The dual PI3K/mTOR pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases

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; Priscilla K. Brastianos

doi:10.1158/1078-0432.CCR-18-3049

The dual PI3K/mTOR pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases

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, Priscilla K. Brastianos

Research output: Contribution to journal › Article › peer-review

69 Scopus citations

Abstract

PURPOSE: 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. Experimental Design: The efficacy of GDC-0084 was evaluated in PIK3CA-mutant and PIK3CA wild-type breast cancer cell lines and the isogenic pairs of PIK3CA wild-type and mutant (H1047R/+) MCF10A cells in vitro. In vitro studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. In vivo, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC.

RESULTS: In vitro, GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in PIK3CA wild-type cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA wild-type brain tumors.

CONCLUSIONS: 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 PIK3CA mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.

Original language	English (US)
Pages (from-to)	3374-3383
Number of pages	10
Journal	Clinical Cancer Research
Volume	25
Issue number	11
DOIs	https://doi.org/10.1158/1078-0432.CCR-18-3049
State	Published - Jun 1 2019

Bibliographical note

Funding Information:
F.M. Ippen is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation- Projektnummer: 325246018). S. Carter is funded by NIH (R01 CA227156). P. Brastianos is funded by Breast Cancer Research Foundation, Susan G. Komen, American Brain Tumor Association, and NIH (R01 CA227156).

Funding Information:
F.M. Ippen is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation-Projektnummer: 325246018). S. Carter is funded by NIH (R01 CA227156). P. Brastianos is funded by Breast Cancer ResearchFoundation, SusanG.Komen, American BrainTumor Association,and NIH (R01 CA227156).

Publisher Copyright:
© 2019 American Association for Cancer Research.

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Ippen, F. M., Alvarez-Breckenridge, C. A., Kuter, B. M., Fink, A. L., Bihun, I. V., Lastrapes, M., Penson, T., Schmidt, S. P., Wojtkiewicz, G. R., Ning, J., Subramanian, M., Giobbie-Hurder, A., Martinez-Lage, M., Carter, S. L., Cahill, D. P., Wakimoto, H., & Brastianos, P. K. (2019). The dual PI3K/mTOR pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases. Clinical Cancer Research, 25(11), 3374-3383. https://doi.org/10.1158/1078-0432.CCR-18-3049

Ippen, FM, Alvarez-Breckenridge, CA, Kuter, BM, Fink, AL, Bihun, IV, Lastrapes, M, Penson, T, Schmidt, SP, Wojtkiewicz, GR, Ning, J, Subramanian, M, Giobbie-Hurder, A, Martinez-Lage, M, Carter, SL, Cahill, DP, Wakimoto, H & Brastianos, PK 2019, 'The dual PI3K/mTOR pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases', Clinical Cancer Research, vol. 25, no. 11, pp. 3374-3383. https://doi.org/10.1158/1078-0432.CCR-18-3049

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title = "The dual PI3K/mTOR pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases",

abstract = "PURPOSE: 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. Experimental Design: The efficacy of GDC-0084 was evaluated in PIK3CA-mutant and PIK3CA wild-type breast cancer cell lines and the isogenic pairs of PIK3CA wild-type and mutant (H1047R/+) MCF10A cells in vitro. In vitro studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. In vivo, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC. RESULTS: In vitro, GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in PIK3CA wild-type cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA wild-type brain tumors. CONCLUSIONS: 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 PIK3CA mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases. ",

author = "Ippen, {Franziska M.} and Alvarez-Breckenridge, {Christopher A.} and Kuter, {Benjamin M.} and Fink, {Alexandria L.} and Bihun, {Ivanna V.} and Matthew Lastrapes and Tristan Penson and Schmidt, {Stephen P.} and Wojtkiewicz, {Gregory R.} and Jianfang Ning and Megha Subramanian and Anita Giobbie-Hurder and Maria Martinez-Lage and Carter, {Scott L.} and Cahill, {Daniel P.} and Hiroaki Wakimoto and Brastianos, {Priscilla K.}",

note = "Funding Information: F.M. Ippen is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation- Projektnummer: 325246018). S. Carter is funded by NIH (R01 CA227156). P. Brastianos is funded by Breast Cancer Research Foundation, Susan G. Komen, American Brain Tumor Association, and NIH (R01 CA227156). Funding Information: F.M. Ippen is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation-Projektnummer: 325246018). S. Carter is funded by NIH (R01 CA227156). P. Brastianos is funded by Breast Cancer ResearchFoundation, SusanG.Komen, American BrainTumor Association,and NIH (R01 CA227156). Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",

year = "2019",

month = jun,

day = "1",

doi = "10.1158/1078-0432.CCR-18-3049",

language = "English (US)",

volume = "25",

pages = "3374--3383",

journal = "Clinical Cancer Research",

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TY - JOUR

T1 - The dual PI3K/mTOR pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases

AU - Ippen, Franziska M.

AU - Alvarez-Breckenridge, Christopher A.

AU - Kuter, Benjamin M.

AU - Fink, Alexandria L.

AU - Bihun, Ivanna V.

AU - Lastrapes, Matthew

AU - Penson, Tristan

AU - Schmidt, Stephen P.

AU - Wojtkiewicz, Gregory R.

AU - Ning, Jianfang

AU - Subramanian, Megha

AU - Giobbie-Hurder, Anita

AU - Martinez-Lage, Maria

AU - Carter, Scott L.

AU - Cahill, Daniel P.

AU - Wakimoto, Hiroaki

AU - Brastianos, Priscilla K.

N1 - Funding Information: F.M. Ippen is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation- Projektnummer: 325246018). S. Carter is funded by NIH (R01 CA227156). P. Brastianos is funded by Breast Cancer Research Foundation, Susan G. Komen, American Brain Tumor Association, and NIH (R01 CA227156). Funding Information: F.M. Ippen is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation-Projektnummer: 325246018). S. Carter is funded by NIH (R01 CA227156). P. Brastianos is funded by Breast Cancer ResearchFoundation, SusanG.Komen, American BrainTumor Association,and NIH (R01 CA227156). Publisher Copyright: © 2019 American Association for Cancer Research.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - PURPOSE: 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. Experimental Design: The efficacy of GDC-0084 was evaluated in PIK3CA-mutant and PIK3CA wild-type breast cancer cell lines and the isogenic pairs of PIK3CA wild-type and mutant (H1047R/+) MCF10A cells in vitro. In vitro studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. In vivo, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC. RESULTS: In vitro, GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in PIK3CA wild-type cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA wild-type brain tumors. CONCLUSIONS: 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 PIK3CA mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.

AB - PURPOSE: 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. Experimental Design: The efficacy of GDC-0084 was evaluated in PIK3CA-mutant and PIK3CA wild-type breast cancer cell lines and the isogenic pairs of PIK3CA wild-type and mutant (H1047R/+) MCF10A cells in vitro. In vitro studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. In vivo, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC. RESULTS: In vitro, GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in PIK3CA wild-type cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA wild-type brain tumors. CONCLUSIONS: 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 PIK3CA mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.

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The dual PI3K/mTOR pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases

Abstract

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