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Combination of tumor targeted therapy with stroma modulating agent for PDAC

Award Number: R16GM145556
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: 06/12/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Combination of tumor targeted therapy with stroma modulating agent for PDAC - Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. It is the seventh leading cause of cancer-related mortality worldwide with the 5-year survival rate standing only at less than 9%. Three major issues in pancreatic tumor treatment are; poor availability of anticancer molecules due to limited blood supply to pancreas, development of resistant to first line agent e.g. Gemcitabine and extensive fibrosis in tumor stroma. There is an urgent need for a novel and effective therapeutic strategy for PDAC via simultaneously targeting tumor and its tumor microenvironment. Given the central role of Myc as a mediator of multiple cell proliferation and survival pathways, it is very essential to target the proto-oncogenic expression of Myc and controlling K-Ras mediated drug resistance in pancreatic cancer. On another side, collagen type I dense extracellular matrix of solid tumor severely restricts the uptake of drug, monoclonal antibodies and nanotherapeutics within pancreatic tumor. Overexpressed focal adhesion kinase (FAK) in pancreatic cancer plays role in angiogenesis, fibrosis and metastasis. We hypothesize that oral delivery of FAK inhibitor (PND1186) will facilitate the uptake and penetration of BRD4 PROTAC albuminosomes. PROTAC is novel class of anticancer molecules which selectively degrades the targeted protein instead of mere inhibiting it. Preliminary studies in our laboratory revealed that BRD4 Proteolysis Targeting Chimera (PROTAC) and FAK inhibitor – PND1186 inhibit the growth of pancreatic cancer cells, and endothelial cells in 2D and 3D culture. Nanoformulation showed significant enhancement in solubility and stability. Thus, we propose a combination therapy using a long circulating albumin coated nanoliposome of BRD4 PROTAC and PND1186 (Albuminosomes). The aim of proposed SuRE award is to explore the albuminosomes for pancreatic tumor specific delivery of BRD4 PROTAC and role of PND in tumor uptake of nanoparticle. To achieve this goal, we propose two specific aims; Specific aim 1. Systematic characterization of ARV-loaded albuminosomes (AAnano) and PND nanoformulation (PNDnano). Specific aim 2. Anticancer efficacy, tumor uptake and toxicity evaluation of AAnano and PNDnano in human pancreatic tumor xenograft model. Considering the scarcity of effective therapy for PDAC, the proposed idea has significant clinical relevance.


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: 2025 ( Subtotal = $164,000 )
2025	2025	ST JOHN'S UNIVERSITY, NEW YORK	8000 UTOPIA PKWY	JAMAICA	NY	11439	QUEENS	USA	Biomedical Research and Research Training	000	3	6/16/2025	NON-COMPETING CONTINUATION	$164,000
														Subtotal = $164,000

Issue Date FY: 2024 ( Subtotal = $257,548 )
2024	2024	ST JOHN'S UNIVERSITY, NEW YORK	8000 UTOPIA PKWY	JAMAICA	NY	11439	QUEENS	USA	Biomedical Research and Research Training	001	2	8/26/2024	SUPPLEMENT FOR EXPANSION	$93,548
2024	2024	ST JOHN'S UNIVERSITY, NEW YORK	8000 UTOPIA PKWY	JAMAICA	NY	11439	QUEENS	USA	Biomedical Research and Research Training	000	2	5/3/2024	NON-COMPETING CONTINUATION	$164,000
														Subtotal = $257,548

Issue Date FY: 2023 ( Subtotal = $164,000 )
2023	2023	ST JOHN'S UNIVERSITY, NEW YORK	8000 UTOPIA PWY	JAMAICA	NY	11439	QUEENS	USA	Biomedical Research and Research Training	000	1	6/12/2023	NEW	$164,000
														Subtotal = $164,000

Grand Total All Awards = $585,548

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Combination of tumor targeted therapy with stroma modulating agent for PDAC

Award Number: R16GM145556

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: 06/12/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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