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Elucidation and targeting of paracrine cascades in PDAC

Award Number: U01CA274312
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Elucidation and targeting of paracrine cascades in PDAC - Abstract Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies due largely to their lack of response to current cytotoxic, targeted, and immune therapies. PDAC tumor tissues harbor an expansive, desmoplastic stroma that both suppresses angiogenesis and limits perfusion and diffusion. Consequently, delivery of therapeutic agents through systemic administration is impeded, lowering drug efficacy and increasing general toxicity. Indeed, multiple components of the PDAC stroma support its survival and growth, for example by conditioning a locally immunosuppressed microenvironment that facilitates tumor survival. Conversely, we previously showed that at least some elements of the tumor stromal restrain PDAC growth and progression, for example Hedgehog pathway-responsive myofibroblasts. Early attempts to modulate the PDAC stroma in order to facilitate drug delivery failed upon clinical translation. Post-clinical trials ultimately demonstrated that stromal remodulation upon inhibition of individual pathways can lead to unpredictable consequences in multiple additional cell types. Based on these data, we hypothesize that individual paracrine pathways typically link together to form “paracrine cascades” that propagate through multiple pathways and cell types. We advance that reconstructing these paracrine cascades offers both the opportunity to better understand the consequences of therapeutic intervention and also to infer candidate targets that act on a broad range of cell types within the PDAC TME to enact stromal remodulation. In order to test this, we will make use of a series of innovative systems biology tools built by members of our transdisciplinary team. These include a suite of algorithms leveraging the computational field of regulatory network analysis, as well as technically innovative techniques for studying outcomes in single cell datasets. Moreover, we will acquire unique dataset from samples collected by members of our multidisciplinary clinical service at the Pancreas Center of New York Presbyterian Hospital. These include acquiring human PDAC tumor interstitial fluid and generating matched sets of tumor, normal pancreas, spleen, and blood samples from PDAC patients. We will also routinely utilize fresh PDAC tissue samples to make tumor “explants” a novel ex vivo model system for the short-term, medium throughput study of PDAC. This new model system enables the dissection of complex multi-cellular phenotypes in ways that are not possible through study of intact tumors or co-cultures of purified cell types Using these approaches, we will reconstruct the network of paracrine cascades in PDAC and validate selected candidates experimentally. We will also test a specific candidate pathway uncovered through study of the Hh pathway that connects myofibroblasts to myeloid derived suppressor cells and cytotoxic lymphocytes. We expect that the proposed studies will provide an expansive understanding of paracrine crosstalk in PDAC and also provide multiple valuable resources and techniques to the PSRC consortium.


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 = $985,518 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	4	9/8/2025	NON-COMPETING CONTINUATION	$985,518
														Subtotal = $985,518

Issue Date FY: 2024 ( Subtotal = $936,242 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	3	8/7/2024	NON-COMPETING CONTINUATION	$936,242
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	3	9/25/2024	NON-COMPETING CONTINUATION	$0
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	2	12/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $936,242

Issue Date FY: 2023 ( Subtotal = $985,518 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	2	8/24/2023	NON-COMPETING CONTINUATION	$985,518
2023	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	1/10/2023	NEW	$0
														Subtotal = $985,518

Issue Date FY: 2022 ( Subtotal = $985,518 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	9/1/2022	NEW	$985,518
														Subtotal = $985,518

Grand Total All Awards = $3,892,796

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Elucidation and targeting of paracrine cascades in PDAC

Award Number: U01CA274312

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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