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Targeting breast cancer progression

Award Number: SC3GM084824
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2008
PERIOD OF PERFORMANCE END DATE: 09/30/2022

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Targeting breast cancer progression - Metastatic disease is the primary cause of cancer mortality, but effective treatments remain elusive. Therefore, our LONG-TERM GOAL is to address the CRITICAL NEED for more targeted strategies to inhibit metastatic cancer. Metastatic cancer cells migrate away from the primary tumor and invade the extracellular matrix to enter the circulatory system and establish secondary tumors at distant sites. Accordingly, this proposal, which aims to study the role of Rho GTPases in breast cancer progression via regulation of cancer cell migration, will test novel anti metastatic cancer therapeutics. The Rho GTPases, Rac and Cdc42, are key molecular switches activated by a myriad of cell surface receptors to promote cancer cell migration/invasion, proliferation, and survival. However, there is a GAP IN KNOWLEDGE on the efficacy of Rac and Cdc42 inhibitors as anti metastatic cancer therapeutics. The OBJECTIVE in this proposal is to characterize small molecule compounds that block the interaction of Rac and/or Cdc42 with their upstream effectors, guanine nucleotide exchange factors (GEFs) in metastatic cancer. The RATIONALE for this research comes from our characterization of the Rac inhibitor EHop- 016 and the Rac/Cdc42 inhibitor MBQ-167 in cancer cell and mouse models. EHop-016 and the improved compound MBQ-167 inhibit cancer cell migration/invasion, viability, and tumor growth, metastasis, and angiogenesis in mouse models with no apparent toxicity. Using rational drug design principles garnered from our studies with these Rac/Cdc42 inhibitors, the PI’s collaborators synthesized a panel of MBQ-167 derivatives (50 compounds). The present proposal will use 6 of these compounds to test the HYPOTHESIS that MBQ- 167 and analogs have potential as anti metastatic breast cancer therapeutics. SPECIFIC AIM 1 will elucidate the mechanism of action of MBQ-167 and analogs in non-metastatic and metastatic cancer cell lines, and a normal mammary epithelial cell line. EHop-016 inhibits the activation of Rac by the oncogenic GEF Vav, but the GEFs that interact with MBQ-167 remain to be identified. Therefore, this Aim will use novel targeted mass spectrometric and protein array approaches to identify the GEFs that interact with MBQ-167 and analogs to inhibit Rac and Cdc42 activities. SPECIFIC AIM 2 will determine the efficacy and toxicity of MBQ-167 in immunocompromised and immunocompetent mouse models. Successful completion of this study will uniquely advance our understanding of metastatic cancer by establishing Rac and Cdc42 proteins as viable targets to impede metastatic breast cancer progression. This study will also result in identification of the variation in GEF expression and activity in non-metastatic and metastatic cancers and elucidate targeted therapeutic strategies. Moreover, these novel chemical probes will be available as tools to validate Rac/Cdc42 signaling as well as the function of specific GEFs in disease models. Ultimately, this study will IMPACT the development of metastasis- targeted therapies for breast cancer. The present request for a research supplement will train a minority postdoctoral fellow and enhance diversity in the biomedical sciences.


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: 2023 ( Subtotal = -$7,178 )
2023	2021	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	001	12	6/13/2023	SUPPLEMENT FOR EXPANSION	-$3,647
2023	2021	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	12	6/13/2023	NON-COMPETING CONTINUATION	-$3,531
														Subtotal = -$7,178

Issue Date FY: 2021 ( Subtotal = $227,725 )
2021	2021	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	12	6/21/2021	NON-COMPETING CONTINUATION	$112,500
2021	2021	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	002	12	7/28/2021	SUPPLEMENT FOR EXPANSION	$116,190
2021	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	001	9	6/26/2021	SUPPLEMENT FOR EXPANSION	-$965
														Subtotal = $227,725

Issue Date FY: 2020 ( Subtotal = $112,500 )
2020	2020	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	11	5/28/2020	NON-COMPETING CONTINUATION	$112,500
														Subtotal = $112,500

Issue Date FY: 2019 ( Subtotal = $175,465 )
2019	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	003	10	7/1/2019	NON-COMPETING CONTINUATION	$112,500
2019	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	002	9	4/26/2019	SUPPLEMENT FOR EXPANSION	$62,965
2019	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	001	9	3/7/2019	COMPETING CONTINUATION	$13,807
2019	2017	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	8	3/7/2019	NON-COMPETING CONTINUATION	-$13,807
														Subtotal = $175,465

Issue Date FY: 2018 ( Subtotal = $112,500 )
2018	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	001	9	4/20/2018	COMPETING CONTINUATION	$112,500
2018	2017	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	8	4/19/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $112,500

Issue Date FY: 2017 ( Subtotal = $112,500 )
2017	2017	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	001	8	6/20/2017	NON-COMPETING CONTINUATION	$11,250
2017	2017	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	8	3/14/2017	NON-COMPETING CONTINUATION	$101,250
														Subtotal = $112,500

Issue Date FY: 2016 ( Subtotal = $112,500 )
2016	2016	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Biomedical Research and Research Training	000	7	3/25/2016	NON-COMPETING CONTINUATION	$112,500
														Subtotal = $112,500

Issue Date FY: 2015 ( Subtotal = $112,500 )
2015	2015	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Biomedical Research and Research Training	000	6	3/12/2015	NON-COMPETING CONTINUATION	$112,500
														Subtotal = $112,500

Issue Date FY: 2014 ( Subtotal = $112,500 )
2014	2014	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Biomedical Research and Research Training	000	5	4/30/2014	COMPETING CONTINUATION	$112,500
														Subtotal = $112,500

Issue Date FY: 2011 ( Subtotal = $111,375 )
2011	2011	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Biomedical Research and Research Training	001	4	8/15/2011	NON-COMPETING CONTINUATION	$111,375
2011	2010	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR	00936	SAN JUAN	USA	Trans-NIH Recovery Act Research Support	000	2	3/11/2011	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $111,375

Issue Date FY: 2010 ( Subtotal = $205,812 )
2010	2010	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Biomedical Research and Research Training	002	3	8/24/2010	NON-COMPETING CONTINUATION	$112,500
2010	2010	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Trans-NIH Recovery Act Research Support	001	2	2/19/2010	SUPPLEMENT FOR EXPANSION	$93,312
2010	2009	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR	00936	SAN JUAN	USA	Biomedical Research and Research Training	000	2	12/31/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $205,812

Issue Date FY: 2009 ( Subtotal = $112,500 )
2009	2009	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Biomedical Research and Research Training	001	2	9/18/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$112,500
2009	2008	UNIVERSIDAD CENTRAL DEL CARIBE ESCUELA DE MED DE CAYEY	POST OFFICE BOX 60-327	BAYAMON	PR	00960	BAYAMON	USA	Biomedical Research and Research Training	000	1	9/18/2009	NEW	$0
														Subtotal = $112,500

Issue Date FY: 2008 ( Subtotal = $100,200 )
2008	2008	UNIVERSIDAD CENTRAL DEL CARIBE ESCUELA DE MED DE CAYEY	POST OFFICE BOX 60-327	BAYAMON	PR	00960	BAYAMON	USA	Biomedical Research and Research Training	000	1	9/9/2008	NEW	$100,200
														Subtotal = $100,200

Grand Total All Awards = $1,600,900

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Targeting breast cancer progression

Award Number: SC3GM084824

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2008

PERIOD OF PERFORMANCE END DATE: 09/30/2022

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