A phase 2 study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group study 0231D

Hyman, David M.; Sill, Michael W.; Lankes, Heather A.; Piekarz, Richard; Shahin, Mark S.; Ridgway, Mildred; Backes, Floor J.; Tenney, Meaghan; Mathews, Cara; Hoffman, James S.; Aghajanian, Carol; Hensley, Martee L.

doi:10.1016/j.ygyno.2016.10.036

Cited by 21 publications

(23 citation statements)

References 37 publications

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“…While alisertib demonstrated preclinical activity against pediatric solid tumors including ES, it did not meet study criteria for significant benefit in single‐agent use in clinical trials . In those studies, because of the myelosuppression caused by the drug at the maximally tolerated dose, it was administered for 7 days followed by 2 weeks of recovery.…”

Section: Discussionmentioning

confidence: 99%

“…However, in the Phase 1 pediatric clinical trial, alisertib had higher toxicity in children than in adults, limiting its maximally tolerated dose . Alisertib failed to meet response criteria in multiple Phase 2 studies when used alone, but next‐generation inhibitors of AURKA are in development, and AURKA inhibition in combination with other treatment approaches may be particularly effective against ES.…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial BRD4 and AURKA inhibition is synergistic against preclinical models of Ewing sarcoma

et al. 2019

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Background: Ewing sarcoma (ES), a bone cancer affecting children, adolescents, and young adults, is driven by the EWS-FLI1 fusion protein in the majority of cases, but the mechanisms of tumorigenesis are still being elucidated. Consequentially, therapeutic advances have been limited in the last 25 years. Two therapeutic targets have been recently examined. Aurora kinase A (AURKA) promotes cell cycling and posttranslational stabilization of the oncoprotein MYC, while bromodomain-containing protein 4 (BRD4) promotes gene expression epigenetically. Studies of AURKA and BRD4 inhibitors showed some impairment of tumorigenesis in ES preclinical models, but this efficacy was limited in single-agent use. AURKA and BRD4 activate common oncogenic pathways through different mechanisms, so we hypothesized dual inhibition would be synergistic against tumorigenesis. Aims: (a) Define the synergistic antineoplastic effects of BRD4 inhibitor I-BET151 and AURKA inhibitor alisertib against ES cell lines in vitro. (b) Confirm the mechanism of activity of each agent in these cell line models. (c) Define the efficacy of I-BET 151 and alisertib alone and in combinations with each other, and with the chemotherapeutic drug vincristine against ES tumor xenografts in vivo. Methods and results: I-BET151 and alisertib synergistically inhibit viability in ES cell lines SK-ES, TC71, and ES2 in vitro. Alisertib alone upregulates transcriptional expression of its targets, but combined use of I-BET151 mitigates that upregulation, likely contributing to the drug synergy and downregulating RNA and protein expression of key oncogenic pathways as shown by RT-qPCR and western blot. Alisertib and I-BET151 significantly prolong survival in three ES xenograft models in vivo, and this efficacy is augmented by the addition of vincristine. Conclusion: Dual targeting of oncogenic drivers in ES epigenetically and posttranslationally, specifically by use of BRD4 and AURKA inhibitors, may have significant clinical efficacy in ES alone and/or in combination with current chemotherapy regimens.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combinatorial BRD4 and AURKA inhibition is synergistic against preclinical models of Ewing sarcoma

et al. 2019

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“…Although alisertib showed preclinical antitumor efficacy, it failed to show meaningful activity in single-agent use in multiple clinical trials [18] , [21] , [45] , in which it was administered for 7 days with 14 days of recovery. We have shown that alisertib treatment induces rebound transcriptional and protein overexpression of its targets, which may be a mechanism of resistance against the drug and account for the lack of clinical efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…However, in the Phase 1 pediatric clinical trial, it had higher toxicity in children than in adults, limiting its maximally tolerated dose [17] . Alisertib failed to meet response criteria in multiple phase 2 studies when used alone [18] , [19] , [20] , [21] but is being examined in combination therapies.…”

