Despite improved early detection and the use of targeted therapies and immunotherapies, the lung cancer 5-year survival rate remains 10-20% in most countries. Tumor hypoxia, i.e., oxygen deprivation, is an independent marker of poor prognosis in many types of human cancer. Substantial tumor hypoxia exists in non-small cell lung cancer (NSCLC), even in early-stage tumors. NSCLC represents 85-90% of all lung cancer cases. Importantly, recent studies in human patients and mice have shown that NSCLC tumors exhibit elevated oxidative metabolism relative to adjacent normal tissues. Our studies also showed that NSCLC cells have intensified oxygen consumption, as well as elevated synthesis and uptak...

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Despite improved early detection and the use of targeted therapies and immunotherapies, the lung cancer 5-year survival rate remains 10-20% in most countries. Tumor hypoxia, i.e., oxygen deprivation, is an independent marker of poor prognosis in many types of human cancer. Substantial tumor hypoxia exists in non-small cell lung cancer (NSCLC), even in early-stage tumors. NSCLC represents 85-90% of all lung cancer cases. Importantly, recent studies in human patients and mice have shown that NSCLC tumors exhibit elevated oxidative metabolism relative to adjacent normal tissues. Our studies also showed that NSCLC cells have intensified oxygen consumption, as well as elevated synthesis and uptake of heme. Heme is a molecule crucial for the functioning of many proteins and enzymes involved in using oxygen to generate cellular energy. We have identified two new drugs that inhibit oxidative metabolism and oxygen consumption in NSCLC cells. These two drugs substantially delay lung tumor growth and progression in mouse models for lung cancer. They have a high potential to alleviate tumor hypoxia. The goal of this project is to illuminate the mechanisms by which the new drugs targeting oxidative metabolism, alone or in combination with chemotherapy or radiotherapy, influence lung tumor growth, vasculature, and oxygenation. We will characterize the responses of lung tumors in several representative mouse models to the new drugs and combination therapies. We will use advanced imaging techniques, together with histological and immunohistochemistry analyses, to monitor how lung tumors and their microenvironment respond to these drugs. We will determine how pretreatment with these drugs alters the responses of lung tumors and their microenvironment to chemotherapy and radiotherapy. The successful completion of this project should discover novel strategies to alleviate tumor hypoxia and dramatically improve the therapeutic outcome of lung cancer patients.

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