Three years ago Patricia LoRusso, DO, Professor of Medicine and Associate Director of Experimental era- peutics at Yale Cancer Center, was drawn to Yale in part because of the strong basic science work done here. e group investigating DNA damage repair (DDR) especially impressed her, but she noticed that little of their work had made the jump from the lab to the clinic. Once she arrived, she began looking for ways to change that.
Around the same time, the FDA approved a new drug called olaparib, a PARP inhibitor. PARPs are a group of pro- teins crucial to the repair of damaged DNA. If defective DNA isn’t xed or removed, the cell weakens and o en dies. PARP inhibitors hasten cell death by blocking DNA repair. BRCA mutations are associated with several cancers, including ovar- ian, breast, pancreatic, and prostate cancers, as well as others. Olaparib stops BRCA de cient tumor cells from repairing their DNA, causing further deterioration and cell death.
Dr. LoRusso had done clinical trials on PARP inhibi- tors before coming to Yale. Yale’s DDR group was deeply involved in research about the mechanisms of DNA repair. “Pat and I started talking,” said Joann Balazs Sweasy, PhD, Ensign Professor of erapeutic Radiology and Professor of Genetics, and Associate Director of Basic Science at Yale Cancer Center, “and we found lots of ways to collaborate. ere’s a natural synergy between the clinic, through Pat, and the basic scientists in the DNA repair group here.”
One current project originated when Dr. LoRusso put two observations together. Clinical research had shown that only about 15 percent of women with triple negative breast cancer respond to immune checkpoint inhibitors—immunotherapy drugs. Other clinical research, done a er genetic pro ling of tumors became common, showed that about 15 percent of women with breast cancer have BRCA mutations.
“So my thought was,” explained Dr. LoRusso, “could these 15 percent responders to immune checkpoint inhib- itors actually be patients who had BRCA mutations? And if we treated BRCA-mutant patients with a PARP inhibi- tor, could we increase the responsiveness of the tumor to immune checkpoint inhibitors?”
To investigate this idea she formed a team of basic sci- entists, translational scientists, and clinicians. ey wrote a clinical trial based on the concept, which was approved by the NCI’s Experimental erapeutics Clinical Trials Network (ETCTN). Dr. LoRusso is now enrolling patients. “We’re using PARP inhibitors, including olaparib, to create more mutations in BRCA-mutant breast cancer patients,” said Dr. Sweasy, “because we know that tumors with high levels of mutations have high levels of neoantigens, and we are trying to gure out if tumor cells with high levels of neoantigens will respond more strongly to immunotherapy.”
Neoantigens are proteins produced in response to genetic changes caused by tumor cells. e more muta- tions, the more neoantigens, which sit on the mutated cells’ surfaces and, as foreign bodies, should draw atten- tion from the immune system. Cancer cells are adept at eluding detection, but the greater the number of neoan- tigens, the less likely that cancer cells can go unnoticed.
“Immunotherapy reactivates the immune system and increases the number of tumor in ltrating lymphocytes (TILs),” explained Dr. Sweasy. “We think the TILs will recognize these neoantigens as targets and kill the tumor cells.” Her lab is testing this hypothesis on mouse models and human cancer cell-lines. She calls the results encouraging but preliminary.
Provoking mutations to improve outcomes sounds coun- terintuitive. “Twenty years ago, the more mutations you had, the worse it was,” said Joseph Paul Eder, MD, Professor of Medicine, who is overseeing several clinical trials on olaparib. “Now, patients with the highest burden of muta- tions are most likely to respond to these new immune checkpoint therapies. But these drugs haven’t worked nearly as well in breast cancer as in some other cancers, so the thought is that by inducing even more DNA damage and more mutations with olaparib, we might push breast cancer into the group that’s sensitive to immunotherapies.”
Dr. Sweasy’s BRCA study is one of four that make up projects that the DNA Repair team is moving forward into a team science grant. is team, led by Drs. LoRusso and Sweasy, collaboratively hopes to submit a new SPORE application (Specialized Programs of Research Excellence), a prestigious grant awarded by the NCI, focusing on DNA Repair. Yale already has two SPOREs, in lung cancer and skin cancer, but this one would be unique – focusing on a mechanism that is important in multiple types of tumors, instead of one tumor type or similar groups of tumors.
“Each has basic scientists, translational scientists, and clinical scientists,” said Dr. LoRusso, “to take discoveries from the labs into the clinic and then back into the labs for re nements, with the ultimate intent to improve outcomes for patients.”