6 Imaging tumour metabolism to guide treatment of breast cancer with drugs targeted at PI3K alpha

Abstract:

Introduction PI3KCA is the most frequently mutated oncogene in oestrogen receptor positive breast cancer. Although several alpha isoform-specific PI3K inhibitors have entered into early-phase clinical trials, intrinsic and acquired resistance limits their utility. Non-invasive real time imaging of tumour metabolism 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. Material and methods To evaluate upfront resistance to Taselisib (GDC-0032, Genentech) we have used cell line and patient-derived xenografts (PDX) models of breast cancer. We have also generated mechanistic-models of acquired resistance and applied combinatorial therapy to overcome single-agent resistance. All these models have been used to identify biomarkers that could predict drug sensitivity, and that could be detected by real time imaging of tumour metabolism. We have monitored the rate of [1-13C]lactate production after injection of hyperpolarized [1-13C]pyruvate using 13C magnetic resonance spectroscopy early following treatment with GDC-0032. We have also tested whether 18FDG PET measurements can serve as an early indicator of treatment response. Results and discussions We have identified a new biomarker for resistance to PI3Kα inhibition, a transcription factor that drives expression of the glycolytic enzyme lactate dehydrogenase (LDHA). LDHA catalyses the exchange of hyperpolarized 13C label between injected pyruvate and the endogenous lactate pool, and these measurements can be used to monitor early response, and upfront or acquired resistance to GDC-0032 treatment. PET measurements showed no change in 18FDG uptake post drug treatment. Conclusion In conclusion, we have found a biomarker for resistance to PI3Kα inhibition, which via its effects on LDHA expression can be detected by 13C MRSI measurements of hyperpolarized [1-13C]pyruvate metabolism. Such measurements could be used in the clinic to detect early response and upfront or acquired resistance to PI3K inhibitors.

Authors:

S Ros, P D’Santos, D Hu, AJ Wright, RL Hesketh, AS Batra, E Mannion, A Bruna, C Caldas, KM Brindle

Journal:

ESMO Open

Citation info:

3:a3

Publication date:

1st Jun 2018

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