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UPR Activators for Cancer Therapy

Award Number: R01CA260749
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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UPR Activators for Cancer Therapy - Project Summary / Abstract The major goal in this application is to evaluate isatin-derived spirocyclic dimers as novel unfolded protein response (UPR) activators in proof-of-concept studies. Despite the dynamic changes in protein levels, protein homeostasis is maintained by a combination of tightly controlled processes which include synthesis, folding, trafficking and degradation. Accumulation of unfolded / misfolded proteins in the ER due to cell intrinsic and / or extrinsic signals results in the activation of UPR, an adaptation mechanism. Failure to resolve this results in irremediable ER stress and triggers UPR mediated programmed cell death. Cell intrinsic situations in cancer such as loss of tumor suppressor gene or oncogene addication result in higher basal UPR levels. Cancer cells maintain the higher basal UPR levels through upregulation of UPR associated proteins. The higher basal UPR levels in cancer cells provides a therapeutic window that can be exploited by UPR activators. This has been attributed to the success of proteasome inhibitors in the treatment of hematological malignancies. Although the success of proteasome inhibitors validates activation of UPR as a therapeutic modality, the need for UPR activators with novel mechanisms of action (MOA) is exemplified by the failure of proteasome inhibitors in patients with solid tumors. In this application we will address the above need by focusing on the development of a UPR activator with a novel MOA. We have identified an isatin-derived spirocyclic dimer (n7) that activates UPR in both normal and cancer cells but selectively induces apoptosis in cancer cells. Here we propose to continue the development of the novel chemical entity n7 through the following specific aims. Aim 1 will focus on characterization of n7 MOA, aim 2 will focus on structure activity relationship through synthesis and evaluation of n7 analogs and aim 3 will assess the efficacy of n7 or an improved UPR activator in in vivo models. Successful completion of the proposed aims will provide critical proof-of-concept for translating isatin-derived spirocyclic dimers as UPR activators.


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 = $330,721 )
2026	2026	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	003	5	1/16/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$330,721
2026	2026	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	001	5	12/30/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$330,721
2026	2026	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	002	5	1/9/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$330,721
2026	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Cancer Treatment Research	000	4	12/30/2025	NON-COMPETING CONTINUATION	$0
2026	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Cancer Treatment Research	004	4	2/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $330,721

Issue Date FY: 2025 ( Subtotal = $351,131 )
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	4	1/8/2025	NON-COMPETING CONTINUATION	$316,018
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Cancer Treatment Research	001	4	6/10/2025	NON-COMPETING CONTINUATION	$35,113
														Subtotal = $351,131

Issue Date FY: 2024 ( Subtotal = $333,575 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	001	3	4/16/2024	NON-COMPETING CONTINUATION	$17,557
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	3	1/9/2024	NON-COMPETING CONTINUATION	$316,018
														Subtotal = $333,575

Issue Date FY: 2023 ( Subtotal = $344,109 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	001	2	3/20/2023	NON-COMPETING CONTINUATION	$28,091
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	2	1/24/2023	NON-COMPETING CONTINUATION	$316,018
														Subtotal = $344,109

Issue Date FY: 2022 ( Subtotal = $350,560 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Treatment Research	000	1	12/28/2021	NEW	$350,560
														Subtotal = $350,560

Grand Total All Awards = $1,710,096

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UPR Activators for Cancer Therapy

Award Number: R01CA260749

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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