A pediatric phase I trial and pharmacokinetic study of MLN8237, an oral selective small molecule inhibitor of aurora a kinase: A Children's Oncology Group Phase I Consortium study.

Mossé, Yaël P.; Lipsitz, Emily; Maris, John M.; Weigel, Brenda; Adamson, P. C.; Ingle, M.; Ahern, Charlotte H.; Blaney, S.

doi:10.1200/jco.2010.28.15_suppl.9529

Cited by 3 publications

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“…Our experiments show that the cytotoxic effects of the combination of vorinostat and MLN8237 are additive for MOLT-4, Daoy, and IMR-32. For MLN8237, the single agent IC 50 s in medulloblastoma, neuroblastoma, and leukemia (<0.04 μM) are well below the average steady state concentrations achieved in adults (~1.7 μM) [30] and children (3.7 μM) [31] at the recommended phase 2 dose of MLN8237. For vorinostat, the single-agent IC 50 s were in or near the clinically achievable range (1–2 μM) [32].…”

Section: Discussionmentioning

confidence: 99%

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Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines

et al. 2012

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Summary Purpose Histone deacetylase (HDAC) inhibitors, such as vorinostat, decrease Aurora kinase activity by a variety of mechanisms. Vorinostat and MLN8237, a selective Aurora A kinase inhibitor, disrupt the spindle assembly and the mitotic checkpoint at different points, suggesting that the combination could have increased antitumor activity. The purpose of this study was to determine the cytotoxicity of vorinostat and MLN8237 in pediatric tumor cell lines. Methods Cell survival was measured after 72 h of drug treatment using a modified methyl tetrazolium assay. For drug combination experiments, cells were exposed to medium alone (controls), single drug alone, or to different concentrations of the combination of the two drugs, for a total of 36 concentration pairs per plate. The interaction of the drug combination was analyzed using the universal response surface approach. Results The cells express the target of MLN8237, Aurora A. For each cell line, the single agent IC50 for MLN8237 and for vorinostat was in the clinically relevant range. Both drugs inhibited cell survival in a concentration-dependent fashion. At concentrations of MLN8237 exceeding approximately 1 μM, there was a paradoxical increase in viability signal in all three lines that may be explained by inhibition of Aurora B kinase. The combination of MLN8237 and vorinostat showed additive cytotoxicity in all three cell lines and nearly abrogated the paradoxical increase in survival noted at high single-agent MLN8237 concentrations. Conclusion MLN8237 and vorinostat are active in vitro against cancer cell lines. These results provide important preclinical support for the development of future clinical studies of MLN8237and vorinostat.

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Section: Discussionmentioning

confidence: 99%

“…The dose limiting toxicities of vorinostat in children were neutropenia, thrombocytopenia, and hypokalemia [9], while the dose limiting toxicities of MLN8237 included mucositis, mood alteration, neutropenia, and thrombocytopenia [31]. Thus the combination of vorinostat and MLN8237 may results in additive myelosuppression.…”

Section: Discussionmentioning

confidence: 99%

Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines

et al. 2012

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“…A secondary analysis of 117 patients enrolled in the phase I trials confirmed 50mg orally twice daily for 7 days every 21 days to produce steady-state average serum concentrations approximately 1.7μM, almost double the serum concentration determined in preclinical models to maximize anti-tumor effects 50. A phase I study in 37 pediatric patients found increased dose-related toxicities of myelosuppression and dermatologic toxicity with multiple daily dosing and determined a phase 2 dose in pediatric patients to be 80mg/m 2 /day orally 51. Based upon these results, numerous phase I and phase II studies are currently ongoing with MLN8237, both as single agent and in combination with other anti-cancer therapies 28…”

Section: 0 Principles and Therapeutic Targeting Of Aurora Kinasesmentioning

confidence: 95%

Update on Aurora Kinase Inhibitors in Gynecologic Malignancies

Tao

Chon

et al. 2008

PRA

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Introduction Mammalian cells contain three distinct serine/threonine protein kinases with highly conserved catalytic domains, including aurora A and B kinases that are essential regulators of mitotic entry and progression. Overexpression of aurora A and/or B kinase is associated with high proliferation rates and poor prognosis, making them ideal targets for anti-cancer therapy. Disruption of mitotic machinery is a proven anti-cancer strategy employed by multiple chemotherapeutic agents. Numerous small molecule inhibitors of the aurora kinases have been discovered and tested in vivo and in vitro, with a few currently in phase II testing. Areas covered This review provides the reader with updated results from both preclinical and human studies for each of the aurora kinase inhibitors (AKI) that are currently being investigated. The paper also covers in detail the late breaking and phase I data presented for AKIs thereby allowing the reader to compare and contrast individual and class-related effects of AKIs. Expert opinion While the successful development and approval of an AKI for anti-cancer therapy remains unresolved, pre-clinical identification of resistant mechanisms would help design better early phase clinical trials where relevant combinations may be evaluated prior to phase II testing. The authors believe that aurora kinases are important anti-cancer targets that operate in collaboration with other oncogenes intimately involved in uncontrolled tumor proliferation and by providing a unique, targeted and complimentary anti-cancer mechanism, expand the available armamentarium against cancer.

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Future of Clinical Genomics in Pediatric Oncology

Janeway

Place

Kieran

et al. 2013

JCO

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The somatic genomic alterations in pediatric cancers to some extent overlap with those seen in adult cancers, but the exact distribution throughout the genome and the types and frequency of alterations differ. The ultimate goal of genomic research in children, as with adults, is translation to the clinic to achieve more accurate diagnosis, more precise risk stratification, and more effective, less toxic therapy. The genomic features of pediatric malignancies and pediatric-specific issues in clinical investigation may make translating genomic discoveries to the clinic more difficult. However, through large-scale molecular profiling of pediatric tumors, continued coordinated efforts to evaluate novel therapies in the pediatric population, thoughtful phase II and III trial design, and continued drug development, genomically based therapies will become more common in the pediatric oncology clinic in the future.

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A pediatric phase I trial and pharmacokinetic study of MLN8237, an oral selective small molecule inhibitor of aurora a kinase: A Children's Oncology Group Phase I Consortium study.

Cited by 3 publications

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Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines

Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines

Update on Aurora Kinase Inhibitors in Gynecologic Malignancies

Future of Clinical Genomics in Pediatric Oncology

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