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Molecular Mechanism of Antiangiogenic Properties of Gold Nanoparticle

Award Number: R01CA136494
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2008
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Molecular Mechanism of Antiangiogenic Properties of Gold Nanoparticle - DESCRIPTION (provided by applicant): Despite frequent initial responses to platinum/taxane therapy after surgical debulking, most patients with advanced epithelial ovarian cancer (EOC) develop drug resistance that leads to low responsiveness to any agent and shortened survival. Thus, devising new and innovative therapeutic strategies is a critical need to combat drug resistant ovarian cancer. In the current proposal, we propose to utilize gold nanoparticle (GNP) as a unique tool to disrupt multicellular crosstalk responsible for drug resistance and devise new and innovative therapeutic strategies to improve dismal prognosis in advanced epithelial ovarian cancer. The importance of angiogenesis in recurrent EOC is underscored by the ICON-6 trial that for the first time demonstrated a significant improvement both in the progression free survival (PFS) and overall survival (OS) using cediranib, a potent oral inhibitor of all three VEGF receptor tyrosine kinases. Also crosstalk between endothelial cell (ECs) and ovarian cancer stem-like cells (OCSCs) has been implicated in drug resistance. In separate studies, abundance of cancer-associated fibroblasts (CAFs) was correlated with advanced stage of the disease and poor prognosis in EOCs. Although the molecular mechanisms are far from clear, a number of GFs and cytokines such as hepatocyte growth factor (HGF), stromal derived factor-1 (SDF- 1), fibroblast growth factor (FGF), transforming growth factor β (TGFβ), are recognized to play critical roles in the pathogenesis of EOCs. Based on these results we hypothesize that a triangular crosstalk among cancer cells (CCs), CAFs and ECs are critical for tumor growth, metastasis and drug resistance in EOC (Scheme 1). In this context, exploiting self-therapeutic property of GNPs to disrupt the triangular crosstalk and identifying key molecules responsible for drug resistance is a highly innovative approach that will drive the design of new therapeutic strategies to treat recurrent, drug resistant EOC. Successful completion of the aims proposed will help to understand the molecular mechanism of desmoplasia, provide a new and innovative way to inhibit it, and device new therapeutic strategies to enhance drug sensitivity that will inhiit tumor growth, metastasis and improve prognosis in PDAC where practically no effective therapy is currently available. We will test the hypothesis using following specific aims; Aim 1: Investigate a role of triangular crosstalk in EOC pathogenesis and its interrogation by GNP; Aim 2: Identify key molecular machineries and pathways responsible for triangular crosstalk using GNP; Aim 3: Interrogating triangular crosstalk in vivo and overcoming therapy resistance by GNP. Results from the present application will determine roles of multicellular crosstalk in the evolution of drug resistance phenotype, identify key molecules responsible for it, provide novel and unique therapeutic strategies to overcome therapy resistance, and pave way for translatable therapy for drug resistant ovarian cancer patients where no effective therapy is currently available.


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: 2022 ( Subtotal = -$4,333 )
2022	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	001	12	9/27/2022	NON-COMPETING CONTINUATION	-$4,333
2022	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	12	11/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = -$4,333

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	12	12/14/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $304,695 )
2020	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	12	1/14/2020	NON-COMPETING CONTINUATION	$304,695
														Subtotal = $304,695

Issue Date FY: 2019 ( Subtotal = $295,553 )
2019	2019	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	11	1/30/2019	NON-COMPETING CONTINUATION	$295,553
														Subtotal = $295,553

Issue Date FY: 2018 ( Subtotal = $304,695 )
2018	2018	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	10	11/20/2017	NON-COMPETING CONTINUATION	$274,225
2018	2018	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	001	10	5/22/2018	NON-COMPETING CONTINUATION	$30,470
														Subtotal = $304,695

Issue Date FY: 2017 ( Subtotal = $304,695 )
2017	2017	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	002	9	11/21/2016	NON-COMPETING CONTINUATION	$274,225
2017	2017	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	007	9	6/8/2017	NON-COMPETING CONTINUATION	$30,470
2017	2016	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	7	10/24/2016	COMPETING CONTINUATION	-$153
2017	2016	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	006	8	1/24/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2017	2016	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	004	7	1/19/2017	COMPETING CONTINUATION	$0
2017	2016	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	005	7	1/24/2017	COMPETING CONTINUATION	$0
2017	2016	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	001	8	10/24/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$153
2017	2013	UNIVERSITY OF OKLAHOMA	1100 N LINDSAY SCB 219	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	003	6	1/19/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $304,695

Issue Date FY: 2016 ( Subtotal = $304,695 )
2016	2016	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Cancer Treatment Research	002	7	6/29/2016	COMPETING CONTINUATION	-$188,191
2016	2016	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Cancer Treatment Research	000	7	12/11/2015	COMPETING CONTINUATION	$304,695
2016	2016	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73126	OKLAHOMA	USA	Cancer Treatment Research	001	8	6/29/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$188,191
														Subtotal = $304,695

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2013	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Cancer Treatment Research	000	6	5/1/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	5	12/20/2013	NON-COMPETING CONTINUATION	-$249,006
2014	2013	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Cancer Treatment Research	001	6	12/20/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$249,006
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $257,291 )
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	5	6/28/2013	NON-COMPETING CONTINUATION	$192,968
2013	2013	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Cancer Treatment Research	003	6	12/20/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$249,006
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	5	5/1/2013	NON-COMPETING CONTINUATION	$64,323
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	002	5	12/20/2013	NON-COMPETING CONTINUATION	-$249,006
														Subtotal = $257,291

Issue Date FY: 2012 ( Subtotal = $273,714 )
2012	2012	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	4	4/11/2012	NON-COMPETING CONTINUATION	$273,714
														Subtotal = $273,714

Issue Date FY: 2011 ( Subtotal = $273,714 )
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	3	5/13/2011	NON-COMPETING CONTINUATION	$19,753
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	3	4/7/2011	NON-COMPETING CONTINUATION	$253,961
														Subtotal = $273,714

Issue Date FY: 2010 ( Subtotal = $282,179 )
2010	2010	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	2	4/9/2010	NON-COMPETING CONTINUATION	$282,179
														Subtotal = $282,179

Issue Date FY: 2009 ( Subtotal = $282,179 )
2009	2009	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	1	5/1/2009	NEW	$282,179
														Subtotal = $282,179

Grand Total All Awards = $2,879,077

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Molecular Mechanism of Antiangiogenic Properties of Gold Nanoparticle

Award Number: R01CA136494

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2008

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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