The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 achieves antitumor activity in PIK3CA-Mutant breast cancer brain metastases
<h3>Purpose:</h3> <p>Previous studies have shown that the PI3K/Akt/mTOR pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR inhibitor that has shown promising acti...
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
February 22, 2019
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| In: |
Clinical cancer research
Year: 2019, Volume: 25, Issue: 11, Pages: 3374-3383 |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-18-3049 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1158/1078-0432.CCR-18-3049 Verlag, Volltext: https://clincancerres.aacrjournals.org/content/25/11/3374 
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| Author Notes: | Franziska M. Ippen, Christopher A. Alvarez-Breckenridge, Benjamin M. Kuter, Alexandria L. Fink, Ivanna V. Bihun, Matthew Lastrapes, Tristan Penson, Stephen P. Schmidt, Gregory R. Wojtkiewicz, Jianfang Ning, Megha Subramanian, Anita Giobbie-Hurder, Maria Martinez-Lage, Scott L. Carter, Daniel P. Cahill, Hiroaki Wakimoto, and Priscilla K. Brastianos |
| Summary: | <h3>Purpose:</h3> <p>Previous studies have shown that the PI3K/Akt/mTOR pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models.</p><p><b>Experimental Design:</b> The efficacy of GDC-0084 was evaluated in <i>PIK3CA</i>-mutant and <i>PIK3CA</i> wild-type breast cancer cell lines and the isogenic pairs of <i>PIK3CA</i> wild-type and mutant (H1047R/+) MCF10A cells <i>in vitro</i>. <i>In vitro</i> studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. <i>In vivo</i>, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC.</p><h3>Results:</h3> <p><i>In vitro</i>, GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in <i>PIK3CA</i>-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in <i>PIK3CA</i> wild-type cell lines <i>in vitro</i>. <i>In vivo</i>, treatment with GDC-0084 markedly inhibited the growth of <i>PIK3CA</i>-mutant, with accompanying signaling changes, and not <i>PIK3CA</i> wild-type brain tumors.</p><h3>Conclusions:</h3> <p>The results of this study suggest that the brain-penetrant PI3K/mTOR targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating <i>PIK3CA</i> mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.</p> |
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| Item Description: | Gesehen am 17.09.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-18-3049 |