Section: Introductionmentioning

confidence: 99%

Dual BRD4 and AURKA Inhibition Is Synergistic against MYCN-Amplified and Nonamplified Neuroblastoma

et al. 2018

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A majority of cases of high-risk neuroblastoma, an embryonal childhood cancer, are driven by MYC or MYCN-driven oncogenic signaling. While considered to be directly “undruggable” therapeutically, MYC and MYCN can be repressed transcriptionally by inhibition of Bromodomain-containing protein 4 (BRD4) or destabilized posttranslationally by inhibition of Aurora Kinase A (AURKA). Preclinical and early-phase clinical studies of BRD4 and AURKA inhibitors, however, show limited efficacy against neuroblastoma when used alone. We report our studies on the concomitant use of the BRD4 inhibitor I-BET151 and AURKA inhibitor alisertib. We show that, in vitro, the drugs act synergistically to inhibit viability in four models of high-risk neuroblastoma. We demonstrate that this synergy is driven, in part, by the ability of I-BET151 to mitigate reflexive upregulation of AURKA, MYC, and MYCN in response to AURKA inhibition. We then demonstrate that I-BET151 and alisertib are effective in prolonging survival in four xenograft neuroblastoma models in vivo, and this efficacy is augmented by the addition of the antitubule chemotherapeutic vincristine. These data suggest that epigenetic and posttranslational inhibition of MYC/MYCN-driven pathways may have significant clinical efficacy against neuroblastoma.

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“…Although alisertib showed preclinical antitumor efficacy, it failed to show meaningful activity in single-agent use in multiple clinical trials 18,44,45 , in which it was administered for 7 days with 14 days of recovery. We have shown that alisertib treatment induces rebound transcriptional overexpression of its targets, which may account for the lack of clinical efficacy.…”

Section: Discussionmentioning

confidence: 99%

Dual BRD4 and AURKA Inhibition is Synergistic against MYCN-amplified and nonamplified Neuroblastoma

Felgenhauer

Tomino

Selich‐Anderson

et al. 2018

Preprint

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A majority of cases of high-risk neuroblastoma, an embryonal childhood cancer, are driven by MYC or MYCN-driven oncogenic signaling. While considered to be directly "undruggable" therapeutically, MYC and MYCN can be repressed transcriptionally by inhibition of Bromodomain-containing protein 4 (BRD4) or destabilized posttranslationally by inhibition of Aurora Kinase A (AURKA). Preclinical and early-phase clinical studies of BRD4 and AURKA inhibitors, however, show limited efficacy against neuroblastoma when used alone. We report our studies on the concomitant use of the BRD4 inhibitor IBET-151 and AURKA inhibitor alisertib. We show that, in vitro, the drugs act synergistically to inhibit viability in three models of high-risk neuroblastoma. We demonstrate that this synergy is driven, in part, by the ability of IBET-151 to mitigate reflexive upregulation of AURKA, MYC, and MYCN in response to AURKA inhibition. We then demonstrate that IBET-151 and alisertib are effective in prolonging survival in three xenograft neuroblastoma models in vivo, and this efficacy is augmented by the addition of the antitubule chemotherapeutic vincristine. These data suggest that epigenetic and posttranslational inhibition of MYC/MYCN-driven pathways may have significant clinical efficacy against neuroblastoma.

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A phase 2 study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group study 0231D

Cited by 21 publications

References 37 publications

Combinatorial BRD4 and AURKA inhibition is synergistic against preclinical models of Ewing sarcoma

Combinatorial BRD4 and AURKA inhibition is synergistic against preclinical models of Ewing sarcoma

Dual BRD4 and AURKA Inhibition Is Synergistic against MYCN-Amplified and Nonamplified Neuroblastoma

Dual BRD4 and AURKA Inhibition is Synergistic against MYCN-amplified and nonamplified Neuroblastoma

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