Aurora kinase inhibition in combination with an oncolytic herpes simplex virus could represent a novel treatment approach for patients with neurofibromatosis type 1 who develop malignant peripheral nerve sheath tumors.
NF1 is a common autosomal dominant disorder caused by a mutation in the NF1 tumor suppressor gene, which results in acti- vation of the RAS pathway. These patients are highly predisposed to develop peripheral nerve tumors.
An MPNST is a rare and aggressive type of soft tissue sarcoma that is associated with a poor prognosis and is a major source of mortality in adult patients with NF1, according to Nancy Ratner, PhD. Currently, the only treatment approach for these tumors is surgery.
Ratner, program leader of the Cancer Biology and Neural Tumors Program, and the Beatrice C. Lampkin Chair of Cancer Biology, Cincinnati Children’s Hospital Medical Center, and colleagues investigated genes that are more commonly upregulated in neurofibroma and MPNSTs, compared with normal cells, to identify potential targets for therapy.
AURKA and AURKB were both expressed at higher levels in MPNST cells than in normal cells. These oncogenes have also been noted at high levels in many other cancer types, Ratner said.
In studies of MPNST xenografts, tumor growth was prevented with Aurora kinase inhibition. “As long as one kept applying the drug, one actually maintained a block in tumor growth,” Ratner said. Yet once the drug was stopped, the tumor regrew.
In a phase II study of alisertib (MLN8237), an oral adenosine triphosphate-competitive AURKA inhibitor, in patients with various types of advanced or metastatic sarcoma, the drug showed a promising benefit in progression-free survival (PFS).1
While the primary endpoint of response rate was not met, with only 2 confirmed responses, the PFS was notable at 11.7 weeks (95% CI, 7.0-13.0). Ten patients (14%) in the trial had MPNSTs.
In this cohort, the median PFS was 13 weeks (95% CI, 3.6- 45); at 12 weeks, the PFS rate was 60% and the median overall survival rate was 69 weeks (95% CI, 16 to not reached).
The AURKA inhibitor was well tolerated, but grade 3/4 adverse events in all patients included oral mucositis (12%), anemia (14%), platelet count decrease (14%), leukopenia (22%), and neutropenia (42%).
“PFS at 12 weeks of >40% has been considered a sign of an active drug in sarcoma. By this metric, the results of alisertib are promising, especially in liposarcoma (PFS of 73% at 12 weeks), leiomyosarcoma (44%), and MPNSTs (60%), although the number of patients in each cohort remains small,” Dickson et al wrote in their paper.
Ratner and colleagues sought to find treatments that could be combined with AURKA inhibition: “this has been extremely frus- trating because many agentsfor example MEK inhibitors—failed to be better than Aurora kinase inhibition alone,” she commented.
MEK inhibition was tested in xenograft models of MPNSTs due to the negative regulation of the MAPK pathway noted in human and mouse MPNST cells compared with normal cells. While it did translate to a modest benefit in survival, she noted that MEK inhibition was not enough.
Ratner and colleagues found a synergy between an oncolytic herpes virus and Aurora kinase inhibition.
Previously, in preclinical studies, MPNST-derived cell lines were found to be sensitive to treatment with the oncolytic herpes simplex virus as a single agent.2The virus was injected into the tumor and blood stream and resulted in a direct lysing of tumor cells and nearby cells, she explained. This effect was increased in the combination with alisertib.
In xenograft models of MPNSTs, alisertib was combined with HSV1716, a virus derived from HSV-1. Alisertib was administered at 20 mg/kg twice a day Monday to Friday, with 2 days off, and 1 dose of the virus.3At this dose, responses were noted in all tumors. However, the 20 mg/kg dose was considered too high for humans to tolerate, so it reduced to 10 mg/kg on the same schedule. The combination reduced tumor growth and increased survival.
“The virus itself causes an increase in the percent of myeloid-derived suppressor cells and natural killer cells that is not present in the combination,” Ratner said, adding that she believed that the combination created a more pronounced effect.
She also noted that her colleague, Timothy P. Cripe, MD, PhD, is working to bring this combination of an oncolytic herpes virus and Aurora kinase inhibition into human trials of patients with MPNSTs.