Lung cancer is the most common cause of cancer-related deaths in US veterans and worldwide. Molecularly targeted therapy and immunotherapy are two recent major breakthroughs in lung cancer treatment that have been shown to extend life and increase cure, but each of them benefits ~20% of non-small cell lung cancer (NSCLC) patients. Novel therapeutic strategies are needed to identify new treatment targets and develop and validate the assays that select the appropriate patients for molecularly targeted therapy and cancer immunotherapy and monitor antitumor responses. We have recently generated and characterized high-affinity peptide ligands for targeting tumor-specific and lymphocyte-specific integrins on the surface of multiple epithelial cancer types including NSCLC and microvesicle exosomes derived from the membranes of specific cancer or immune cells. We hypothesize that these high affinity peptide ligands can be used to improve the sensitivity of detecting tumor- and immune cell-specific biomarkers in lung cancer patients. The overall objective of this proposal is to develop easily operable, low cost, sensitive, multiplex assays to improve the sensitivity of current molecular and immune biomarker tests, in a single blood draw or thoracentesis for clinical decision-making in cancer treatment selection and monitoring. We will use biofluid samples collected from patients with advanced NSCLC under IRB-approved protocol to optimize our novel in vitro diagnostic platforms.
In specific aim 1, we develop an assay for sensitive detection and enrichment of tumor cells from malignant body fluids of NSCLC patients using LXY30 (for ?3?1 integrin).
In specific aim 2, we will develop a novel in vitro platform for rapid and simple isolation of tumor-specific exosomes yielding high quantity and quality tumor DNA to increase the success of clinical molecular biomarker assays.
In specific aim 3, we will develop a novel in vitro platform for rapid and simple isolation of functional immune cells in the blood from NSCLC patients for flow cytometry, T cell receptor diversity, and single cell genomic characterization. We anticipate that the clinical application of our novel, integrated, simple, low cost, in vitro diagnostic platform in a serial noninvasive ?liquid biopsy? can select the most effective treatment for cancer patients in real time and thus has great potential to advance individual cancer patient care towards the goal of precision medicine.

Public Health Relevance

Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer, which is the leading cause of cancer- related deaths in the US veterans and general population. Molecularly targeted therapy and immunotherapy are two recent major breakthroughs in NSCLC. Each treatment modality benefits about 20% of NSCLC patient populations that can be enriched by a molecular or immunologic biomarker. We and others have shown that synthetic high affinity integrin ligands can be used to improving the diagnosis, imaging and drug delivery to lung cancer. The objective of this proposal is to optimize and characterize peptide ligands for targeting integrins in lung cancer. Our project has immediate translational potential in improving drug delivery and clinical assays currently used for molecular and immune biomarkers in lung cancer patients receiving molecularly targeted and/or immune checkpoint inhibitor therapy, a step forward to precision cancer care in lung cancer.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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VA Northern California Health Care System
United States
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