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TGFBeta Receptor Mutations in Cancer and Other Diseases

Award Number: R01CA129125
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2014

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TGFBeta Receptor Mutations in Cancer and Other Diseases - DESCRIPTION (provided by applicant): Transforming Growth Factor-? (TGF?) controls tissue homeostasis and orchestrates the response to tissue injury and repair. Cancers escape from TGF? 's homeostatic function but can activate the tissue repair function to enhance their invasive/metastatic phenotype. This concept has led to the development of TGF? pathway antagonists for cancer treatment. However, the absence of biomarkers for TGF? "pathway addiction" is a major roadblock in the development of these agents for clinical use. Our central hypothesis is that TGF? receptor gene mutations are indicative of pathway addiction and, therefore, predictive of response to antagonists. Over 40 cancer-associated missense mutations of the types I or -II TGF? receptor genes (TGFBR1, TGFBR2) have been identified. We have recently found that some of these constitutively activate the T?R-II receptor kinase, associated with loss of Smad2/3 activation on the one hand, and with de novo activation of Smad1/5 and a highly motile and invasive phenotype on the other. Moreover, treatment with selective T?R-ll kinase inhibitors reversed the transformed phenotype. In parallel, Marfan syndrome-like genetic disorders have recently been attributed to mutations of TGFBR1 or TGFBR2. These mutations also confer an activated phenotype on patient fibroblasts and vascular smooth muscle cells. Moreover, striking parallels exist between cancer- and Marfan-like syndrome-associated TGFBR mutations: (1) TGFBR2 gene mutations are much more common than TGFBR1 mutations; (2) TGFBR2 mutations are clustered in the C-lobe of the T?R-II kinase; and (3) many of the TGFBR2 mutated in human cancers coincide with those involved in Marfan-like syndromes as well as with the TGFBR2 orthologue in D. melanogaster. Thus, converging experimental evidence from these three very different sources strongly supports the hypothesis that TGF? receptor gene mutations can confer an aberrant activated cellular phenotype. Our specific aims are: 1. To predict the effects of TGFBR2 gene mutations on interactions with other proteins using structural biology approaches; 2. To determine which TGFBR2 gene mutations confer gain-of- function phenotypes using genetic assays in D. melanogaster; 3. To determine the effects of TGFBR2 gene mutations on TGF? signaling in mammalian cells; 4. To utilize selective chemical T?R kinase inhibitors to determine their potential therapeutic effects on gain-of-function TGFBR2 mutant cells. These studies are particularly important because TGF? antagonists are in (pre)clinical development for the treatment of (metastatic) cancer as well as fibrotic disorders. Thus, not only will our studies provide a precise understanding of the molecular pathobiology of disease-causing TGFBR mutations, but they will also inform the clinical development of TGF? pathway inhibitors for cancer and other disorders.


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: 2014 ( Subtotal = $0 )
2014	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	6	1/8/2014	NON-COMPETING CONTINUATION	$30,415
2014	2012	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cancer Cause and Prevention Research	001	7	1/8/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$30,415
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	001	6	8/13/2013	NON-COMPETING CONTINUATION	-$66,938
2013	2012	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Cancer Cause and Prevention Research	000	7	8/13/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$66,938
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $295,204 )
2012	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	6	5/14/2012	NON-COMPETING CONTINUATION	$295,204
														Subtotal = $295,204

Issue Date FY: 2011 ( Subtotal = $273,797 )
2011	2011	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	001	5	5/16/2011	NON-COMPETING CONTINUATION	$19,758
2011	2011	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	5	4/6/2011	NON-COMPETING CONTINUATION	$254,039
														Subtotal = $273,797

Issue Date FY: 2010 ( Subtotal = $0 )
2010	2010	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	4	7/26/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2009 ( Subtotal = $293,299 )
2009	2009	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	3	4/30/2009	NON-COMPETING CONTINUATION	$293,299
														Subtotal = $293,299

Issue Date FY: 2008 ( Subtotal = $293,299 )
2008	2008	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	2	6/16/2008	NON-COMPETING CONTINUATION	$293,299
														Subtotal = $293,299

Issue Date FY: 2007 ( Subtotal = $306,574 )
2007	2007	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	1	7/1/2007	NEW	$306,574
														Subtotal = $306,574

Grand Total All Awards = $1,462,173

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TGFBeta Receptor Mutations in Cancer and Other Diseases

Award Number: R01CA129125

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2014

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