Cancer Prevention Research Sunitinib Prolongs Survival in Genetically Engineered Mouse Models of Multistep Lung Carcinogenesis

Non–small cell lung cancer (NSCLC) has a poor prognosis, with substantial mortality rates even among patients diagnosed with early-stage disease. There are few effective measures to block the development or progression of NSCLC. Antiangiogenic drugs represent a new class of agents targeting multiple aspects of tumor progression, including cell proliferation, invasion, migration, and outgrowth of metastatic deposits. We tested the multitargeted angiogenesis inhibitor sunitinib in a novel endogenous mouse model of NSCLC, which expresses a conditional activating mutation in Kras with or without conditional deletion of Lkb1; both alterations are frequent in human NSCLC. We showed that daily treatment with sunitinib reduced tumor size, caused tumor necrosis, blocked tumor progression, and prolonged median survival in both the metastatic (Lkb1/Kras) and nonmetastatic (Kras) mouse models; median survival was not reached in the nonmetastatic model after 1 year. However, the incidence of local and distant metastases was similar in sunitinib-treated and untreated Lkb1/Kras mice, suggesting that prolonged survival with sunitinib in these mice was due to direct effects on primary tumor growth rather than to inhibition of metastatic progression. These collective results suggest that the use of angiogenesis inhibitors in early-stage disease for prevention of tumor development and growth may have major survival benefits in the setting of NSCLC. Non–small cell lung cancer (NSCLC) represents about 85% of all lung cancer and frequently has a dismal outcome. Even among early-stage patients, relapse rates are significant. The relapse rate among stage I/II patients is 35% to 67% (1) and nearly all patients who relapse, frequently with metastatic disease, go on to die of their lung cancer. Therefore, identifying targets for early interventions designed to prevent tumor development and suppress early tumor progression could favorably affect the survival rates of NSCLC patients. Cytotoxic therapies in the metastatic setting have made marginal improvements in progression-free or overall survival. A recent meta-analysis showed a 1.5-month increase in median survival over best supportive care alone, with no improvement in benefit since the prior analysis in 1995 (2). In the adjuvant setting, multiple large-scale trials have shown a reduction in the risk of relapse of only 5% to 9%, showing that these drugs have little effect in preventing local or distant recurrences (3–6). Angiogenesis inhibitors represent a new class of drugs geared to interfere with the genesis of tumor vasculature, with the potential to affect not only primary tumor growth but also invasion through the basement membrane to seed cells into the bloodstream, extravasation into tissues, and outgrowth of metastatic deposits, all of which are critical components of tumor progression, relapse, and death. Several antiangiogenic agents have been developed and are currently in use in cancer therapy for a wide variety of solid tumors. Themost extensively studied is bevacizumab (Avastin, Genentech), an antibody that targets vascular endothelial growth factor (VEGF) and has been shown to prolong survival when combined with chemotherapy in metastatic colorectal and NSCLC (5, 6). Newer drugs from this class of agents include multitargeted small-molecule tyrosine kinase inhibitors that block one or more receptors of VEGF. One of the most well-characterized agents is sunitinib (Sutent), a small-molecule tyrosine kinase Authors' Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute; Departments of Medicine and Pathology, Brigham and Women's Hospital/Harvard Medical School; Ludwig Center at Dana-Farber/Harvard Cancer Center; Massachusetts General Hospital Cancer Center/Harvard Medical School, Boston, Massachusetts Received 11/19/09; revised 1/11/09; accepted 1/26/09; published OnlineFirst 3/31/09. Grant support: K-K. Wong was supported by NIH grants R01 CA122794 and R01 AG2400401, Dana-Farber/Harvard Cancer Center Lung Cancer Specialized Program of Research Excellence grant P50 CA090578, Joan Scarangello Foundation to Conquer Lung Cancer, Cecily and Robert Harris Foundation, and Flight Attendant Medical Research Institute. L. Gandhi is supported in part by the Steve and Alice Cutler fund for Young Investigators. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/). L. Gandhi and K.L. McNamara contributed equally to this work. Requests for reprints: Kwok-Kin Wong, Dana-Farber Cancer Institute, 44 Binney Street, Dana Building 810B, Boston, MA 02115. Phone: 617-6325301; Fax: 617-632-5786; E-mail: [email protected]. ©2009 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-08-0213 330 Cancer Prev Res 2009;2(4) April 2009 www.aacrjournals.org Published Online First on March 31, 2009 as 10.1158/1940-6207.CAPR-08-0213 Cancer Research. on April 28, 2017. © 2009 American Association for cancerpreventionresearch.aacrjournals.org Downloaded from Published OnlineFirst March 31, 2009; DOI: 10.1158/1940-6207.CAPR-08-0213