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PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer

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Abstract

The incidence of breast cancer brain metastases has increased in recent years, largely due to improved control of systemic disease with human epidermal growth factor receptor 2 (HER2)-targeted agents and the inability of most of these agents to efficiently cross the blood–blood barrier (BBB) and control central nervous system disease. There is, therefore, an urgent unmet need for treatments to prevent and treat HER2+ breast cancer brain metastases (BCBMs). Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently observed in many cancers, including primary breast tumors and BCBMs. Agents targeting key components of this pathway have demonstrated antitumor activity in diverse cancers, and may represent a new treatment strategy for BCBMs. In preclinical studies, several inhibitors of PI3K and mTOR have demonstrated an ability to penetrate the BBB and down-regulate PI3K signaling, indicating that these agents may be potential therapies for brain metastatic disease. The PI3K inhibitor buparlisib (BKM120) and the mTOR inhibitor everolimus (RAD001) are currently under evaluation in combination with trastuzumab in patients with HER2+ BCBMs.

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Acknowledgments

We thank Amanda Quinn for her medical editorial assistance with this manuscript. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. Dr. Hurvitz receives support from the National Cancer Institute of the National Institutes of Health under Award Number P30CA016042. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Peddi receives support from the Conquer Cancer Foundation of the American Society of Oncology through a Young Investigator Award for year 2013–2014.

Conflict of interest

Dr. Hurvitz has received Novartis reimbursement for travel to international conference. Dr. Peddi has no conflict of interest to report.

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  1. Division of Hematology Oncology, University of California, Los Angeles, 10945 Le Conte Avenue, PVUB Suite 3360, Los Angeles, CA, 90095, USA

    Parvin F. Peddi & Sara A. Hurvitz

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  2. Sara A. Hurvitz
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Correspondence to Sara A. Hurvitz.

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Peddi, P.F., Hurvitz, S.A. PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer. J Neurooncol 117, 7–13 (2014). https://doi.org/10.1007/s11060-014-1369-6

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