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Impact of CLDN1 inhibition on chemoresistance and metastasis of colon cancer

Award Number: R01CA250383
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/12/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Impact of CLDN1 inhibition on chemoresistance and metastasis of colon cancer - CRC is the third leading cause of tumor-related deaths attributed to vital organ metastasis. CRC patient survival is highly dependent on the cancer staging at the time of diagnosis and, despite the recent progresses made in the clinical management of this disease, it remains a meagre 13% for the patients diagnosed with cancer metastasis. Remarkably, resistance to the anti-cancer therapy contributes heavily to the metastasis as ~90% of patients with metastatic cancer are also resistant to the therapies. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is essential and urgent. In this regard, extensive preclinical and clinical studies from our laboratory, and of other laboratories, have now validated a causal role for the upregulated claudin-1 expression in promoting CRC metastasis. In a comprehensive analysis examining a large CRC-patient cohort, cell lines and mouse models, we have reported a highly significant association of the deregulated claudin-1 expression with CRC metastasis. Mechanistic investigations into these findings revealed physical binding of claudin-1 with proto-oncogene Src, in promoting CRC metastasis. So far, no known small molecule inhibitor for claudin-1 exists. Using a rigorous analytical design that included in vitro and in vivo testing, we identified a claudin-1 specific inhibitor. Further analogs were synthesized, we now have narrowed down our search to a novel and specific small molecule inhibitor, PDS-0330, for efficient inhibition of the CLDN1 dependent CRC progression. These data have led to the central hypothesis of this proposal that PDS-0330 can inhibit CLDN1/Src association to inhibit CRC progression and metastasis. In this grant proposal, we will optimize the potency, pharmacokinetic properties of PDS-0330 analogs to develop novel tool compounds. We will also determine binding specificity and characterize the binding epitope of PDS-0330 to inhibit colon cancer progression. Finally, we will determine the efficacy of PDS0330 in inhibiting Claudin- 1-dependent phenotypes in mouse and organoid model of aggressive CRC.


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 = $538,197 )
2026	2026	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Cancer Treatment Research	001	6	7/1/2026	NON-COMPETING CONTINUATION	$538,197
2026	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Cancer Treatment Research	000	4	1/5/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $538,197

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Cancer Treatment Research	002	4	9/17/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Cancer Treatment Research	000	4	4/22/2025	NON-COMPETING CONTINUATION	-$474,168
2025	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Cancer Treatment Research	001	5	4/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$474,168
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $687,940 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	003	4	6/7/2024	SUPPLEMENT FOR EXPANSION	$11,252
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	002	4	4/11/2024	NON-COMPETING CONTINUATION	-$177,563
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	001	4	3/1/2024	SUPPLEMENT FOR EXPANSION	$202,519
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	4	2/12/2024	NON-COMPETING CONTINUATION	$651,732
														Subtotal = $687,940

Issue Date FY: 2023 ( Subtotal = $786,939 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	001	3	8/15/2023	SUPPLEMENT FOR EXPANSION	$238,397
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	3	1/30/2023	NON-COMPETING CONTINUATION	$548,542
														Subtotal = $786,939

Issue Date FY: 2022 ( Subtotal = $461,779 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	001	2	6/17/2022	NON-COMPETING CONTINUATION	$37,699
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	2	2/18/2022	NON-COMPETING CONTINUATION	$424,080
														Subtotal = $461,779

Issue Date FY: 2021 ( Subtotal = $571,142 )
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	1	2/15/2021	NEW	$571,142
														Subtotal = $571,142

Grand Total All Awards = $3,045,997

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Impact of CLDN1 inhibition on chemoresistance and metastasis of colon cancer

Award Number: R01CA250383

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/12/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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