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Investigation of novel signaling protein in 3D and in vivo PDAC models using second generation Ref-1 inhibitors

Award Number: R01CA254110
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Investigation of novel signaling protein in 3D and in vivo PDAC models using second generation Ref-1 inhibitors - PROJECT SUMMARY/ABSTRACT Five-year survival rate of pancreatic ductal adenocarcinoma (PDAC) still remains at a dismal 10%. This poor outcome is attributed to PDAC’s complex tumor microenvironment (TME) containing a desmoplastic stroma, which consists of cancer-associated fibroblasts (CAFs) and a dense extracellular matrix (ECM). This stroma affects proliferation, invasion and drug resistance of pancreatic cancer cells (PCCs). Unexpectedly, the ablation of CAFs or targeting of certain ECM proteins in the stroma led to changes that actually accelerated tumor growth and impaired treatment outcome. To address this challenge, we are pursuing targets that selectively kill PCCs rather than CAFs. Redox effector factor-1 (Ref-1) is upstream of several key signaling pathways as a regulator of transcription factors (TFs). Blockade of Ref-1 redox function with our first-generation inhibitor blocks the activation of key TFs including HIF-1α, NFkB, and AP-1, all of which are implicated in growth and metastasis signaling in the tumor. However more potent second-generation compounds are necessary to effectively treat PDAC. We recently synthesized new analogs and obtained data showing that these are more potent with a significant decrease in tumor cell survival with minimal changes in CAF survival. This selective cancer cell killing is a novel characteristic of our new analogs, as gemcitabine kills both PCCs and CAFs. The underlying mechanism and therapeutic efficacy of these compounds are the focus of this proposal. Our overarching goal is to evaluate second-generation Ref-1 inhibitors for treatment of PDAC by comparing the mechanisms of Ref-1 inhibition in PCCs and CAFs. Our hypothesis is that through inhibition of Ref-1, multiple cancer-associated pathways are simultaneously and effectively targeted leading to suppression of survival signaling in PCCs while sparing the CAFs. The heterogeneity and complexity of PDAC poses a significant challenge in screening and evaluating the efficacy of new compounds on tumors and on stromal components. To overcome these technical challenges and ultimately lead to new treatments, we will perform mechanistic screening of Ref-1 inhibitors using newly developed in vitro tumor models based on patient-derived PCCs and CAFs - 1) 3D co-culture spheroids for screening and tumor-stroma interaction; and 2) a microfluidic tumor-microenvironment-on-chip (T-MOC) model for mechanistic evaluation. Findings using these novel in vitro systems will be validated with orthotopic PDAC models. Specific aims are: Aim 1. Investigate the selectivity of Ref-1 signaling and the effects of its inhibition in PCCs and CAFs using T-MOC models; Aim 2. Characterize the mechanism of Ref-1 inhibition for second-generation compounds; and Aim 3. Validate the efficacy and pharmacodynamic profiles of Ref-1 analogs in orthotopic PDAC models. The aims of this proposal will provide invaluable information regarding both the effectiveness of new Ref-1 analogs in sophisticated in vivo and in vitro PDAC models and validate our in vitro co-culture models for novel target and compound screening in a cancer that is in need of therapeutic options.


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 = $433,463 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Treatment Research	000	5	5/29/2025	NON-COMPETING CONTINUATION	$433,463
														Subtotal = $433,463

Issue Date FY: 2024 ( Subtotal = $411,790 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Treatment Research	000	4	5/17/2024	NON-COMPETING CONTINUATION	$411,790
														Subtotal = $411,790

Issue Date FY: 2023 ( Subtotal = $424,794 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Treatment Research	000	3	5/30/2023	NON-COMPETING CONTINUATION	$424,794
														Subtotal = $424,794

Issue Date FY: 2022 ( Subtotal = $424,794 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Treatment Research	000	2	5/26/2022	NON-COMPETING CONTINUATION	$424,794
														Subtotal = $424,794

Issue Date FY: 2021 ( Subtotal = $448,088 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Treatment Research	000	1	5/31/2021	NEW	$448,088
														Subtotal = $448,088

Grand Total All Awards = $2,142,929

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Investigation of novel signaling protein in 3D and in vivo PDAC models using second generation Ref-1 inhibitors

Award Number: R01CA254110

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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