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ROLE OF KI-RAS IN THE PATHOGENESIS OF LUNG CANCER

Award Number: R01CA091909
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2002
PERIOD OF PERFORMANCE END DATE: 03/30/2006

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ROLE OF KI-RAS IN THE PATHOGENESIS OF LUNG CANCER - DESCRIPTION (provided by applicant): Studies in humans and animal models have shown that mutation of Ki-ras is a critical, early event in lung tumorigenesis. We and others have shown that the type of mutation present in Ki-ras may influence tumor progression and appears to correlate with patient survival. We thus hypothesize that different mutations induced in Ki-ras by environmental carcinogens exhibit different oncogenic potential, and that the type of mutation initially induced in this gene will determine how rapidly tumors progress to adenocarcinomas. It is difficult to definitively determine the role of mutated ras genes in tumor initiation and progression because treatment with chemical carcinogens may cause alterations at other genetic loci. We thus propose to develop 3 strains of transgenic mice that contain either the wild type, VAL12, or CYS12 mutant alleles of the human Ki-ras gene linked to a tet-inducible promoter that specifies lung specific expression of the transgene. The biochemical characteristics and activity of the 3 alleles will be compared and correlated with the oncogenicity of each allele. Carcinogenicity bioassays will be employed to determine the effects of different ras mutations on tumor development and progression. The effect of each of the 3 alleles on subsequent damage to tumor suppressor loci implicated in both human and murine lung tumor pathogenesis, in particular the pl6Ink4a, Rb, and cyclin D1 genes, will be assessed by PCR-SSCP, methylation specific PCR, and determination of the levels of expression of the gene products by reverse transcription PCR. The development of these "humanized" Ki-ras transgenic mice will represent a critical advance in this field and provide an important new research tool that will allow us to determine the role of Ki-ras mutations in the pathogenesis of lung cancer. We anticipate that the proposed studies will elucidate the effect of different mutant ras alleles on lung tumor pathogenesis and will have important long term implications for future research on the etiology, genetics, prevention, and development of novel therapies for lung cancer.


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: 2005 ( Subtotal = $294,123 )
2005	2005	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Cause and Prevention Research	001	4	3/14/2005	SUPPLEMENT FOR EXPANSION	$23,894
2005	2005	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Cause and Prevention Research	000	4	3/10/2005	NON-COMPETING CONTINUATION	$270,229
														Subtotal = $294,123

Issue Date FY: 2004 ( Subtotal = $306,925 )
2004	2004	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Cause and Prevention Research	000	3	3/3/2004	NON-COMPETING CONTINUATION	$270,938
2004	2004	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Cause and Prevention Research	001	3	3/16/2004	SUPPLEMENT FOR EXPANSION	$35,987
														Subtotal = $306,925

Issue Date FY: 2003 ( Subtotal = $307,238 )
2003	2003	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Cause and Prevention Research	001	2		SUPPLEMENT FOR EXPANSION	$35,198
2003	2003	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Cause and Prevention Research	000	2		NON-COMPETING CONTINUATION	$272,040
														Subtotal = $307,238

Issue Date FY: 2002 ( Subtotal = $314,232 )
2002	2002	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Cancer Cause and Prevention Research	000	1	3/25/2002	NEW	$314,232
														Subtotal = $314,232

Grand Total All Awards = $1,222,518

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ROLE OF KI-RAS IN THE PATHOGENESIS OF LUNG CANCER

Award Number: R01CA091909

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2002

PERIOD OF PERFORMANCE END DATE: 03/30/2006

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