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TUMOR-TARGETING SALMONELLA EXPRESSING TUMOR-SELECTIVE CYTOTOXIC PROTEINS IN COMBINATION WITH PROTEASE INHIBITORS

Award Number: SC3GM098207
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Tumor-targeting bacteria offer a number of advantages over other cancer drug delivery systems, including targeting of multiple tumors from a distant inoculation site, selective intratumoral replication, a high degree of attenuation and safety, and the ability to express anti-cancer proteins directly within the tumor. Remarkably, attenuated Salmonella localize within solid tumors at levels at least 1000 times greater than other tissues. Human clinical studies have validated the safety of intravenously administered attenuated Salmonella mutant VNP20009, established tolerated multiple doses, and have shown that tumor targeting occurs in some patients. However, no anti-tumor activity was observed, even in patients in whom the Salmonella were verified to have colonized their tumors. We hypothesize that the lack of antitumor efficacy in the human clinical trials can be overcome by engineering antitumor apoptosis (programmed cell death) -inducing cytotoxic proteins that are able to selectively kill tumor cells, and that the ability of these proteins to kill cancer cells can be enhanced by blocking their degradation by tumor proteases through co-expression of protease inhibitors. The specific aims are designed to test the tumor-selective toxin generated during the initial SC3 funding period in murine models of cancer. The specific aims are also directed toward generation and analysis of individual protease inhibitor combinations expressed by VNP20009 in order to prevent proteolytic degradation of the therapeutic protein and develop tumor-targeted Salmonella vectors with enhanced antitumor activity. VNP20009 expressing a tumor-cell targeted toxin will be analyzed alone and in combination with one or more protease inhibitors using optical imaging of the bacterial interaction with murine tumor models of highly aggressive breast cancer. The results are expected to indicate the effectiveness of the targeted toxin and the effect(s) of the protease inhibitors alone and in combination with the toxin. These results have the potential to improve VNP20009 without increasing its toxicity, and therefore could lead to translational studies in humans. .


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: 2024 ( Subtotal = $0 )
2024	2022	THE UNIVERSITY CORPORATION	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	12/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $108,750 )
2022	2022	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	8	6/27/2022	NON-COMPETING CONTINUATION	$10,875
2022	2022	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	12/22/2021	NON-COMPETING CONTINUATION	$97,875
														Subtotal = $108,750

Issue Date FY: 2021 ( Subtotal = $108,750 )
2021	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	7	2/17/2021	NON-COMPETING CONTINUATION	$10,875
2021	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	7	12/22/2020	NON-COMPETING CONTINUATION	$97,875
														Subtotal = $108,750

Issue Date FY: 2020 ( Subtotal = $117,671 )
2020	2020	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	002	6	3/17/2020	NON-COMPETING CONTINUATION	$10,875
2020	2020	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	6	12/23/2019	NON-COMPETING CONTINUATION	$97,875
2020	2019	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	12/5/2019	COMPETING CONTINUATION	$8,921
														Subtotal = $117,671

Issue Date FY: 2019 ( Subtotal = $108,750 )
2019	2019	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	1/15/2019	COMPETING CONTINUATION	$108,750
														Subtotal = $108,750

Issue Date FY: 2018 ( Subtotal = -$8,921 )
2018	2016	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	7/27/2018	EXTENSION WITH OR WITHOUT FUNDS	-$8,921
														Subtotal = -$8,921

Issue Date FY: 2016 ( Subtotal = $108,750 )
2016	2016	THE UNIVERSITY CORPORATION	18111 NORDHOFF STREET	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	3/22/2016	EXTENSION WITH OR WITHOUT FUNDS	$108,750
														Subtotal = $108,750

Issue Date FY: 2015 ( Subtotal = $108,750 )
2015	2015	THE UNIVERSITY CORPORATION	18111 NORDHOFF STREET	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	3/3/2015	NON-COMPETING CONTINUATION	$108,750
														Subtotal = $108,750

Issue Date FY: 2014 ( Subtotal = $108,750 )
2014	2014	THE UNIVERSITY CORPORATION	18111 NORDHOFF STREET	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	3/25/2014	NON-COMPETING CONTINUATION	$108,750
														Subtotal = $108,750

Issue Date FY: 2013 ( Subtotal = $108,750 )
2013	2013	THE UNIVERSITY CORPORATION	18111 NORDHOFF STREET	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	5/9/2013	NEW	$108,750
														Subtotal = $108,750

Grand Total All Awards = $870,000

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TUMOR-TARGETING SALMONELLA EXPRESSING TUMOR-SELECTIVE CYTOTOXIC PROTEINS IN COMBINATION WITH PROTEASE INHIBITORS

Award Number: SC3GM098207

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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