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Targeting tumor architecture as a novel therapeutic strategy for pancreatic cancer

Award Number: R37CA242070
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Targeting tumor architecture as a novel therapeutic strategy for pancreatic cancer - PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemorefractory cancers among solid tumors. Even with the most effective chemotherapy (i.e., FOLFIRINOX), only 30% of PDAC patients respond. Therefore, identifying novel therapies is an urgent and unmet need in the PDAC field. One of the emerging strategies for treating these patients is targeting tumor architecture. The rationale of these therapies is to target tissue-specific properties, either in the stroma or in the tumor compartment, to disrupt tumor tissue homeostasis during disease progression or in response to treatment (chemotherapies). The majority of the previous studies have focused on targeting the stroma compartment (cellular or extracellular matrix portion), leaving the tumor compartment (e.g., tumor tissue-specific properties) a relatively unexplored territory. The goal of this proposal is to fill this knowledge gap by identifying tissue-specific properties in the tumor compartment to impair disease progression and to overcome PDAC chemoresistance. The rationale and feasibility of our proposed research studies are supported by our recent published work (Ligorio et al., Cell, 2019), in which we showed the existence of 8 different types of tumor glands, based on their internal composition of cells, with distinct proliferation (PRO) and metastatic (EMT) capabilities. Moreover, we found that tumor glands can be considered discrete functional “units” with distinct levels of aggressiveness and different chemorefractory behaviors. Therefore, our overarching hypothesis is that tissue-specific properties exist that govern tumor architecture by regulating the formation, internal structure, and evolution of tumor glands during disease progression and under treatment. To test this central hypothesis, we have recently developed (i) a method that allows us to characterize the cell identity (i.e., different PRO and EMT phenotypes) while preserving architectural information within human tissue, and (ii) an ad hoc mouse model to study tumor gland-forming ability using a time-course in vivo imaging technique (i.e., two-photon microscopy). By integrating these two methodologies, we (a) will clarify the functional behavior of tumor glands as a consequence of their internal structure (AIM.1), (b) will target an aggressive subpopulation of cancer cells to impair tissue homeostasis (AIM.2), and (c) will define the role of tumor architecture in PDAC chemoresistance and as a potential novel biomarker to predict the response to FOLFIRINOX chemotherapy (AIM.3). The proposed study will uncover new mechanisms (i.e., tumor tissue-specific properties) that drive tumor progression and PDAC chemoresistance with the ultimate intent (i) to find novel therapeutic avenues for PDAC patients, (ii) to define the role of tumor architecture in PDAC chemoresistance, and (iii) discover new FOLFIRINOX-predictive biomarkers to improve the dismal prognosis of PDAC patients.


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: 2026 ( Subtotal = $458,086 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	000	6	4/6/2026	EXTENSION WITH OR WITHOUT FUNDS	$458,086
														Subtotal = $458,086

Issue Date FY: 2025 ( Subtotal = $469,327 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	000	5	4/11/2025	NON-COMPETING CONTINUATION	$422,396
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	001	5	5/23/2025	NON-COMPETING CONTINUATION	$46,931
														Subtotal = $469,327

Issue Date FY: 2024 ( Subtotal = $445,861 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	001	4	4/18/2024	NON-COMPETING CONTINUATION	$23,465
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	000	4	2/6/2024	NON-COMPETING CONTINUATION	$422,396
														Subtotal = $445,861

Issue Date FY: 2023 ( Subtotal = $459,941 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	000	3	3/8/2023	NON-COMPETING CONTINUATION	$459,941
														Subtotal = $459,941

Issue Date FY: 2022 ( Subtotal = $459,799 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	001	2	5/25/2022	NON-COMPETING CONTINUATION	$45,983
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	000	2	2/1/2022	NON-COMPETING CONTINUATION	$413,816
														Subtotal = $459,799

Issue Date FY: 2021 ( Subtotal = $493,658 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	000	1	12/29/2020	NEW	$493,658
														Subtotal = $493,658

Grand Total All Awards = $2,786,672

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Targeting tumor architecture as a novel therapeutic strategy for pancreatic cancer

Award Number: R37CA242070

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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