Monday, December 22, 2025 12/22/2025

Impact of CREB-driven mechanism in shaping the tumor-immune landscape

Award Number: R01CA262526
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Impact of CREB-driven mechanism in shaping the tumor-immune landscape - PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to current therapies, a high degree of desmoplasia, and an immunosuppressive tumor microenvironment (TME). This scientific proposal focuses on cyclic AMP Response Element Binding protein 1 (CREB) as a transcriptional factor downstream of KRAS that promotes disease aggressiveness and poor survival. Genetic loss or pharmacological inhibition of CREB leads to significant attenuation of PDAC tumor burden and improved survival in multiple murine PDAC models. Utilizing high throughput sequencing approaches, we have identified tumor cell-derived leukemia inhibitory factor (LIF) as a key CREB-regulated immunomodulatory cytokine, serving as a possible paracrine mediator of tumor- macrophage crosstalk in the TME. We hypothesize that targeting the CREB-LIF signaling axis can remodel the immunosuppressive TME by significantly impacting tumor-associated macrophages (TAM)s and reinvigorating the T cell-based adaptive anti-tumor immune response to improve the efficacy of checkpoint immunotherapy. Based on our preliminary data, the critical role of the CREB regulated LIF signaling will be investigated through three specific aims. 1) Elucidate the molecular mechanism and impact of CREB regulated LIF in PDAC oncogenesis. Here, we will assess the CREB-mediated regulation and functional roles of tumor cell-derived LIF by exploring the nucleo-cytoplasmic localization, interaction with transcriptional complexes, and gene regulatory networks. We identify the CREB-LIF axis requirement in the tumor cell growth using CRISPR/Cas9 genome editing with CREB on or off in vivo pancreas tissues and evaluate the expression of LIF relative to CREB in patient PDAC tissues, patient-derived xenografts, and primary tumor derivative organoids. 2) Determine how CREB-dependent LIFR signaling in macrophages impacts the tumor immune landscape. We hypothesize that the CREB modulates LIF release and promotes TAM infiltration/polarization towards a tumor-promoting M2-like phenotype via activating STAT3 in macrophages. We will determine the effect of CREB-regulated LIF release on TAM activity using CREB on or off with LIF knockout tumor cells and assess the impact of CREB-regulated LIF signaling on the adaptive immune response and TME during PDAC progression in myeloid-specific knockout models of Lifr and Stat3, and 3) Determine if CREB inhibition and conventional immunotherapeutic approaches reduce tumor growth and improve overall survival. We hypothesize that the tumor cell-intrinsic CREB-LIF activation is a pivotal switch that drives immune suppression in the pancreatic TME, which can synergize with immune checkpoint inhibition. We will use CREB inhibitor with checkpoint inhibitor to establish the safety of the therapies and study tumor growth and overall survival in genetic mouse models, patient-derived xenografts, and organoids to further complement these preclinical studies. Together, these results will provide new therapeutic strategies to reduce mortality from this disease. Furthermore, these studies can be broadly applicable to the myriad of other malignancies where CREB-LIF signaling is altered.


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 = $303,150 )
2026	2026	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	$303,150
														Subtotal = $303,150

Issue Date FY: 2025 ( Subtotal = $357,796 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	000	3	12/20/2024	NON-COMPETING CONTINUATION	$322,017
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	001	3	6/3/2025	NON-COMPETING CONTINUATION	$35,779
														Subtotal = $357,796

Issue Date FY: 2024 ( Subtotal = $329,883 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	001	2	4/22/2024	NON-COMPETING CONTINUATION	$17,362
2024	2024	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	2	12/4/2023	NON-COMPETING CONTINUATION	$312,521
														Subtotal = $329,883

Issue Date FY: 2023 ( Subtotal = $324,760 )
2023	2023	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Cancer Biology Research	000	1	12/23/2022	NEW	$324,760
														Subtotal = $324,760

Grand Total All Awards = $1,315,589

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Impact of CREB-driven mechanism in shaping the tumor-immune landscape

Award Number: R01CA262526

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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