Achilles heel for two rare inherited cancer syndromes namely Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and Succinate Dehydrogenase-related Hereditary Paraganglioma and Pheochromocytoma (SDH PGL/PCC) has been discovered by Yale Cancer Center (YCC) scientists. The discovery, published today in Nature Genetics, suggests a promising strategy for treatment with drugs recently approved for other forms of cancer, said the researchers. The two rare inherited tumors can be treated using a new type of medication, called a PARP inhibitor, said Peter Glazer, M.D., Ph.D., chair of the Department of Therapeutic Radiology at YCC, and co-corresponding author on the study.
‘The high levels of metabolites can degrade a process known as homologous recombination, by which cells mend DNA damage that occurs when they divide in rare inherited cancer syndromes.’
Tweet it Now
The two conditions -- called Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and Succinate Dehydrogenase-related Hereditary Paraganglioma and Pheochromocytoma (SDH PGL/PCC) -- boost the risk of tumors that may be benign or cancerous. Oncologists aim to remove tumors by surgery, but treatments are largely ineffective if the tumors have become metastatic. In both inherited cancer syndromes, cells produce abnormally high amounts of metabolites, which are part of the biochemical process that the body uses to turn carbohydrates, fats, and proteins into energy. This is due to inherited defects in the genes that encode for enzymes that normally process these metabolites.
PARP (poly ADP-ribose polymerase) inhibitors are designed to kill off cancer cells that already have lost some of their ability to repair their DNA via homologous recombination. The inhibitors aim to wipe out DNA repair completely, thus killing the cell. The Food and Drug Administration has approved three such drugs to treat breast, ovarian, and other types of cancers with mutations in BRCA genes that disrupt homologous recombination.
Scientists have struggled to find which clues, aside from BRCA status, can predict exactly which patients will benefit from the drugs. "Our research is identifying additional biomarkers for tumors that are sensitive to PARP inhibitors, which will be helpful to the field," said Parker Sulkowski, a graduate student in Glazer's lab and lead author on the paper.
Analysis of these sample tumors indicated defects in DNA repair. The investigators then performed experiments in multiple kinds of human cells that model the two inherited syndromes. These studies demonstrated that the two metabolites could suppress the homologous recombination pathway and leave the cells sensitive to PARP inhibitors.
Advertisement
Given the strength of these pre-clinical findings, co-corresponding authors Brian Shuch, M.D., and Ranjit Bindra, M.D., plan to test PARP inhibitors in clinical trials for these inherited cancer syndromes. Meanwhile, Glazer's lab will continue to probe the underlying biology of the syndromes, seeking a more detailed understanding of how the metabolites suppress DNA repair. The scientists also hope to shed light on related abnormalities in metabolism that might make other cancer indications vulnerable to PARP inhibitors or eventually to other targeted DNA repair inhibitors.
Advertisement
Source-Eurekalert