Mitochondrial alterations promoting malignant transformation and resistance of non-small lung cancer

• Applicant: Dr. Silvio Terra Stefanello
• Subject Area: Anatomy and Physiology ; Biochemistry
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 580471151

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, driven by its capacity to metastasize and develop resistance to targeted therapies such as tyrosine kinase inhibitors (TKIs). Addressing this resilience requires a paradigm shift in therapeutic strategy. The proposed project targets a critical gap in our understanding of NSCLC’s metabolic adaptability by focusing on mitochondrial dysfunction as a central driver of malignancy and therapeutic escape. Mitochondria are essential regulators of energy production, apoptosis, and cellular signaling. In NSCLC, these organelles undergo profound structural and functional alterations that support tumor progression and resistance. This project will systematically investigate mitochondrial dynamics, mitophagy, genome integrity, and transference mechanisms across metastatic and drug-resistant NSCLC models. By identifying which mitochondrial markers are altered and at which stages of disease progression, we aim to define actionable vulnerabilities that can be exploited therapeutically. Compounds such as 1,6-hexanediol (1,6-HD), previously characterized in our publications, offer a targeted approach to disrupt glycolysis and impair mitochondrial resilience. We will elucidate the molecular mechanisms underlying their anticancer effects, including ATP depletion, caspase activation, and vesicular remodeling. Furthermore, we will explore the potential of combining glycol-based compounds with TKIs using nanoparticle-based delivery systems engineered for mitochondrial targeting. This dual strategy aims to restore drug sensitivity and inhibit tumor growth in resistant NSCLC phenotypes. The project integrates advanced imaging, metabolomics, and functional assays with in vivo validation in Caenorhabditis elegans and Drosophila melanogaster, ensuring translational relevance and alignment with the 3Rs principles. All data will be managed according to FAIR principles and disseminated through open-access platforms. By targeting mitochondrial structure and metabolism, this research offers a novel framework for overcoming NSCLC resistance and metastasis. It represents a strategic step toward personalized medicine, where therapies are tailored to the metabolic and genetic profile of each tumor, transforming NSCLC from a fatal diagnosis into a manageable condition.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Victor Shahin, Ph.D.