Spontaneous lung cancer metastasis models as a novel platform for lung cancer translational research

Abstract

Lung cancer is the leading cause of cancer mortality in the U.S., most of which is due to metastatic disease. Although the addition of immune checkpoint inhibitors (ICI) has transformed therapy for metastatic lung cancer, the vast majority of patients experience disease resistance to ICI and eventual mortality. Therefore, greater knowledge of the metastasis is critical for sorely needed novel and more potent therapies. Such knowledge is limited by the current models of lung cancer metastasis (LCM). Intracardiac or tail vein injection of cancer cells are the most commonly used metastasis models. These models simulate the circulation, extravasation and colonization of cancer cells to distant organs but do not simulate the local invasion and extravasation of cancer cells into the vasculature. We have optimized an orthotopic lung cancer model by injecting tumor cells into the left lung of NSG mice that results in metastases to contralateral lung, liver, adrenal glands and brain - faithfully replicating the pattern of human LCM. We have identified 4 small cell lung cancer (SCLC) patient-derived xenograft (PDX) lines and 5 non-small cell lung cancer (NSCLC) cell lines that consistently metastasize spontaneously to distant organs. We will also utilize of 3D quantitative bioluminescence tomography (QBLT) with Antares, a fusion of NanoLuc andCyOFP1 luciferases which generates a much stronger signal than firefly luciferase, in our models to significantly increase imaging sensitivity and rapid imaging than MRIs. Hypothesis: Spontaneous LCM models is a novel platform that will more accurately enable insights into the mechanisms driving metastases and their therapeutic responses than current in vivo models of LCMs. We will test our hypothesis with following specific aims: 1) Validate the orthotopic lung cancer model and compare with current metastasis models. 2) Develop in vivo human and murine spontaneous metastasis models of SCLC and NSCLC. 3). Establish the lung orthotopic model as a preclinical model to evaluate efficacy of metastatic lung cancer treatments. IMPACT: We have developed a model that consistently generates spontaneous metastases that faithfully mirrors human metastases. Successful completion of our proposal will establish a preclinical platform for studies are more relevant to human LCMs than current models. The results of studies on our platform will be more readily translatable to clinical trials. Thus, our platform will significantly improve our understanding of lung cancer BM mechanisms, facilitate development of new treatment options, and offer unique opportunities for preclinical in vivo trials that closely model human clinic studies.