Roman Groisberg, MD
Investigators will challenge therapeutic convention by testing a PARP inhibitor instead of an IDH-targeted therapy in patients with metastatic IDH1/2
-mutated glioma, cholangiocarcinoma, and other solid tumors that are refractory to standard treatment.
mutations don’t repair DNA properly,” Roman Groisberg, MD, principal investigator at 2 of the sites conducting the phase II study, Rutgers Cancer Institute of New Jersey and the Robert Wood Johnson University Hospital New Brunswick, both in New Brunswick, New Jersey. “We’re giving these cells a double whammy, prompting them to go into cell death,” added Groisberg, a medical oncologist at Rutgers Cancer Institute.
Figure. Olaparib in Advanced Glioma, Cholangiocarcinoma, and Other Tumors With IDH1/2 Mutations (Click to Enlarge)
Sulkowski et al’s research not only established that IDH1/2
-mutated cells have reduced DNA repair capability but also showed that 2-hydroxyglutarate (2-HG) may be the driving force of this cellular weakness. IDH
mutations are neomorphic, which means the alterations induce a change in the traditional function of the IDH protein. Whereas normal, unmutated IDH proteins produce energy, mutated proteins generate the 2-HG oncometabolite, which amplifies HR deficiency and, consequently, sensitivity to PARP inhibitors.1-3
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