mln-8237 and Glioma

We conducted a phase I trial of alisertib, an oral aurora kinase inhibitor, with fractionated stereotactic re-irradiation therapy (FSRT) for patients with recurrent high grade glioma (HGG).. Adult patients with recurrent HGG were enrolled from Feb 2015 to Feb 2017. Patients were treated with concurrent FSRT and alisertib followed by maintenance alisertib. Concurrent alisertib dose was escalated from 20 mg to 50 mg twice daily (BID).. 17 patients were enrolled. Median follow-up was 11 months. Median FSRT dose was 35 Gy. There were 6, 6, 3, and 2 patients enrolled in 20 mg, 30 mg, 40 mg, and 50 mg cohort, respectively. Only one DLT was observed. One patient in the 20 mg cohort had severe headache (Grade 3) resolved with steroids. There was no non-hematological grade 3 or higher toxicity. There were two Grade 4 late toxicities (one with grade 4 neutropenia and leukopenia, one with pulmonary embolism). One patient developed radiation necrosis (Grade 3). Sixteen patients finished concurrent treatment and received maintenance therapy (median cycles was 3, range 1-9). OS for all cohorts at 6 months was 88.2% with median survival time of 11.1 months. PFS at 6 months was 35.3% with median time to progression of 4.9 months. The trial stopped early due to closure of alisertib program with only 2 of 3 planned patients enrolled in the 50 mg cohort.. Re-irradiation with FSRT combined with alisertib is safe and well tolerated for HGG with doses up to 40 mg BID. Although no DLT observed in the 50 mg cohort, this cohort was not fully enrolled and MTD was not reached. Clinical outcomes appear comparable to historical results. (NCT02186509).

Topics: Adult; Aged; Azepines; Brain Neoplasms; Chemoradiotherapy; Cohort Studies; Female; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Radiosurgery; Re-Irradiation; Treatment Outcome

Aurora A is critical for mitosis and is overexpressed in several neoplasms. Its overexpression transforms cultured cells, and both its overexpression and knockdown cause genomic instability. In transgenic mice, Aurora A haploinsufficiency, not overexpression, leads to increased malignant tumor formation. Aurora A thus appears to have both tumor-promoting and tumor-suppressor functions. Here, we report that Aurora A protein, measured by quantitative protein gel blotting, is differentially expressed in major glioma types in lineage-specific patterns. Aurora A protein levels in WHO grade II oligodendrogliomas (n=16) and grade III anaplastic oligodendrogliomas (n=16) are generally low, similar to control epilepsy cerebral tissue (n=11). In contrast, pilocytic astrocytomas (n=6) and ependymomas (n=12) express high Aurora A levels. Among grade II to grade III astrocytomas (n=7, n=14, respectively) and grade IV glioblastomas (n=31), Aurora A protein increases with increasing tumor grade. We also found that Aurora A expression is induced by hypoxia in cultured glioblastoma cells and is overexpressed in hypoxic regions of glioblastoma tumors. Retrospective Kaplan-Meier analysis revealed that both lower Aurora A protein measured by quantitative protein gel blot (n=31) and Aurora A mRNA levels measured by real-time quantitative RT-PCR (n=58) are significantly associated with poorer patient survival in glioblastoma. Furthermore, we report that the selective Aurora A inhibitor MLN8237 is potently cytotoxic to glioblastoma cells, and that MLN8237 cytotoxicty is potentiated by ionizing radiation. MLN8237 also appeared to induce senescence and differentiation of glioblastoma cells. Thus, in addition to being significantly associated with survival in glioblastoma, Aurora A is a potential new drug target for the treatment of glioblastoma and possibly other glial neoplasms.

Topics: Adolescent; Adult; Aged; Aurora Kinase A; Aurora Kinases; Azepines; Biomarkers; Brain Neoplasms; Cell Differentiation; Cell Line, Tumor; Cellular Senescence; Child; Female; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioma; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Staging; Protein Serine-Threonine Kinases; Pyrimidines; Radiation, Ionizing; Retrospective Studies; RNA, Messenger; Young Adult