Tumor-targeted SN38 inhibits growth of early stage non-small cell lung cancer (NSCLC) in a KRas/p53 transgenic mouse model

• Published in: PloS one 2017-04, Vol.12 (4), p.e0176747
• Main Authors: Deneka, Alexander Y, Haber, Leora, Kopp, Meghan C, Gaponova, Anna V, Nikonova, Anna S, Golemis, Erica A
• Format: Article
• Language: English
• Subjects: Adenoviruses; Age; Analysis; Animals; Antigens; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biology and life sciences; Bladder; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cancer; Carcinogenesis - drug effects; Carcinoma, Non-Small-Cell Lung - diagnostic imaging; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - physiopathology; Care and treatment; Causes of; Cell cycle; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Damage tolerance; Deoxyribonucleic acid; DNA; DNA Damage - drug effects; Drug Evaluation, Preclinical; Drugs; Epithelial-Mesenchymal Transition - drug effects; Genetic engineering; Growth; Health aspects; Heat shock proteins; Humans; Irinotecan; K-Ras protein; Lung cancer; Lung diseases; Lung Neoplasms - diagnostic imaging; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lung Neoplasms - physiopathology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Medical prognosis; Medicine and Health Sciences; Metastasis; Mice, Transgenic; Mortality; Mutation; Neoplasm Staging; Non-small cell lung cancer; Non-small cell lung carcinoma; p53 Protein; Patients; Phosphorylation; Phosphorylation - drug effects; Protein binding; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Research and Analysis Methods; Resorcinols - pharmacology; Rodents; Signal transduction; Surgery; Toxicity; Tumor Burden - drug effects; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Urinary bladder; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0176747

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, with a 5-year survival of only ~16%. Potential strategies to address NSCLC mortality include improvements in early detection and prevention, and development of new therapies suitable for use in patients with early and late stage diagnoses. Controlling the growth of early stage tumors could yield significant clinical benefits for patients with comorbidities that make them poor candidates for surgery: however, many drugs that limit cancer growth are not useful in the setting of long-term use or in comorbid patients, because of associated toxicities. In this study, we explored the use of a recently described small molecule agent, STA-8666, as a potential agent for controlling early stage tumor growth. STA-8666 uses a cleavable linker to merge a tumor-targeting moiety that binds heat shock protein 90 (HSP90) with the cytotoxic chemical SN38, and has been shown to have high efficacy and low toxicity, associated with efficient tumor targeting, in preclinical studies using patient-derived and other xenograft models for pancreatic, bladder, and small cell lung cancer. Using a genetically engineered model of NSCLC arising from induced mutation of KRas and knockout of Trp53, we continuously dosed mice with STA-8666 from immediately after tumor induction for 15 weeks. STA-8666 significantly slowed the rate of tumor growth, and was well tolerated over this extended dosing period. STA-8666 induced DNA damage and apoptosis, and reduced proliferation and phosphorylation of the proliferation-associated protein ERK1/2, selectively in tumor tissue. In contrast, STA-8666 did not affect tumor features, such as degree of vimentin staining, associated with epithelial-mesenchymal transition (EMT), or downregulate tumor expression of HSP90. These data suggest STA-8666 and other similar targeted compounds may be useful additions to control the growth of early stage NSCLC in patient populations.