Novel Inhibitors of Neuropeptide Signal Pathways for Lung Cancer Treatment

University Of Colorado Denver, Aurora CO

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Abstract

Peptide growth factors play a major role in the autocrine/paracrine growth of lung cancers. Despite proof of concept and exciting preclinical data, no neuropepfide growth factor inhibitors are approved for the treatment of lung cancer and our ability to select patients for growth factor inhibitor therapy is poor. Peptide growth factor inhibitors are likely to play a role in chemoprevention as well as therapy because increased expression develops early in the carcinogenesis process and the toxicity of these agents appears to be low. We developed a bradykinin antagonist dimer, "CU201," that inhibited the growth of both SCLC and NSCLC cell lines in vitro and in vivo through a unique "biased agonist" mechanism. CU201 inhibited proliferation and stimulated apoptosis in lung cancer cell lines. Through an NCI-RAID grant, we have obtained sufficient quantities of CU201 to conduct additional animal studies that are designed to determine the utility of CU201 as a chemoprevention agent and determine the effectiveness and toxicity of combinations of CU201 with other agents for treatment. We developed peptidomimetic compounds (CU317 and CU429) that induce apoptosis in lung cancer cell lines and inhibit their growth in vitro and in vivo. These compounds do not act as "biased agonists." Their advantage is their small size and inexpensive production. We will pursue the development of these and related agents during the renewal period. Lung cancers with neuroendocrine features have reduced expression of several peptidases including neutral endopeptidase. Reduced expression is associated with lung cancer risk and with some measures of poor outcome. We will explore the genetics of peptidase expression as a biomarker for risk and the implications of low peptidase levels in development of effective chemoprevention strategies using genetically engineered NEP knock-out mice. Thus, the specific aims of this project are: 1) to evaluate the chemotherapeutic and chemoprevention potential of "biased agonists" such as CU201; 2) to evaluate the chemotherapeutic and chemoprevention potential of peptidomimetics such as CU317 and CU429; 3) to evaluate and test other new peptide antagonists; 4) to conduct phase I trials of novel growth factor inhibitors alone and in combinations; 5) to define the abnormalities in peptide and peptidase gene regulation that lead to preneoplasia and lung cancer and to develop animal models based on these genetic alterations.