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.

Autor:	Davis SL; University of Colorado Cancer Center, Aurora, Colorado., Ionkina AA; University of California, Irvine, Irvine, California., Bagby SM; University of Colorado Cancer Center, Aurora, Colorado., Orth JD; University of Colorado Boulder, Boulder, Colorado., Gittleman B; University of Colorado Cancer Center, Aurora, Colorado., Marcus JM; University of Alabama at Birmingham, Birmingham, Alabama., Lam ET; University of Colorado Cancer Center, Aurora, Colorado., Corr BR; University of Colorado Cancer Center, Aurora, Colorado., O'Bryant CL; University of Colorado Cancer Center, Aurora, Colorado., Glode AE; University of Colorado Cancer Center, Aurora, Colorado., Tan AC; Moffitt Cancer Center, Tampa, Florida., Kim J; University of Colorado Cancer Center, Aurora, Colorado., Tentler JJ; University of Colorado Cancer Center, Aurora, Colorado., Capasso A; Department of Oncology, The University of Texas at Austin, Dell Medical School, Austin, Texas., Lopez KL; University of Colorado Cancer Center, Aurora, Colorado., Gustafson DL; Colorado State University, Fort Collins, Colorado., Messersmith WA; University of Colorado Cancer Center, Aurora, Colorado., Leong S; University of Colorado Cancer Center, Aurora, Colorado., Eckhardt SG; Department of Oncology, The University of Texas at Austin, Dell Medical School, Austin, Texas., Pitts TM; University of Colorado Cancer Center, Aurora, Colorado., Diamond JR; University of Colorado Cancer Center, Aurora, Colorado. Jennifer.Diamond@cuanschutz.edu.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Sep 01; Vol. 26 (17), pp. 4633-4642. Date of Electronic Publication: 2020 May 15.
DOI:	10.1158/1078-0432.CCR-19-3498
Abstrakt:	Purpose: 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. Experimental Design: 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). Results: 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. Conclusions: 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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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