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10780432ccr120436-sup-tab1-4.pdf (39.86 kB)

Supplementary Tables 1 - 4 from Dual Targeting of mTOR and Aurora-A Kinase for the Treatment of Uterine Leiomyosarcoma

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posted on 2023-03-31, 17:52 authored by Kari J. Brewer Savannah, Elizabeth G. Demicco, Kristelle Lusby, Markus PH. Ghadimi, Roman Belousov, Eric Young, Yiqun Zhang, Kai-Lieh Huang, Alexander J. Lazar, Kelly K. Hunt, Raphael E. Pollock, Chad J. Creighton, Matthew L. Anderson, Dina Lev

PDF file, 39K, Table S1: correlation between biomarker expression and tumor status; Table S2: correlation between mTOR associated biomarkers' expression; Table S3: univariable and multivariable Cox analyses for biomarker expression correlation with ULMS patients outcome; Table S4: averaged fraction affected, combination index, averages and standard deviation values for in vitro synergy experiments.

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ARTICLE ABSTRACT

Purpose: The significance of mTOR activation in uterine leiomyosarcoma (ULMS) and its potential as a therapeutic target were investigated. Furthermore, given that effective therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora-A kinase (Aurk-A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated.Experimental Design: Immunohistochemical staining was used to evaluate expression of activated mTOR components in a large (>200 samples) ULMS tissue microarray. Effects of mTOR blockade (using rapamycin) and Aurk-A inhibition (using MLN8237) alone and in combination on human ULMS cell growth, cell-cycle progression, and apoptosis were assessed in cellular assays. Drug interactions were determined via combination index analyses. The antitumor effects of inhibitors alone or in combination were evaluated in vivo.Results: Enhanced mTOR activation was seen in human ULMS samples. Increased pS6RP and p4EBP1 expression correlated with disease progression; p4EBP1 was found to be an independent prognosticator of patient outcome. Rapamycin inhibited growth and cell-cycle progression of ULMS cell strains/lines in culture. However, only a cytostatic effect on tumor growth was found in vivo. Combining rapamycin with MLN8237 profoundly (and synergistically) abrogated ULMS cells' growth in culture; interestingly, these effects were seen only when MLN8237 was preadministered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo.Conclusions: mTOR and Aurk-A pathways are commonly deregulated in ULMS. Preclinical data support further exploration of dual mTOR and Aurk-A therapeutic blockade for human ULMS. Clin Cancer Res; 18(17); 4633–45. ©2012 AACR.

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