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

Authors' Affiliations: ¹ Department of Medical Oncology, Dana-Farber Cancer Institute; Departments of ² Medicine and ³ Pathology, Brigham and Women's Hospital/Harvard Medical School; ⁴ Ludwig Center at Dana-Farber/Harvard Cancer Center; ⁵ Massachusetts General Hospital Cancer Center/Harvard Medical School, Boston, Massachusetts

Requests for reprints: Kwok-Kin Wong, Dana-Farber Cancer Institute, 44 Binney Street, Dana Building 810B, Boston, MA 02115. Phone: 617-632-5301; Fax: 617-632-5786; E-mail: kwong1{at}partners.org.

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.

Key Words: lung cancer • mouse model • angiogenesis • metastasis

Commentary

Targeting Angiogenesis from Premalignancy to Metastases

Jennifer R. Grandis and Athanassios Argiris
Cancer Prevention Research 2009 2: 291-294. [Full Text] [PDF]

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