Alisertib demonstrates significant antitumor activity in bevacizumab resistant, patient derived orthotopic models of glioblastoma

Kurokawa, Cheyne; Geekiyanage, Hirosha; Allen, Cory; Iankov, Ianko; Schroeder, Mark A.; Carlson, Brett L.; Bakken, Katie; Sarkaria, Jann N.; Ecsedy, Jeffrey; D’Assoro, Antonino B.; Friday, Bret Edward Buckley; Galanis, Evanthia

doi:10.1007/s11060-016-2285-8

Cited by 27 publications

(18 citation statements)

References 32 publications

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“…We also used a selective AURKA inhibitor, the Food and Drug Administration-approved MLN8237 (Alisertib), with an indicative inhibitory effect in a variety of malignancies including GBM (59)(60)(61)(62)(63). The IC 50 concentrations of MLN8237 in the CDC20-M-high N5, N9, and N33 glioma cell lines were about 100-fold lower than that of proTAME.…”

Section: The Cdc20-m Signature Is a Robust Marker Of Poor Prognosis Formentioning

confidence: 99%

Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Genomic instability (GI) drives tumor heterogeneity and promotes tumor progression and therapy resistance. However, causative factors underlying GI and means for clinical detection of GI in glioma are inadequately identified. We describe here that elevated expression of a gene module coexpressed with CDC20 (CDC20-M), the activator of the anaphase-promoting complex in the cell cycle, marks GI in glioma. The CDC20-M, containing 139 members involved in cell proliferation, DNA damage response, and chromosome segregation, was found to be consistently coexpressed in glioma transcriptomes. The coexpression of these genes was conserved across multiple species and organ systems, particularly in human neural stem and progenitor cells. CDC20-M expression was not correlated with the morphological subtypes, nor with the recently defined molecular subtypes of glioma. CDC20-M signature was an independent and robust predictor for poorer prognosis in over 1,000 patients from four large databases. Elevated CDC20-M signature enabled the identification of individual glioma samples with severe chromosome instability and mutation burden and of primary glioma cell lines with extensive mitotic errors leading to chromosome mis-segregation. AURKA, a core member of CDC20-M, was amplified in one-third of CDC20-M–high gliomas with gene-dosage–dependent expression. MLN8237, a Food and Drug Administration-approved AURKA inhibitor, selectively killed temozolomide-resistant primary glioma cells in vitro and prolonged the survival of a patient-derived xenograft mouse model with a high–CDC20-M signature. Our findings suggest that application of the CDC20-M signature may permit more selective use of adjuvant therapies for glioma patients and that dysregulated CDC20-M members may provide a therapeutic vulnerability in glioma.

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Section: The Cdc20-m Signature Is a Robust Marker Of Poor Prognosis Formentioning

confidence: 99%

Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…AURKA interferes with GSK3/axin/b-catenin through interaction with axin. In patient-derived orthotopic models of GBM resistant to bevacizumab, alisertib prolonged survival, induced mitotic arrest and decreased histone H3 phosphorylation (209). In a recent phase I clinical trial for GBM patients, alisertib was safe and well tolerated (210).…”

Section: Crosstalk Between Autophagy Epithelial-mesenchymal Transitimentioning

confidence: 98%

Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma

et al. 2020

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“…In THCA cells, MLN8237 disrupts c-Myc/AURKA complex formation, and c-Myc is a major determinant of MLN8237 responsiveness both in vitro and in vivo [138]. MLN8237 has demonstrated efficacy in cell-derived and patient-derived xenograft (PDX) models of numerous tumor types, including glioblastoma [139], bladder cancer [140], esophageal adenocarcinoma [136], multiple myeloma [132], neuroblastoma [141] and colon cancer [142].…”

Section: Specific Akismentioning

confidence: 99%

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

et al. 2021

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Aurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

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Alisertib demonstrates significant antitumor activity in bevacizumab resistant, patient derived orthotopic models of glioblastoma

Cited by 27 publications

References 32 publications

Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma

Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma

Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

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