The objectives of this project are to develop new agents for the chemoprevention and treatment of lung cancer. Lung cancers, especially those with a neuroendocrine phenotype, have specific cell surface receptors for a variety of neuropeptides. Binding of the peptide to the receptor activates a specific signal transduction pathway characterized by activation of G-proteins, phospholipase C, diacylglycerol, protein kinase C (PKC) and liberation of intracellular calcium by inositol trisphosphate. Activation of PKC and other proteins by the increase in [Ca2+]i leads to transcription of specific genes (jun, fos, myc) and proliferation. the activating peptides may be produced by tumor cells themselves (autocrine) and by pulmonary epithelial cells (paracrine). Cigarette smoke increases the production of these peptides. In a Syrian hamster model of lung cancer, chemical carcinogens present in cigarette smoke produced neuroendocrine hyperplasia, elevated levels of bombesin, calcitonin and other peptides and neuroendocrine cancers. We and others showed that the signal transduction pathway induced by multiple peptides could be blocked by using substance P derivatives which appear to down regulate multiple peptide receptors and by using B8509-035 which is a calcium/calmodulin/PKC antagonist. These compounds inhibited the growth of lung cancer cell lines in vitro at concentrations considerably below those which inhibit breast cancer cell line growth. B8509-035 was shown to prevent the development of neuroendocrine hyperplasia and neuroendocrine tumors in the Syrian hamster model. It was also shown to be non-toxic in animals and humans. Non-toxic doses in animals gave concentrations which were well above those which inhibited lung cancer cell line growth in vitro. In this proposal, we will perform in vitro studies to further elucidate the mechanism of action of these compounds, perform in vivo animal studies to allow these compounds to enter human clinical trials alone and in combination and perform initial phase I and phase II studies in human patients with supportive laboratory evaluations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA058187-02
Application #
3774005
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
McDaniel, Nellie K; Cummings, Christopher T; Iida, Mari et al. (2018) MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents. Mol Cancer Ther 17:2297-2308
Ghosh, Moumita; Miller, York E; Vandivier, R William et al. (2018) Reply to Sohal: Airway Basal Cell Reprogramming and Epithelial-Mesenchymal Transition: A Potential Key to Understanding Early Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 197:1645-1646
Ghosh, Moumita; Miller, York E; Nakachi, Ichiro et al. (2018) Exhaustion of Airway Basal Progenitor Cells in Early and Established Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 197:885-896
Farago, Anna F; Taylor, Martin S; Doebele, Robert C et al. (2018) Clinicopathologic Features of Non-Small-Cell Lung Cancer Harboring an NTRK Gene Fusion. JCO Precis Oncol 2018:
He, Yayi; Liu, Sangtian; Mattei, Jane et al. (2018) The combination of anti-KIR monoclonal antibodies with anti-PD-1/PD-L1 monoclonal antibodies could be a critical breakthrough in overcoming tumor immune escape in NSCLC. Drug Des Devel Ther 12:981-986
Genova, Carlo; Socinski, Mark A; Hozak, Rebecca R et al. (2018) EGFR Gene Copy Number by FISH May Predict Outcome of Necitumumab in Squamous Lung Carcinomas: Analysis from the SQUIRE Study. J Thorac Oncol 13:228-236
Merrick, Daniel T; Edwards, Michael G; Franklin, Wilbur A et al. (2018) Altered Cell-Cycle Control, Inflammation, and Adhesion in High-Risk Persistent Bronchial Dysplasia. Cancer Res 78:4971-4983
Li, Howard Y; McSharry, Maria; Walker, Deandra et al. (2018) Targeted overexpression of prostacyclin synthase inhibits lung tumor progression by recruiting CD4+ T lymphocytes in tumors that express MHC class II. Oncoimmunology 7:e1423182
Ravichandran, Kameswaran; Holditch, Sara; Brown, Carolyn N et al. (2018) IL-33 deficiency slows cancer growth but does not protect against cisplatin-induced AKI in mice with cancer. Am J Physiol Renal Physiol 314:F356-F366
Hilberg, Frank; Tontsch-Grunt, Ulrike; Baum, Anke et al. (2018) Triple Angiokinase Inhibitor Nintedanib Directly Inhibits Tumor Cell Growth and Induces Tumor Shrinkage via Blocking Oncogenic Receptor Tyrosine Kinases. J Pharmacol Exp Ther 364:494-503

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