Targeting tumor metabolism to improve radio-sensitivity in non-small cell lung cancer (NSCLC)

Lung tumor metabolism is severely altered involving enhanced levels of glucose uptake, glycolysis, lipogenesis and protein synthesis. These events are essential for the support of enhanced energy demands and increased need for ribonucleotides, proteins and membrane biogenesis that are required for rapid proliferation. Combined treatment with cytotoxic therapy and metabolism modulating agents may improve outcomes in NSCLC. We observed that radiotherapy (RT) alone activates the metabolic stress sensor AMP-activated kinase (AMPK) within an Ataxia Telengiectasia Mutated (ATM) – AMPK – p53/p21 pathway to mediate the RT-induced G2-M checkpoint and cytotoxicity. Further, inhibition of biosynthetic pathways and energy production through blockade of OxPhos inhibits tumor growth. In human NSCLC cells and xenografts, we combined RT with the anti-diabetic agent metformin, which blocks OxPhos complex I, and showed that metformin activates the ATM-AMPK-p53/p21 axis and inhibits the AktmTOR-4EBP1 pathway, tumor growth and angiogenesis and induces apoptosis and radio-sensitization. Based on these observations and supporting retrospective clinical evidence from locally advanced lung cancer patients treated with Chemo-RT, we launched phase II studies combiningmetforminwith chemo-RT. NRG-LU001 (NCT02186847) and OCOG ALMERA (NCT02186847) are on-going randomized phase II studies investigating whether targeting metabolism with metformin can improve progression free survival in stage III NSCLC. In recent studies we observed that combined treatment with metabolism modulating agents can enhance anti-tumor activity in NSCLC. Combined treatment with Metformin and Salicylate, which activate AMPK through different mechanisms, mediated increased inhibition of clonogenic survival in part through AMPK and suppression of de-novo lipogenesis. Further, in earlier studies we showed that blockade of the cholesterol synthesis pathway with lovastatin (HMG-CoA reductase inhibitor) mediated activation of AMPK, suppression of the Akt-PI3k pathways and radio-sensitization of NSCLC. In current studies we observe that lovastatin also activates the ATM-AMPK-p53 axis, inhibit the Akt-mTOR pathway and mediate tumor suppression in an AMPKdependent manner through suppression of de novo lipogenesis along both the mevalonate and the fatty acid synthesis pathways. Further, in retrospective clinical studies we find that in locally advanced NSCLC patients treated with Chemo-RT, statin treatment is associated with increased survival. These observations suggest that targeting tumor metabolism is promising in NSCLC to improve outcomes of standard cytotoxic therapy. Completion of on-going trials with metformin will provide the first prospective evidence on this concept. We plan to investigate combinations of well-tolerated metabolism modulating agents that show promising pre-clinical activity in future rolling phase II studies.