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|Ref Type||Journal Article|
|Authors||Davis SL, Ionkina AA, Bagby SM, Orth JD, Gittleman B, Marcus JM, Lam ET, Corr BR, O'Bryant CL, Glode AE, Tan AC, Kim J, Tentler JJ, Capasso A, Lopez KL, Gustafson DL, Messersmith WA, Leong S, Eckhardt SG, Pitts TM, Diamond JR|
|Title||Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2020 May 15|
|Abstract Text||The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors.TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD).The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia.The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo, resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Alisertib||MLN8237||Aurka Inhibitors 23||Alisertib (MLN8237) binds to and inhibits Aurora A kinase, which may result in disruption of the assembly of the mitotic spindle apparatus, disruption of chromosome segregation, and inhibition of cell proliferation (PMID: 26999067, PMID: 32414750).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||Alisertib + Sapanisertib||Phase I||Actionable||In a Phase I trial, the combination of Alisertib (MLN8237) and Sapanisertib (MLN0128) demonstrated tolerability in patients with advanced solid tumors, with 70% (7/10) of patients demonstrating stable disease for a median duration of 4 months (PMID: 32414750).||32414750|
|Unknown unknown||triple-receptor negative breast cancer||not applicable||Alisertib + Sapanisertib||Preclinical - Pdx||Actionable||In a preclinical study, the combination treatment of Alisertib (MLN8237) and Sapanisertib (MLN0128) resulted in decreased proliferation in triple-receptor negative breast cancer (TNBC) cell lines in culture and reduced tumor growth in patient-derived xenograft (PDX) TNBC models, with one model showing tumor growth inhibition of 94.27% compared to 54.47% with Sapanisertib (MLN0128) alone and 35.09% with Alisertib (MLN8237) alone (PMID: 32414750).||32414750|