Tuesday, July 1, 2025 7/1/2025

Discovery of Novel Inhibitors Targeting trans-Golgi Network Acidification in Pancreatic Cancer

Award Number: R01CA276193
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/22/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Discovery of Novel Inhibitors Targeting trans-Golgi Network Acidification in Pancreatic Cancer - PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer-related deaths in the United States by 2030. With a 5-year relative survival rate of just 10%, PDAC has the highest death rate among the most common cancers, underscoring the urgent need for new therapeutic strategies that improve clinical outcomes. Recent years have witnessed a growing appreciation of the role that metabolic reprogramming plays in conferring survival advantages to PDAC cells, and the targeting of metabolic processes is considered a promising area for the development of novel therapies. In contrast to normal cells, cancer cells favor glycolysis for energy production, a phenomenon called the Warburg effect. As a glycolytic byproduct, transformed cells produce an excessive amount of H+ ions. This cytosolic accumulation of H+ would be detrimental to cell fitness; therefore, tumor cells have evolved mechanisms to achieve pH homeostasis. Using PDAC as a model system, we discovered that cytosolic pH in cancer cells is regulated by organellar sequestration of H+ ions via compartmental ion transport and that the trans-Golgi network (TGN) can act as a “sink” for cytosolic H+. Importantly, normal cells do not employ this homeostatic mechanism. Using the NHE7 Na+/H+ antiporter, which is primarily localized to the TGN, we have shown that targeting NHE7 causes acidification of the cytosol and subsequent cell death in PDAC cells but not normal cells. We have further validated these findings in mouse models of PDAC. Patient-centric data analyses show that TGN localized transporters are frequently overexpressed in PDAC and their elevated expression is correlated with worse overall survival. To robustly quantify pH in the lumen of the TGN, we have developed an innovative TGN-targeted pH biosensor assay, which has been optimized for high-throughput (HT) screening of small molecule compound libraries to identify novel TGN-selective acidification inhibitors. We have validated our TGN pH biosensor HT assay in a set of clinical trial and approved drugs, as well as kinase inhibitors. To complement our HT screen, we have designed a cutting- edge secondary and tertiary assay pipeline to further validate TGN-selective compounds. We hypothesize that novel Golgi–specific small molecule inhibitors of organelle acidification will selectively prevent cancer cells from achieving proper pH homeostasis, resulting in acidic cytosolic pH and cell death. In this grant we will: 1) perform a large-scale HT screen to identify inhibitors of TGN acidification and confirm the hits, 2) validate the confirmed hits using secondary assays and prioritize hit scaffolds, and 3) map compound effects to TGN components and select and characterize final probe(s). Successful completion of this work will provide novel small molecule chemical probes validated to interfere with TGN acidification and cause cancer-selective cell death, serving as starting points to be further developed into safe and effective therapeutic agents for PDAC.


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 = $645,331 )
2025	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$64,533
2025	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	3	2/12/2025	NON-COMPETING CONTINUATION	$580,798
														Subtotal = $645,331

Issue Date FY: 2024 ( Subtotal = $612,825 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	2	2/28/2024	NON-COMPETING CONTINUATION	$580,572
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$32,253
														Subtotal = $612,825

Issue Date FY: 2023 ( Subtotal = $647,398 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	1	3/22/2023	NEW	$647,398
														Subtotal = $647,398

Grand Total All Awards = $1,905,554

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Discovery of Novel Inhibitors Targeting trans-Golgi Network Acidification in Pancreatic Cancer

Award Number: R01CA276193

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/22/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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