The autocrine growth system for bombesin-like peptides (BLP) in human small cell lung carcinoma (SCLC) has generated much interest as one growth factor receptor system which may have clinical utility. Originally thought to involve gastrin releasing peptide (GRP, mammalian bombesin) and its receptor, evidence is now emerging that abnormal expression of one or more related receptors, including a previously uncharacterized BLP receptor, contributes to the malignant growth of human SCLC. The hypothesis to be tested is that BLP receptors are overexpressed in human SCLC, pulmonary dysplasia and in some smokers. This overexpression contributes to the proliferative advantage of malignant or premalignant cells and can be exploited to improve patient management via diagnostic, prognostic and/or therapeutic maneuvers. The overall goal of this proposal is to exploit preclinical studies of BLP receptors to further develop and apply tools to determine whether BLP receptors can be utilized to improve management of patients with lung cancer. The unique collaborative opportunities provided by the SPORE will expedite the success of this endeavor.
The specific aims of this project are: 1) Determination of the distribution of various BLP receptors in normal human lung and human lung cancer using in situ hybridization to identify cells expressing receptor mRNA and immunocytochemistry with highly specific antibodies to identify cells expressing receptor proteins; 2) Assessment of whether changes in human pulmonary BLP receptor expression: a) occur in smokers compared with nonsmokers, b) precede or accompany development of pulmonary dysplasia, c) predict SCLC patient outcome, and d) occur after smoking cessation and/or chemoprevention; 3) Identification and cloning of novel BLP receptors in human SCLC using degenerate oligonucleotide primers derived from very homologous sequences in the GRP and neuromedin b receptors and PCR as has been used to clone other new members of the family of seven membrane- spanning domain receptors; 4) Investigation of the utility of BLP receptors as potential targets for SCLC tumor imaging and/or treatment using human tumor xenografts in nude mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA058187-01
Application #
3796268
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
Noonan, Sinead A; Patil, Tejas; Gao, Dexiang et al. (2018) Baseline and On-Treatment Characteristics of Serum Tumor Markers in Stage IV Oncogene-Addicted Adenocarcinoma of the Lung. J Thorac Oncol 13:134-138
DeHart, David N; Fang, Diana; Heslop, Kareem et al. (2018) Opening of voltage dependent anion channels promotes reactive oxygen species generation, mitochondrial dysfunction and cell death in cancer cells. Biochem Pharmacol 148:155-162
Patil, Tejas; Smith, Derek E; Bunn, Paul A et al. (2018) The Incidence of Brain Metastases in Stage IV ROS1-Rearranged Non-Small Cell Lung Cancer and Rate of Central Nervous System Progression on Crizotinib. J Thorac Oncol 13:1717-1726
Suda, Kenichi; Kim, Jihye; Murakami, Isao et al. (2018) Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naïve Lesions. J Thorac Oncol 13:1496-1507
Helfrich, Barbara A; Gao, Dexiang; Bunn Jr, Paul A (2018) Eribulin inhibits the growth of small cell lung cancer cell lines alone and with radiotherapy. Lung Cancer 118:148-154
Kleczko, Emily K; Heasley, Lynn E (2018) Mechanisms of rapid cancer cell reprogramming initiated by targeted receptor tyrosine kinase inhibitors and inherent therapeutic vulnerabilities. Mol Cancer 17:60
McCoach, Caroline E; Le, Anh T; Gowan, Katherine et al. (2018) Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non-small Cell Lung Cancer. Clin Cancer Res 24:3334-3347
Drilon, Alexander; Laetsch, Theodore W; Kummar, Shivaani et al. (2018) Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378:731-739

Showing the most recent 10 out of 435 publications