17 July 2018
PARP inhibitors like AstraZeneca’s Lynparza and Tesaro’s Zejula have revolutionized the treatment of ovarian cancers with BRCA mutations and are starting to take off in breast cancer treatment too. But the way that these drugs work could make them applicable to many more cancer types, some oncology researchers believe.
The latest evidence of that comes from Yale University, where a group of researchers have been investigating the potential of PARP inhibitors in two rare, inherited cancers: hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC). Both tumor types share an “Achilles heel” that could make them vulnerable to PARP inhibition, they discovered.
PARP inhibitors work by targeting cancer cells that have lost some of their ability to repair their own DNA with a process known as “homologous recombination.” Blocking the PARP enzyme shuts down DNA repair altogether, which ultimately kills the cancer cells. BRCA mutations also hamper homologous recombination, and the addition of PARP inhibition has been shown to be effective in patients with the mutations.
But BRCA status may not be the only predictor of which patients might benefit from PARP inhibition, the Yale researchers believe. In HLRCC and SDH PGL/PCC, tumor cells churn out high levels of metabolites that interfere with homologous recombination. So they posited that PARP inhibitors might work in those cancers, too.
Using samples of multiple types of human cells, the Yale team demonstrated that two metabolites suppressed homologous recombination and made cells vulnerable to PARP inhibition. They then implanted human cancer cells into mice, and discovered that PARP-inhibiting drugs slowed tumor growth. They reported their findings in the journal Nature Genetics.
The Yale researchers aren’t alone in their belief that PARP inhibitors may be able help a much larger patient population beyond ovarian and breast cancer. BRCA mutations are also prevalent in aggressive prostate cancer, and several ongoing clinical trials are investigating the efficacy of FDA-approved PARP inhibitors in men with the disease. Last year, scientists at the University of Toronto reported that abnormalities in the gene ATM may also make prostate tumors amenable to PARP inhibition.
And researchers in the U.K. have found that Lynparza combined with the chemotherapy drug temozolomide could be effective in treating the brain tumor glioblastoma. After treating 35 patients with the cocktail last year, they discovered that the drug not only penetrated the blood-brain barrier and burrowed into the core of the glioblastoma tumors, it also reached cancer cells that had spread to areas of the brain that would be difficult for surgeons to access.
The Yale team is now planning clinical trials of PARP inhibitors in patients with HLRCC and SDH PGL/PCC. They will also continue to study the underlying biology of the two cancers, in the hopes of finding related abnormalities in metabolism that might point to other cancers that could be treated with PARP inhibition.
"Our finding of this unexpected link between metabolism and DNA repair in these cancers is opening up a whole area of research," said co-author Peter Glazer, M.D., Ph.D., chair of the department of therapeutic radiology at Yale Cancer Center, in a statement.Print
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