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Preclinical Development of the Novel Inhibitor of Apoptosis Proteins S2/IAPinh for Cancer Therapy

Award Number: R01CA276378
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/29/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Preclinical Development of the Novel Inhibitor of Apoptosis Proteins S2/IAPinh for Cancer Therapy - Scientific abstract Epithelial ovarian cancer (EOC) and pancreatic ductal adenocarcinoma (PDAC) are two of the most devastating human malignancies in desperate need for improved treatment concepts. Treatment resistance in cancer therapy frequently includes, among others, reduced drug uptake, increased drug efflux, improved adaptation to chemotherapy-induced stress/DNA damage and inhibition of apoptosis. An example of such a resistance mechanism is the X-linked inhibitor of apoptosis proteins (XIAP), a potent negative regulator of caspases and promoter of cancer cell survival in both ovarian and pancreatic cancer. Inhibition of XIAP has been studied to increase apoptosis and to overcome drug resistance in vitro and in preclinical mouse models. Second mitochondria-derived activator of caspases (SMAC) is an endogenous inhibitor of both XIAP and cellular IAP (cIAP) by reactivating caspase activity (XIAP blockade) and cIAP degradation, leading to cancer cell death. These findings have initiated the development of synthetic small molecule mimics of endogenous SMAC, which have been studied in a wide variety of human malignancies either as single agents but also in combination with systemic chemotherapy as a means to further improve patient outcomes. The foundation of our work with respect to small molecule drug development is based on sigma-2 ligands (S2) that facilitate fast and selective uptake into the cancer cells due to ~10-fold higher abundancy of the corresponding sigma-2 receptor (S2R) compared to normal host cells. By generating chemical conjugates between S2 and a variety of small molecule drug cargos, we are now capable of delivering therapeutic payloads more efficiently and selectively than their non-targeted counterparts to the tumors (targeted therapy). LCL161 is a clinically explored IAP inhibitor (IAPinh) that induces target activation but failed to demonstrate objective responses in patients. In this grant, we propose to study an innovative experimental cancer therapeutic by chemically linking IAPinh (LCL161) to S2 ligand SW43, resulting in S2/IAPinh for tumor- selective drug delivery and therapy. We hypothesize that S2/IAPinh can be combined with systemic, low-dose chemotherapy to result in synergistic treatment regimens that lead to tumor eradication while systemic toxicities are reduced to a minimum. The overall goal of our current study is to find effective therapies for ovarian and pancreatic cancer. The proposed aims maximize the chance that a novel drug candidate, S2/IAPinh, will be effective clinically. This is envisioned either as single-agent, low-dose S2/IAPinh therapy in the context of a TNF-α gene signature in patient tumors or as combination regimens with clinically approved pathway enhancers, such as Nab-paclitaxel (Abraxane) (ovarian cancer) and Gemcitabine/Nab-paclitaxel (pancreatic cancer) but also statin-based inhibitors of cholesterol de novo synthesis. Our new findings represent an exciting innovative opportunity to enhance the activity profile of S2/IAPinh employing novel drug combinations for the benefit of cancer 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 = $345,411 )
2026	2026	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Treatment Research	001	5	4/16/2026	NON-COMPETING CONTINUATION	$34,541
2026	2026	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Treatment Research	000	5	2/10/2026	NON-COMPETING CONTINUATION	$310,870
														Subtotal = $345,411

Issue Date FY: 2025 ( Subtotal = $180,811 )
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Treatment Research	002	4	5/22/2025	NON-COMPETING CONTINUATION	$33,775
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Treatment Research	001	4	4/25/2025	NON-COMPETING CONTINUATION	$147,036
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	2	12/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $180,811

Issue Date FY: 2024 ( Subtotal = $337,922 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Treatment Research	003	2	9/18/2024	NON-COMPETING CONTINUATION	-$325,083
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Treatment Research	002	2	4/24/2024	NON-COMPETING CONTINUATION	$17,786
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Treatment Research	004	3	9/18/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$325,083
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Treatment Research	001	2	12/15/2023	NON-COMPETING CONTINUATION	$320,136
2024	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Treatment Research	000	1	10/30/2023	NEW	$0
														Subtotal = $337,922

Issue Date FY: 2023 ( Subtotal = $346,659 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	1	12/29/2022	NEW	$346,659
														Subtotal = $346,659

Grand Total All Awards = $1,210,803

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Preclinical Development of the Novel Inhibitor of Apoptosis Proteins S2/IAPinh for Cancer Therapy

Award Number: R01CA276378

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/29/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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