Abstract
Abstract PI3KCA (which encodes the phosphoinositide-3 kinase alpha isoform) is the most frequently mutated oncogene in breast cancer. Recently, several alpha isoform-specific PI3K inhibitors have been developed and have entered into early-phase clinical trials. However, intrinsic and acquired resistance limits their utility. Non-invasive imaging methods could be used to guide treatment by not only allowing selection of the most effective drug in individual patients, but also by detecting intrinsic and acquired resistance. We have been evaluating the effectiveness of a selective PI3K alpha inhibitor, Taselisib (GDC-0032 Genentech S.A.), by monitoring the rate of [1-13C]lactate production after injection of hyperpolarized [1-13C]pyruvate in cell lines and patient-derived xenografts (PDX) models of breast cancer using 13C magnetic resonance spectroscopic imaging. Hyperpolarization of the 13C nucleus increases its sensitivity to detection in the MR experiment by 104 - 105x, thus allowing real time imaging of tumor metabolism. Preliminary data suggest that labeled lactate production can distinguish sensitive and resistant breast cancer models to Taselisib a few days after treatment. We are currently broadening the panel of PDXs analyzed and also including genetically engineered mechanistic-models of drug resistance. The present study highlights the effectiveness of hyperpolarized 13C spectroscopy/spectroscopic imaging for detecting early response or resistance to next generation PI3K inhibitors. This clinically applicable technique can provide insights into in vivo response in real-time and identify new strategies to increase the efficacy of therapy in individual patients. Citation Format: Susana Ros, Paula D'Santos, De-en Hu, Ankita S. Batra, Alan J. Wright, Elizabeth Mannion, Alejandra Bruna, Carlos Caldas, Kevin M. Brindle. Imaging tumor metabolism to guide treatment of breast cancer with drugs targeted at PI3K alpha [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2853. doi:10.1158/1538-7445.AM2017-2853
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