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Unraveling lung cancer signaling pathways

Institution: Scripps Research Institute
Investigator(s): Jiing-Dwan Lee, Ph.D.
Award Cycle: 2006 (Cycle 15) Grant #: 15RT-0104 Award: $780,780
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Lung cancer is among the most common and most deadly smoking-related cancer. Lung cancer contributes to less than 30% of the smoking-attributable deaths. Existing therapies for lung cancer are generally ineffective since the five-year survival rate for lung cancer patients has stayed unchanged at 14% for the last twenty years. Recently, scientists have identified that cigarette smoke contains various toxic chemicals whose motabolites bind to DNA and induce activating point mutation in the K-ras gene. In fact, oncogenic mutations of the K-ras gene alone can cause cancer and this mutation is found in 30% of human lung adenocarcinomas.

The oncogenic K-ras triggers a range of the intracellular signal transduction pathways leads to lung tumorigenesis. With regard to this, others and we have found that the BMK1/ERK5 signaling pathway is strongly activated in response to the expression of oncogenic ras as well as is required for uncontrolled growth of lung cancer cells induced by oncogenic ras. To identify the key components of the BMK1 signaling pathway that is critical for oncogenic ras induced tumorigenesis, our lab has previously discovered essential regulatory molecules and molecular targets for the BMK1 signaling pathway. Additionally, we have generated adenoviral vectors encoding blockers that specifically suppress distinct steps of the BMK1-mediated oncogenic signaling. These adenoviral vectors will be tested for their effectiveness in inhibiting lung tumor development in lung cancer models. Importantly, our lab has recently developed animal models allowed us to analyze the role of the BMK1 pathway in lung tumor initiation and progression as well as to evaluate key elements in the BMK1 pathway as target(s) for lung cancer prevention and therapy.

BMK1’s role in carcinogenesis is not limited to its contribution to the malignant nature of tumor cells. Recently, data generated from BMK1-deficient mice (from us and two other labs) revealed that BMK1 is critical for new blood vessel formation during development. Since angiogenesis contributes to the pathological process of tumor growth, we hypothesize that BMK1 activity is also involved in pulmonary tumor-induced neovascularization, which is vital for sustaining lung tumor growth. As such, most recently, my lab has published results describing the important role of the BMK1 pathway in lung tumor-induced angiogenesis, which suggests that intervention in this kinase cascade could represent a practical and effective approach to deterring the development of lung tumor.

Herein we propose to study the role of deregulated BMK1 pathway for lung tumor initiation and progression as well as identifying and evaluating the critical elements in this signaling pathway as target(s) for lung cancer prevention and therapy. Importantly, strategies to prevent or cure lung cancer through blocking this oncogenic BMK1 pathway could be examined quite promptly and precisely using our lung cancer models along with adenoviral vectors encoding blockers specific for the BMK1 pathway. In combination, these studies will likely yield novel and important targets for a more effective and specific therapeutic intervention for lung cancer.
Publications

CDC25B mediates rapamycin-induced oncogenic responses in cancer cells.
Periodical: Cancer Research Index Medicus:
Authors: Chen, RQ; Yang, QK; Lu, BW; Wei, Y; Cantin, G; Chen, YL; Fearns, C; Yates, J, III; Lee, J ART
Yr: 2009 Vol: 69 Nbr: 6 Abs: Pg: 2663-2668

Combined integrin phosphoproteomic analyses and siRNA-based functional screening identified key regulators for cancerl cell adhesion and migration.
Periodical: Cancer Research Index Medicus:
Authors: Chen, Y; Lu, B; Yang, Q; Fearns, C; Yates, J, III; Lee, JD ART
Yr: 2009 Vol: 69 Nbr: 8 Abs: Pg: 3713-3120

Kinome siRNA scteen identifies SMG-1 as a negative regulator of HIF-1alpha in hypoxia.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Chen, RQ; Yang, QK; Chen, YL; Oliveira, VA; Dalton, WS; Fearns, C; Lee, JD; ART
Yr: 2009 Vol: Nbr: Abs: Pg:

Pharmacological inhibition of BMK1 suppresses tumor growth through PML
Periodical: Cancer Cell Index Medicus:
Authors: Yang, Q; Deng, X; Lu, B; Cameron, M; Fearns, C; Patricelli, M; Yates, J; Gray, N; Lee, J ART
Yr: 2010 Vol: Nbr: Abs: Pg: