist and consultant medical oncologist at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, according to the press release. “These early results are very exciting because preclinical data had suggested that the olaparib and AZD5363 combination had the potential to be effective in a much wider population of patients than just those harboring germline BRCA1/2 mutations.”
Yap reports that of 20 patients there are four confirmed RECIST (Response Evaluation Criteria in Solid Tumours) partial responses; two ongoing, prolonged RECIST disease stabilization; and one patient with sustained response. One patient with peritoneal mesothelioma was included within the prolonged stabilization group.
Mesothelioma, a signature cancer of asbestos, affecting the lining of the lung or abdomen, is an aggressive cancer with limited treatment options. Cancer cells thrive by splitting and dividing, resulting in metastasis of the mesothelioma to other organs. The combination of these two drugs inhibits the action that is required for the cells to reproduce and spread and leads to cell death.
AZD5363, an AKT inhibitor from AstraZeneca, is a new-generation drug inhibiting the three forms of the AKT protein: AKT1, AKT2 and AKT3. The proteins are critical in cellular processes including glucose metabolism, apoptosis and cell growth.
Olaparib, known as Lynparza from AstraZeneca, a PARP inhibitor, was approved by the U.S. Food and Drug Administration in Dec. 2014 for the treatment of patients with BRCA mutated, advanced ovarian cancer who have previously been treated with chemotherapy.
PARP inhibitors target the enzyme poly (ADP-ribose) polymerase (PARP). Cancers often depend on PARP to repair damaged DNA, but, according to the National Cancer Institute, blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die.
Researchers from France previously reported that cisplatin resistance is linked to changes in cancer cells that render them vulnerable to PARP inhibitors. When a PARP inhibitor was introduced in a mouse with a human non-small cell lung cancer line it “significantly slowed tumor growth.”
Elaine Shattner of Forbes wrote in a May 4 article, “When combined with other treatment – either old-fashioned chemo or novel targeted therapy – the effects (and potential toxicity) of PARP inhibition may be extended to other tumor types, and be more powerful.”
Dr. Mark Robson, a medical oncologist and clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, who has been involved in previous PARP studies, told Shattner, “These drugs will definitely be useful for people who have cancer and known BRCA mutations, and also for some people with other genetic changes in the tumors.”
The findings of the ComPAKT trial were reported at the AACR Annual Meeting 2015.