Anticancer Synergy

Two investigational antitumor agents work better together against peripheral nerve sheath tumors and neuroblastoma

Timothy CripeTwo investigational agents—the aurora A kinase inhibitor alisertib and the oncolytic herpesvirus HSV1716—have separately shown some antitumor efficacy as monotherapies in early clinical trials. However, a new study demonstrates that their use in combination increases antitumor efficacy in models of malignant peripheral nerve sheath tumor (MPNST) and neuroblastoma.

“We investigated this combination in MPNST and neuroblastoma because these are two difficult-to-treat sarcomas that have shown susceptibility to these agents individually,” explains senior author Timothy Cripe, MD, PhD, a professor of Pediatrics and a researcher at the OSUCCC – James.

“MPNST is a rare pediatric cancer, but for patients with neurofibromatosis 1, a genetic cancer predisposition disorder, it is the leading cause of death. More importantly, MPNST is resistant to chemotherapy,” says Cripe, who also is division chief of Hematology/Oncology and BMT at Nationwide Children’s Hospital (NCH) and a principal investigator at the Center for Childhood Cancer and Blood Diseases in The Research Institute at NCH.

Cripe says many mechanisms likely worked synergistically to increase the antitumor effect in this study. Particularly, HSV1716 increased the sensitivity of uninfected cells to alisertib cytotoxicity. Alisertib also increased peak virus production and slowed virus clearance from tumors. The team also found that alisertib inhibited virus-induced accumulation of intratumoral myeloid-derived suppressor cells.

“Our study shows that alisertib helps the infection phase of HSV1716 because innate immunity is impacted,” Cripe says. “It’s possible that it could inhibit the second phase, the downstream immunotherapeutic effects of the virotherapy, but based on data from other studies, we don’t think that’s the case.”

Published in the journal OncoTarget.

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