Yale Cancer Center scientists find that some rare hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair.
Scientists at the Yale Cancer Center (YCC) have recently found that in 2 rare, hereditary cancer syndromes, 2 metabolites—fumarate and succinate—suppress the homologous recombination pathway required for DNA repair and render tumor cells vulnerable to synthetic-lethal targeting via the use of a new treatment: poly ADP-ribose polymerase (PARP) inhibitors.
The two cancers syndromes—Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and Succinate Dehydrogenase-related Hereditary Paraganglioma and Pheochromocytoma (SDC PGL/PCC)—increase the risk of potentially cancerous tumors. Tumors can be removed via surgery, but if the tumors become metastatic in nature, available treatments are largely ineffective.
“Our finding identifies an Achilles heel for these tumors, which potentially can be treated using a new type of medication, called a PARP inhibitor,” Peter Glazer, MD, PhD, chair of the Department of Therapeutic Radiology at YCC, and co-corresponding author of the study said in a recent statement.
PARP inhibitors are a new treatment that has been recently approved by the US Food and Drug Administration for use in patients with breast, ovarian, or other cancers that have mutations in the BRCA genes. These inhibitors were developed to eliminate cancer cells that have already lost some of their ability to repair their DNA through homologous recombination. By “wiping out” DNA repair completely, the inhibitors are able to kill the cancer cell.
Aside from BRCA status, predicting which patients will benefit from the drug has remained a challenge for scientists. As such, for their study, the scientists set out to identify other biomarkers for tumors that may be susceptible to PARP inhibitors.
In both cancer syndromes, there are inherited defects in the genes that are responsible for encoding for enzymes that work to process metabolites. Due to these defects, cells produce abnormally high amounts of metabolites. After an analysis of the sample tumors, the scientists found that high levels of metabolites can damage the process of homologous recombination, a process in which cells repair DNA damage that occurs when they divide.
The scientists then performed experiments in several types of human cells that modeled the 2 conditions. Their research suggested that the 2 metabolites—fumarate and succinate—were capable of suppressing the homologous recombination pathway, leaving the cancer cells vulnerable to PARP inhibitors.
The team went a step further by modeling the disease using xenographs; for these experiments, human tumor cells were implanted into mice. Their findings supported what they noted in the cell experiments: treatment with a PARP inhibitor proved to consistently and significantly slow the growth of the tumors in the mice.
“These results identify HLRCC and SDH PGL/PCC as familial DNA-repair deficiency syndromes, providing a mechanistic basis to explain their cancer predisposition and suggesting a potentially therapeutic approach for advanced HLRCC and SDH PGL/PCC, both of which are incurable when metastatic,” the study authors conclude.