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NOVEL STRATEGY FOR LUNG CANCER TREATMENT USING IGF-1R INHIBITOR

Award Number: R01CA100816
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2003
PERIOD OF PERFORMANCE END DATE: 04/30/2015

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NOVEL STRATEGY FOR LUNG CANCER TREATMENT USING IGF-1R INHIBITOR - New methods for treating non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths in the United States, are needed. Deregulated signaling through the IGF-1 receptor (IGF-1R) has been linked to development, maintenance, and progression of cancer. Hence, one potentially effective therapeutic strategy for patient with NSCLC is to target the insulin-like growth factor (IGF) signaling axis. One potential concern about the use of IGF-1R-targeted agents in lung cancer therapy, however, is overexpression/hyperactivity of Src-family kinases (SFKs), which could be activated by a myriad of cellular stimuli, including overexpression and/or mutation of growth factors and their receptors, components of tobacco smoke, hormones, alterations in integrin regulation and overexpression of focal adhesion kinase. We recently found evidence for the involvement of Src-family kinases (SFKs) in the activation of IGF-1R in NSCLC. The potent tobacco carcinogen (TC) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acting as an agonist for ¿-adrenergic receptor (¿-AR) and nicotinic acetylcholine receptors, induced IGF-1R phosphorylation and proliferative, angiogenic, invasive activities in NSCLC cell lines, which were abrogated by inhibitors of SFK or ¿-AR but not by anti-IGF-1R monoclonal antibody, IGF-1R tyrosine kinase inhibitor, or nAChR antagonists. These findings suggest that SFKs activated via signaling involving NNK-stimulated ¿-AR induced IGF-1R phosphorylation in an IGF-1R tyrosine kinase-independent manner, providing an alternative intracellular mechanism for IGF-1R activation thus counteracting the antitumor action of IGF-1R-targeted intervention. Sustained inhibition of IGF-1R by IGF-1R-targeted agents induced activation of c-Src, further implicating SFKs in resistance to IGF-1R-targeted therapy. Thus, overexpression and hyperactivity of SFKs in NSCLC could be a potential obstacle to the use of IGF-1R-targeted agents in patients with NSCLC. Accordingly, integration of SFK-targeted agents could circumvent potential resistance towards IGF-1R-targeted therapy. In our ongoing efforts to determine the mechanisms underlying NNK-induced activation of IGF-1R signaling, we found that NNK stimulation resulted in the association of IGF-1R and RACK1, a scaffold protein that binds to a number of signaling molecules and regulates their function, in parallel with phosphorylation of IGF-1R by Src. These findings suggest a possible involvement of RACK1 in NNK-induced activation of IGF-1R signaling via Src. On the basis of on our findings, we hypothesize that the IGF-1R and Src interact to promote the development and progression of NSCLC. In this project, we propose to: 1) assess the ability of NNK to stimulate development, growth and progression of pulmonary adenocarcinoma in mouse models with lung-specific overexpression of IGF-1R, with or without concomitant increase in Src or c-SRC tyrosine kinase (CSK) expression; 2) investigate the mechanisms and cellular roles of NNK-induced activation of IGF-1R in NSCLC cells; and 3) To determine whether inactivation of Src overrides resistance to IGF-1R-targeted therapy in mouse models of NSCLC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2013 ( Subtotal = $160,786 )
2013	2013	SEOUL NATIONAL UNIVERSITY	M424 Bldg. 16,Seoul National Univer	Seoul				KOR	Cancer Treatment Research	000	9	5/16/2013	EXTENSION WITH OR WITHOUT FUNDS	$40,197
2013	2013	SEOUL NATIONAL UNIVERSITY	M424 Bldg. 16,Seoul National Univer	Seoul				KOR	Cancer Treatment Research	001	9	7/3/2013	EXTENSION WITH OR WITHOUT FUNDS	$120,589
														Subtotal = $160,786

Issue Date FY: 2012 ( Subtotal = $171,049 )
2012	2012	SEOUL NATIONAL UNIVERSITY	M424 Bldg. 16,Seoul National Univer	Seoul				KOR	Cancer Treatment Research	000	8	5/1/2012	NON-COMPETING CONTINUATION	$171,049
														Subtotal = $171,049

Issue Date FY: 2011 ( Subtotal = $170,273 )
2011	2011	SEOUL NATIONAL UNIVERSITY	M424 Bldg. 16,Seoul National Univer	Seoul				KOR	Cancer Treatment Research	001	7	7/12/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$170,273
2011	2010	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	6	7/12/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $170,273

Issue Date FY: 2010 ( Subtotal = $251,447 )
2010	2010	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	6	3/23/2010	NON-COMPETING CONTINUATION	$251,447
														Subtotal = $251,447

Issue Date FY: 2009 ( Subtotal = $251,447 )
2009	2009	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	6/5/2009	COMPETING CONTINUATION	$251,447
														Subtotal = $251,447

Issue Date FY: 2007 ( Subtotal = $234,807 )
2007	2007	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	5/7/2007	NON-COMPETING CONTINUATION	$234,807
														Subtotal = $234,807

Issue Date FY: 2006 ( Subtotal = $241,820 )
2006	2006	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	6/8/2006	NON-COMPETING CONTINUATION	$241,820
														Subtotal = $241,820

Issue Date FY: 2005 ( Subtotal = $247,640 )
2005	2005	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	4/27/2005	NON-COMPETING CONTINUATION	$247,640
														Subtotal = $247,640

Issue Date FY: 2004 ( Subtotal = $247,640 )
2004	2004	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	4/15/2004	NEW	$247,640
														Subtotal = $247,640

Grand Total All Awards = $1,976,909

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NOVEL STRATEGY FOR LUNG CANCER TREATMENT USING IGF-1R INHIBITOR

Award Number: R01CA100816

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2003

PERIOD OF PERFORMANCE END DATE: 04/30/2015

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