Concurrent Inhibition of Neurosphere and Monolayer Cells of Pediatric Glioblastoma by Aurora A Inhibitor MLN8237 Predicted Survival Extension in PDOX Models

Abstract

Pediatric glioblastoma multiforme (pGBM) is a highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which model system (monolayer or neurosphere) can predict therapeutic efficacy AURKA mRNA expressions were screened with qRT-PCR. antitumor effects were examined in three matching pairs of monolayer and neurosphere lines established from patient-derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-3752GBM), and terminal (IC-R0315GBM) tumors, and therapeutic efficacy through log rank analysis of survival times in two models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, orally, 12 days). Drug concentrations and mechanism of action and resistance were also investigated. AURKA mRNA overexpression was detected in 14 pGBM tumors, 10 PDOX models, and 6 cultured pGBM lines as compared with 11 low-grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited , but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM). Apoptosis-mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133 cells appears to have contributed to therapy resistance. MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133 pGBM cells to prevent tumor recurrence. .

Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives

“…These authors used a pan-AURK inhibitor, VX680 (33), followed by radiation, in cell culture and xenograft models, and demonstrated the induction of apoptosis and reduction of tumor growth [172]. Hong and coworkers also demonstrated that MLN8237 (alisertib) (34) [214][215][216], a highly selective AURK inhibitor, inhibits colony formation in GSCs and potentiates the effects of radiation and TMZ in glioblastoma monolayers and GSCs [217]. Importantly, MLN8237 is relatively non-toxic to normal human astrocytes.…”

A novel 3D in vitro model of glioblastoma reveals resistance to temozolomide which was potentiated by hypoxia

“…However, data from the 2D cultures are largely unreliable, as cells cultured in this model are not a true representative of the in vivo tumour microenvironment and, animal studies, as a result of interspecies differences, fail to fully recapitulate the response to drugs in humans with about 95% of anti-cancer drug candidates failing to make it to the clinic, thereby wasting significant time and resources [ 7 ]. The neurosphere assay is an acceptable 3D model for maintaining glioblastoma in vitro [ 8 – 10 ]. Although this assay has undoubtedly been regarded as the gold standard assay that selects for stem cell populations, it has a major drawback of allowing cells to form their own niche, with more differentiated cells positioned at the center than on the surface as well as containing a mixed population of cells and a small number of true stem cells [ 11 ].…”

Identification of key genes related to dexamethasone-resistance in acute lymphoblastic leukemia

“…Our study also indicated that KPNA2 could be a biomarker for ALL prognosis. AURKA plays an important role in the development of pediatric glioblastoma (pGBM), and its inhibitor is considered as the effective therapy of pGBM [32] . AURKA, is a type of Aurora kinases.…”