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Cancer-associated fibroblasts (CAFs) support the growth of lung cancer cells in vivo by secretion of soluble factors that stimulate the growth of tumor cells. One such soluble factor is CLCF1. Functional studies in our laboratory identified an important role for CLCF1–CNTFR signaling in promoting growth of NSCLCs. NSCLC cell lines as well as patient-derived xenografts were found to express CNTFR, and knock-down of CNTFR leads to decreased proliferation. To test the use of CNTFR blockade as an anti-cancer therapy, we developed a soluble version of CNTFR (i.e., a CNTFR “receptor decoy”) that can be expressed from an adenoviral vector (Ad-sCNTFR-Fc). Preliminary experiments indicate that Ad-sCNTFR-Fc can block proliferation of a NSCLC cell line in vitro. Our proposed studies build on an established translational research program that includes intensive efforts to harvest and analyze primary tumor samples and CAFs directly from patients. In Aim 1, we will test the therapeutic efficacy of Ad-sCNTFR-Fc in a panel of patient-derived xenografts (PDX) as well as established cell lines. In Aim 2, to increase therapeutic efficacy, we will use protein engineering to develop a high-affinity sCNTFR that can more effectively block CLCF1-CNTFR interactions, and will evaluate this therapeutic candidate in PDX models. In Aim 3, we will establish the utility of using plasma CLCF1 as a biomarker for CLCF1 production in CAFs isolated directly from patient tumors. Parallel analysis of CAF and plasma CLCF1 will establish if CLCF1 in plasma correlates with CLCF1 in tumors and is thus a useful biomarker.

Small cell lung carcinoma (SCLC) remains one of the most lethal human cancers. More than 25,000 patients are diagnosed with SCLC every year in the United States. Unfortunately, most patients usually survive only 6-12 months after diagnosis. Except for the combination of radiation therapy and chemotherapy, there has been no novel therapeutic approach implemented in the past 30 years. Despite a large number of clinical trials, no targeted therapy has been approved for SCLC patients, whose survival rate hovers around 5%. Previous attempts to identify therapeutic targets in SCLC patients have mostly focused on signaling networks within the tumor cells. Here we propose to test a novel immunotherapeutic approach to promote the anti-cancer activity of macrophages. Specifically, we found that SCLC cells express high levels of the CD47 antigen, a marker of self that inhibits the phagocytic activity of macrophages. Based on previous studies from the laboratories of Dr. Weissman and Dr. Garcia at Stanford, we propose to block the interaction between CD47 and SIRPa, an inhibitory receptor expressed on macrophages, to stimulate the engulfment of SCLC cells by macrophages and their eradication. Furthermore, we will identify SCLC-specific antigens and combine CD47-blocking therapies with these antibodies to enhance the recruitment and the activity of macrophages against SCLC cells. Clinical trials testing the CD47-blocking strategies are being initiated in patients with blood cancer and some solid tumors. If successful, our pre-clinical experiments may lead to the rapid implementation of this novel anti-cancer immunotherapy strategy in SCLC patients.

Better methods are required to accurately risk stratify patients with a solitary pulmonary nodule (SPN) who may undergo unnecessary procedures to exclude a cancer diagnosis. 18F-FDG Positron Emission Tomography (PET) is a widely available clinical test used to evaluate concerning SPNs and stage malignant lung nodules. It therefore facilitates clinical assessment but remains an imperfect tool for the diagnosis, localization, and prognostication of SPNs, be they infectious or malignant in nature. Furthermore, it performs well for staging lung cancer, but inaccurately categorizes patients in some cases who receive futile thoracotomies for disseminated disease, or conversely, are undertreated for localized disease. The applicant therefore plans on investigating whether circulating molecular biomarkers can increase the utility of 18F-FDG-PET imaging in clinical practice using statistical models that incorporate in vivo and in vitro diagnostics The concept here is “one-stop shopping,” where a patient can obtain routine molecular imaging and molecular diagnostics from routine blood work during an appointment that in combination increase the accuracy of a clinician’s diagnosis and facilitate the appropriate decision-making process. For this proposal we will develop a model that incorporates a circulating microRNA profile to discriminate infectious from malignant SPNs for patients along with clinical and FDG-PET data and, secondly, identify patients with malignant nodules and detectable circulating tumor cells to determine whether these cells upstage or augment clinical staging or prognosis post-operatively when compared to FDG-PET alone.