Recent work from our laboratories and others has shown that the LKB1 (STKII) tumor suppressor gene is frequently inactivated (through deletions or point mutations) in a wide variety of human cancers. Although Lkb1 inactivation facilitates tumor progression by enhanced invasion and metastasis and therefore appears to be an adverse prognostic feature, the mechanisms whereby Lkb1 deficiency promotes tumorigenesis are poorly understood at the molecular level. Our current understanding of Lkb1 suggests that it acts in part through the AMPK and mTOR pathway, but there is strong evidence that Lkb1 also acts through alternative parallel pathways that remain to be elucidated. Consequently, our ability to exploit Lkb1 deficiency to develop new targeted therapies is rather limited. This proposal represents a joint effort by four investigators with complementary areas of expertise and an established track record of productive collaborations in the areas of Lkb1 biology, mouse cancer models, and translational cancer research. We will refine faithful murine Lkb1-based genetic models we have already developed of pancreatic adenocarcinoma, non-small cell lung cancer, uterine cancer, and melanoma. These murine models will be used to 1) study the mechanisms whereby Lkb1 regulates tumor progression;2) identify biomarkers expressed by Lkb1-deficient cancers and explore their utility as predictors of adverse outcomes and therapeutic responses in humans, taking advantage of our existing banks for the above tumors;and 3) develop and test novel therapeutic agents and strategies against Lkb1-deficient cancers. These models will employ state-of-the-art conditional and somatic inactivation strategies, and combine Lkb1 deficiency with other established oncogenic driver events well-studied in the four laboratories. These efforts will leverage the unique strengths of the four participating institutions in molecular biology, small animal imaging, comparative pathology, pharmacology, and experimental therapeutics. This research will lead to an enhanced understanding of the role of Lkb1 inactivation in a variety of neoplasms, and translate this new understanding into novel predictive biomarkers and therapeutic approaches.
Progress in the treatment of cancer will depend on the development of highly specific agents that target distinct signaling pathways, thereby minimizing the side effects associated with traditional agents (personalized medicine). By combining mouse models of cancer with studies of human cell lines and primary tumor samples, this research will enhance the identification of novel therapies effective against cancers harboring signature genetic lesions, and a Iso lead to tests to predict these therapeutic responses.
|Van Allen, Eliezer M; Golay, Hadrien G; Liu, Yan et al. (2015) Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation. Cancer Immunol Res 3:855-63|
|Baker, M D; Ezzati, M; Aloisio, G M et al. (2014) The small GTPase Rheb is required for spermatogenesis but not oogenesis. Reproduction 147:615-25|
|Sakamaki, Jun-Ichi; Fu, Accalia; Reeks, Courtney et al. (2014) Role of the SIK2-p35-PJA2 complex in pancreatic Î²-cell functional compensation. Nat Cell Biol 16:234-44|
|Xu, Chunxiao; Fillmore, Christine M; Koyama, Shohei et al. (2014) Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 25:590-604|
|Chen, Zhao; Akbay, Esra; Mikse, Oliver et al. (2014) Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 20:1204-11|
|Herter-Sprie, Grit S; Korideck, Houari; Christensen, Camilla L et al. (2014) Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models. Nat Commun 5:5870|
|Zhu, Zehua; Aref, Amir R; Cohoon, Travis J et al. (2014) Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov 4:452-65|
|Burd, Christin E; Liu, Wenjin; Huynh, Minh V et al. (2014) Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov 4:1418-29|
|Aguilera, Kristina Y; Rivera, Lee B; Hur, Hoon et al. (2014) Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma. Cancer Res 74:1032-44|
|Liu, Yan; Marks, Kevin; Cowley, Glenn S et al. (2013) Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. Cancer Discov 3:870-9|
Showing the most recent 10 out of 30 publications