Aurora-A Inhibition Offers a Novel Therapy Effective against Intracranial Glioblastoma

Brocklyn, James R. Van; Wojton, Jeffrey; Meisen, Walter H.; Kellough, David A.; Ecsedy, Jeffrey; Kaur, Balveen; Lehman, Norman L.

doi:10.1158/0008-5472.can-14-0386

Cited by 47 publications

(52 citation statements)

References 24 publications

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“…Other investigators have demonstrated activity of alisertib against orthotopic models deriving from neurosphere cells with stem cell-like properties, the subpopulation of cells being viewed as the most difficult to eradicate and responsible for recurrence following chemotherapy and radiation [30]. Cell line data also indicates additive or synergistic effect with temozolomide and ionizing radiation [31].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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Aurora A Kinase (AURKA), a member of the serine/threonine kinase family, plays a critical role in cell division, and it is widely overexpressed in a variety of tumors including glioblastoma (GBM). Alisertib (MLN8237) is an orally administered selective AURKA inhibitor with potent antiproliferative activity, currently undergoing clinical testing in different tumor types. In vitro evaluation of alisertib against the primary glioblastoma (GBM) lines GBM10, GBM6 and GBM39 showed significant antitumor activity with IC50s ranging between 30–150 nM. Orthotopic xenografts of GBM39, GBM6 and GBM10 were established by implantating 3×105 cells in the caudate nucleus of nude mice; animals were randomized to treatment with either alisertib 30 mg/kg/day or vehicle. In all three models, treatment with alisertib resulted in a statistically significant prolongation of survival (p<0.0001). Alisertib administered in these mice decreased phosphorylated, Aurora-A induced mitotic arrest, and significantly decreased histone H3 phosphorylation in tumors. The same primary glioma lines were previously characterized in orthotopic in vivo models for response to the anti-VEGF antibody bevacizumab; GBM6 and GBM39 were resistant to bevacizumab treatment. In conclusion, alisertib displays significant antitumor activity against primary GBM lines and xenografts, including patient derived GBM lines resistant to bevacizumab; these data support clinical translation in GBM.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Aurora-A is widely expressed in several types of cancer and has been observed to be inversely correlated with patient prognosis (14,15). Previous studies indicated that Aurora-A is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells (26).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, Aurora-A may be an effective target for gene therapy and chemotherapy. A study by Van Brocklyn et al (14) indicated that knockdown of Aurora-A in GBM by alisertib (MLN8237), a highly selective Aurora-A kinase inhibitor, extended the median survival time of mice bearing intracranial human GBM neurosphere tumor xenografts. However, whether knockdown of Aurora-A sensitizes GBM cells to TMZ treatment remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Aurora-A is also overexpressed in terms of mRNA and protein levels in various types of cancer. Ectopic overexpression of Aurora-A has been shown to transform rodent cell lines (14,15), establishing it as a proto-oncogene. Aurora-A has been documented to be involved in p53 regulation as it phosphorylates p53 at Ser315, leading to its mouse double minute 2-mediated ubiquitination and subsequent proteolysis (16).…”

Section: Introductionmentioning

confidence: 99%

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RNA interference targeting Aurora-A sensitizes glioblastoma cells to temozolomide chemotherapy

Gan

Wang

et al. 2016

Oncology Letters

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Clinically, temozolomide (TMZ) is widely used in glioblastoma (GBM) treatment. However, the toxicity of TMZ may influence the quality of patient life. Thus, novel treatment options for sensitizing GBM cells to TMZ chemotherapy are necessary. Aurora-A is widely expressed in GBM and correlated with poor prognosis. It has been proven to be an effective target for gene therapy and chemotherapy. In the present study, short hairpin (sh)RNA targeting Aurora-A was employed to knockdown Aurora-A expression in GBM cells. Cell Counting Kit-8 assays, flow cytometry, colony formation assays, invasion assays and tube formation assays were used to determine the effects of Aurora-A knockdown when combined with TMZ treatment. A U251 subcutaneous cancer model was established to evaluate the efficacy of combined therapy. The results of the present study indicated that the proliferation, colony formation, invasion and angiogenesis of GBM cells were significantly inhibited by combined therapy when compared with TMZ treatment alone. In vivo results demonstrated that knockdown of Aurora-A significantly (P=0.0084) sensitizes GBM cells to TMZ chemotherapy. The results of the present study demonstrated that knockdown of Aurora-A in GBM cells enhances TMZ sensitivity in vitro and in vivo. Therefore, Aurora-A knockdown may be a novel treatment option for decreasing TMZ toxicity and improving patient quality of life.

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“…97-101 A number of xenografted-mouse studies have shown remarkable growth inhibition of solid tumours or haematologic malignancies when treated with alisertib alone or in combination with other anticancer agents. 22,[102][103][104][105][106]…”

Section: Mechanism Of Action and Binding Mode Of Alisertibmentioning

confidence: 99%

An update on the pharmacokinetics and pharmacodynamics of alisertib, a selective Aurora kinase A inhibitor

Durlacher

Chen

et al. 2016

Clin Exp Pharma Physio

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SUMMARYHuman Aurora kinases, including Aurora kinase A (AURKA), B (AURKB), and C (AURKC), play an essential role in mitotic events such as monitoring of the mitotic checkpoint, creation of bipolar mitotic spindle and alignment of centrosomes on it, also regulating centrosome separation, bioorientation of chromosomes and cytokinesis. AURKA and AURKB are key regulators of mitosis and centrosome via polymerizing microfilaments and controlling chromatid segregation. In particular, AURKA plays critical roles in the regulation of mitotic entry, centrosome function, bipolar spindle assembly, and chromosome segregation. AURKA has been found to be overexpressed in various solid and haematological cancers and has been linked with poor prognosis. Its important role in cancer initiation, growth, and metastasis has brought the focus to search for potent and selective AURKA inhibitors for cancer treatment. MLN8237, also known as alisertib, is one selective AURKA inhibitor that has shown remarkable anticancer effects in preclinical studies. Alisertib exhibits favourable pharmacokinetic properties. Alisertib has generally showed good partial response rates of 4-52% and good safety profiles in Phase I and II trials when it is solely administered as well as combined with cytotoxic chemotherapeutic drugs. Recently, the multicentre, randomized Phase III study of alisertib in patients with relapsed or refractory peripheral T-cell lymphoma has been discontinued due to unsatisfactory efficacy. The low risk of side effects, accessibility, and effectiveness of alisertib makes it a new promising anticancer therapy and further mechanistic and clinical studies are warranted.

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Aurora-A Inhibition Offers a Novel Therapy Effective against Intracranial Glioblastoma

Cited by 47 publications

References 24 publications

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

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

RNA interference targeting Aurora-A sensitizes glioblastoma cells to temozolomide chemotherapy

An update on the pharmacokinetics and pharmacodynamics of alisertib, a selective Aurora kinase A inhibitor

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