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Regulation of heparanase in cancer progression

Award Number: R01CA106456
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2004
PERIOD OF PERFORMANCE END DATE: 02/28/2014

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Regulation of heparanase in cancer progression - Project Summary/Abstract Mammalian heparanase, heparan sulfate degrading endoglycosidase, first cloned and characterized in our laboratory, is preferentially expressed in human tumors and its over-expression in tumor cells confers an invasive phenotype in experimental animals. Heparanase also releases angiogenic factors from the extracellular matrix and tumor microenvironment and thereby induces an angiogenic response in vivo. Moreover, the heparanase protein exerts non-enzymatic activities that further promote tumor angiogenesis, growth, survival and dissemination. Enhanced heparanase expression correlates with metastatic potential, tumor vascularity and reduced postoperative survival of cancer patients. These observations, the anti- cancerous effect of heparanase gene silencing and inhibitory molecules, and the unexpected identification of a single functional heparanase, indicate that the enzyme is a promising target for anti-cancer drug development. The proposed research combines basic and clinical aspects of heparanase enzymatic and non-enzymatic functions, emphasizing, among other aspects, the contribution of heparanase expressed by the tumor microenvironment to cancer progression. Aim 1 focuses on the regulation and causal involvement of heparanase in inflammation associated colon carcinoma, radiation resistance of pancreatic carcinoma, and impact of host- vs. tumor- derived heparanase on cancer progression. Aim 2 focuses on non-enzymatic activities of heparanase, emphasizing the contribution and mode of action of the heparanase C-terminus domain and the involvement of heparanase mediated EGF-receptor activation, in tumorigenesis. The main objective of Aim 3 is to crystallize and establish the 3D structure of the latent and active forms of the heparanase protein and its functional domains. Precise structure/function analysis of the heparanase protein will pave the way for rational design of inhibitory molecules directed against its enzymatic and non-enzymatic functions. The proposed research stems from studies performed during the last 5 years of research supported by the NCI (RO1 CA106456) and the development of molecular tools (i.e., highly purified active and inactive species of heparanase and the respective molecular constructs), inhibitory molecules (i.e., chemically modified non-anticoagulant species of heparin, siRNA), antibodies directed against specific domains of the heparanase protein, assay systems (i.e., in vivo imaging of tumor growth, vascularization and promoter activity, highly sensitive heparanase ELISA and enzymatic activity assays, receptor binding and signal transduction, site directed mutagenesis, ChIP analysis), animal models (i.e., orthotopic models of pancreatic, prostate and inflammation-associated colon carcinoma, heparanase transgenic and knock-out mice) and collaborative arrangements (i.e., crystallization and structural analysis) to carry out and accomplish each of the proposed specific aims.


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	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	SENATE BLDG, ROOM 157	TECHNTON CITY				ISR	Cancer Biology Research	003	10	1/16/2014	EXTENSION WITH OR WITHOUT FUNDS	$163,342
2014	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	SENATE BLDG, ROOM 157	TECHNTON CITY				ISR	Cancer Biology Research	002	10	1/14/2014	EXTENSION WITH OR WITHOUT FUNDS	-$163,342
2014	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	SENATE BLDG, ROOM 157	TECHNTON CITY				ISR	Cancer Biology Research	000	10	12/12/2013	EXTENSION WITH OR WITHOUT FUNDS	-$163,342
2014	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	SENATE BLDG, ROOM 157	TECHNTON CITY				ISR	Cancer Biology Research	001	10	12/17/2013	EXTENSION WITH OR WITHOUT FUNDS	$163,342
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $163,342 )
2013	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	000	10	2/7/2013	EXTENSION WITH OR WITHOUT FUNDS	$78,196
2013	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	003	10	12/17/2013	EXTENSION WITH OR WITHOUT FUNDS	$163,342
2013	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	004	10	1/14/2014	EXTENSION WITH OR WITHOUT FUNDS	-$163,342
2013	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	002	10	12/12/2013	EXTENSION WITH OR WITHOUT FUNDS	-$163,342
2013	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	001	10	7/2/2013	EXTENSION WITH OR WITHOUT FUNDS	$85,146
2013	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	005	10	1/16/2014	EXTENSION WITH OR WITHOUT FUNDS	$163,342
														Subtotal = $163,342

Issue Date FY: 2012 ( Subtotal = $173,769 )
2012	2012	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	001	9	3/27/2012	NON-COMPETING CONTINUATION	$173,769
2012	2011	TECHNION ISRAEL INSTITUTE TECHNOLOGY	SENATE BLDG, ROOM 157	TECHNTON CITY				ISR	Cancer Biology Research	000	8	3/13/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $173,769

Issue Date FY: 2011 ( Subtotal = $168,708 )
2011	2011	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	000	8	2/15/2011	NON-COMPETING CONTINUATION	$161,230
2011	2011	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	001	8	5/17/2011	NON-COMPETING CONTINUATION	$7,478
														Subtotal = $168,708

Issue Date FY: 2010 ( Subtotal = $179,143 )
2010	2010	TECHNION-ISRAEL INSTITUTE OF TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	000	7	2/5/2010	NON-COMPETING CONTINUATION	$179,143
														Subtotal = $179,143

Issue Date FY: 2009 ( Subtotal = $179,143 )
2009	2009	TECHNION-ISRAEL INSTITUTE OF TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Cancer Biology Research	000	6	4/28/2009	COMPETING CONTINUATION	$179,143
														Subtotal = $179,143

Issue Date FY: 2008 ( Subtotal = $167,942 )
2008	2008	TECHNION ISRAEL INSTITUTE TECHNOLOGY	SENATE BLDG, ROOM 157	TECHNTON CITY				ISR	Cancer Biology Research	000	5	1/31/2008	NON-COMPETING CONTINUATION	$167,942
														Subtotal = $167,942

Issue Date FY: 2007 ( Subtotal = $167,942 )
2007	2007	TECHNION ISRAEL INSTITUTE TECHNOLOGY	SENATE BLDG, ROOM 157	TECHNTON CITY				ISR	Cancer Biology Research	000	4	3/5/2007	NON-COMPETING CONTINUATION	$167,942
														Subtotal = $167,942

Issue Date FY: 2006 ( Subtotal = $172,958 )
2006	2006	TECHNION ISRAEL INSTITUTE TECHNOLOGY	SENATE BLDG, ROOM 157	TECHNTON CITY				ISR	Cancer Biology Research	000	3	3/24/2006	NON-COMPETING CONTINUATION	$172,958
														Subtotal = $172,958

Issue Date FY: 2005 ( Subtotal = $177,120 )
2005	2005	TECHNION ISRAEL INSTITUTE TECHNOLOGY	SENATE BLDG, ROOM 157	TECHNTON CITY				ISR	Cancer Biology Research	000	2	4/22/2005	NON-COMPETING CONTINUATION	$177,120
														Subtotal = $177,120

Issue Date FY: 2004 ( Subtotal = $177,120 )
2004	2004	TECHNION ISRAEL INSTITUTE TECHNOLOGY	SENATE BLDG, ROOM 157	TECHNTON CITY				ISR	Cancer Biology Research	000	1	3/19/2004	NEW	$177,120
														Subtotal = $177,120

Grand Total All Awards = $1,727,187

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Regulation of heparanase in cancer progression

Award Number: R01CA106456

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2004

PERIOD OF PERFORMANCE END DATE: 02/28/2014

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