84P - Metabolic stress to sensitize non-small cell lung cancer (NSCLC) to radiotherapy: Studies from bench to bedside

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Poster lunch
Topics Supportive Measures
Thoracic Malignancies
Translational Research
Surgical Oncology
Basic Principles in the Management and Treatment (of cancer)
Therapy
Radiation Oncology
Presenter Theos Tsakiridis
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors T. Tsakiridis, L. Villani, K. Marcinko, G. Pond, J. Wright, G. Steinberg
  • Radiation Oncology, Juravinski Cancer Centre, L8V 5C2 - Hamilton/CA

Abstract

Background

Lung cancer (LC) shows high metabolic rates needed to support the enhanced energy demands and increased need for ribonucleotides, proteins and membrane biogenesis. Modulation of LC metabolism could provide a therapeutic avenue.

Methods

We observed that radiotherapy (RT) alone activates the metabolic stress sensor AMP-activated kinase (AMPK) within an Ataxia Telengiectasia Mutated (ATM)–AMPK–p53/p21cip1 pathway to mediate G2-M checkpoint and cytotoxicity. In human NSCLC cells and xenografts, we combined RT with the anti-diabetic agent metformin, which blocks OxPhos complex I. We showed that metformin also activates the ATM-AMPK-p53/p21cip1 axis and inhibits the Akt-mTOR-4EBP1 pathway, tumor growth and angiogenesis and induces apoptosis and radio-sensitization.

Results

In recent studies we observed that combined treatment with metabolism modulating agents offers enhanced 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. This combination has enhanced radio-sensitizing activity compared to each one of the agents alone. Based on above data and supporting retrospective clinical evidence from locally advanced NSCLC cancer patients treated with Chemo-RT, we lunched phase II studies combining metformin with 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 treated with standard chemo-RT. These studies are open throughout North America and accrue well.

Conclusions

Targeting tumor metabolism is promising and may be able to improve outcomes of standard cytotoxic therapy in NSCLC. Completion of on-going trials with metformin will provide the first prospective evidence on this concept. Combinations of metabolism modulating agents with promising pre-clinical activity would be investigated in future rolling phase II studies.

Clinical trial identification

NRG-LU001 (NCT02186847) OCOG-ALMERA (NCT02186847)

Legal entity responsible for the study

OCOG, NRG Oncology

Funding

Juravinski Cancer Center Foundation, CARO, CIHR

Disclosure

All authors have declared no conflicts of interest.