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Sunitinib prolongs survival in genetically engineered mouse models of multistep lung carcinogenesis
Leena Gandhi1, Kate L McNamara, Danan Li
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Abstract:
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.
Insights
Sunitinib, an antiangiogenic drug, reduced tumor size and prolonged survival in mouse models of non-small cell lung cancer (NSCLC). This suggests angiogenesis inhibitors may benefit early-stage NSCLC by targeting primary tumor growth.
Area of Science:
- Oncology
- Cancer Research
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) has a high mortality rate, with limited options for blocking tumor development and progression.
- Angiogenesis inhibitors offer a novel therapeutic strategy by targeting tumor growth, invasion, and metastasis.
Purpose of the Study:
- To evaluate the efficacy of the multitargeted angiogenesis inhibitor sunitinib.
- To assess sunitinib's impact on tumor progression and survival in preclinical mouse models of NSCLC.
Main Methods:
- Utilized a novel endogenous mouse model of NSCLC with Kras mutations and/or Lkb1 deletion, common in human NSCLC.
- Administered daily sunitinib treatment to assess effects on tumor size, necrosis, progression, and survival.
Main Results:
- Sunitinib treatment significantly reduced tumor size and caused necrosis in both metastatic and nonmetastatic NSCLC mouse models.
- Prolonged median survival was observed in sunitinib-treated mice, with survival not reached in the nonmetastatic model after one year.
- Sunitinib did not alter the incidence of local or distant metastases, indicating its survival benefit was primarily due to direct effects on primary tumor growth.
Conclusions:
- Sunitinib demonstrates efficacy in reducing primary tumor burden and improving survival in preclinical NSCLC models.
- Angiogenesis inhibitors may offer significant survival benefits when used for early-stage NSCLC prevention and treatment.
- Targeting angiogenesis in early disease stages holds promise for improving outcomes in non-small cell lung cancer.
