Exploiting FAsting-mimicking Diet and MEtformin to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactivated Lung Adenocarcinoma: The FAME Trial
| Autor: | Filippo de Braud, Mirko Marabese, Elisa Caiola, Giancarlo Pruneri, Valter Torri, Monica Ganzinelli, Elena Tamborini, Rosaria Gallucci, Giulia Galli, Mario P. Colombo, Massimo Moro, Marina Chiara Garassino, Alessandra Fabbri, Gabriella Sozzi, Angela Maria Rizzo, Lital Hollander, Diego Signorelli, Tiziana Triulzi, Massimo Broggini, Giulia Vandoni, Paola Antonia Corsetto, Cecilia Gavazzi, Claudio Vernieri |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Pulmonary and Respiratory Medicine Oncology Cancer Research medicine.medical_specialty Lung Neoplasms Adolescent medicine.medical_treatment Adenocarcinoma of Lung Platinum Compounds Pemetrexed Protein Serine-Threonine Kinases Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine AMP-Activated Protein Kinase Kinases Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Progression-free survival Lung cancer Aged Neoplasm Staging Chemotherapy business.industry Fasting Middle Aged medicine.disease Survival Analysis Metformin Carboplatin 030104 developmental biology Tolerability chemistry 030220 oncology & carcinogenesis Mutation Adenocarcinoma Female business Diet Therapy medicine.drug |
| Zdroj: | Clinical Lung Cancer. 20:e413-e417 |
| ISSN: | 1525-7304 |
| DOI: | 10.1016/j.cllc.2018.12.011 |
| Popis: | Advanced lung adenocarcinoma with inactive liver kinase B1 (LKB1) tumor suppressor protein is associated with poor response to immune checkpoint inhibitors and molecularly targeted agents, and with dismal patient prognosis. LKB1 is a central orchestrator of cancer cell metabolism, and halts tumor growth/proliferation during metabolic stress. Recent preclinical evidence suggests that LKB1-inactive lung adenocarcinoma is highly sensitive to metformin, a safe and low-cost antidiabetic compound that inhibits mitochondrial oxidative phosphorylation. The effects of metformin can be enhanced by nutrient deprivation (ie, glucose, amino acids), which reduces intracellular levels of ATP and anabolic precursors and can be achieved by the fasting mimicking diet (FMD). Noticeably, metformin also prevents resistance to cisplatin in preclinical in vitro and in vivo models of LKB1-inactive lung adenocarcinoma. Based on such preclinical evidence, the phase II FAME trial was designed to test the hypothesis that the addition of metformin, with or without cyclic FMD, to standard platinum-based chemotherapy improves the progression-free survival of patients with advanced, LKB-1 inactive lung adenocarcinoma. Enrolled patients will be randomized in a 1:1 ratio to receive cisplatin/carboplatin and pemetrexed with the addition of metformin alone (Arm A) or metformin plus FMD (Arm B). The FAME study will use a “pick-the-winner” design with the aim of establishing which of the 2 experimental treatments is superior in terms of antitumor efficacy and safety. The primary assumption of the study is that the combination of the 2 experimental treatments shall improve median progression-free survival from 7.6 months (historical data with chemotherapy alone) to 12 months. Secondary study endpoints are: objective response rate, overall survival, treatment tolerability, and compliance to the experimental treatment. |
| Databáze: | OpenAIRE |
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