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Developmental therapy for selectively targeting MEK-ERK pathway in cancer cells and tumor stromal compartment

Award Number: R01CA254938
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/07/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Developmental therapy for selectively targeting MEK-ERK pathway in cancer cells and tumor stromal compartment - Project Summary/Abstract Carcinogenic mutations in the RAS-RAF-MEK-ERK pathway are present in 46% of all human cancers. This has inspired the successful development of many small molecule BRAF and MEK pathway inhibitors. These agents are currently FDA approved for the treatment of metastatic melanomas containing BRAF mutations. Although BRAF and MEK inhibitors have shown some benefits to patients, these “targeted” therapeutics have a very low therapeutic index, since these small molecules also target normal cells, causing undesirable, even fatal, side effects. Moreover, whether the clinical efficacy of these inhibitors is via direct effects on the tumor or through modulation of the tumor stromal compartment remains elusive. In this application, we address the above critical unmet needs and will develop a potent and highly tumor-selective MEK inactivator by engineering an anthrax toxin-based protein delivery system. Through manipulating the expression of the toxin receptor on specific tumor stromal cell types, we will also delineate how stromal MEK inhibition regulates tumor development. We propose two parallel, but independent Specific Aims to achieve these goals. In Aim 1, we will generate an anthrax toxin-based, highly tumor-selective MEK inactivator and evaluate its anti-tumor activity in a variety of tumor models. This MEK inactivator specifically binds to the major toxin receptor CMG2 (capillary morphogenesis protein-2) on tumor cells and tumor stromal cells. Specificity is ensured through strict reliance on the simultaneous presence of two distinct tumor-associated proteases, MMPs and urokinase, to gain entry into tumor cells and tumor stromal cells. Once inside, it inactivates MEK-ERK signaling, achieving potent selective targeting. In Aim 2, we will employ our unique tumor-host-toxin system to determine the roles of MEK-ERK signaling in tumor stromal cells in tumor development and in the toxin’s tumor targeting. We have previously established a genetic system allowing CMG2 gain-of-function or loss-of-function in various specific cell types in the tumor microenvironment. Thus, we hypothesize that a genetic manipulation of CMG2 expression on cancer cells and various tumor stromal cells in the whole body of CMG2-/- mice will provide the first tractable genetic system to delineate the role of specific cell types in the tumor microenvironment. Therefore, in this Aim 2, we will determine the roles of selected tumor stromal cell types including tumor endothelial cells (EC), tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF), B cells, and regulatory T cells (Treg), and the molecular mechanisms of MEK-ERK inhibition in these cells in tumor development. Upon completion of these studies, we expect to have developed a highly potent, tumor-selective MEK inactivator as a novel tumor-targeted therapeutic. These studies will also unambiguously determine the role of MEK-ERK signaling in both the tumor and the stroma, thereby validating and identifying specific tumor stromal cell types as targets for future therapeutics development.


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 = $452,287 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$45,230
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	5	3/3/2025	NON-COMPETING CONTINUATION	$407,057
														Subtotal = $452,287

Issue Date FY: 2024 ( Subtotal = $425,913 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	4	3/25/2024	NON-COMPETING CONTINUATION	$403,494
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$22,419
														Subtotal = $425,913

Issue Date FY: 2023 ( Subtotal = $443,241 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	3	3/23/2023	NON-COMPETING CONTINUATION	$443,241
														Subtotal = $443,241

Issue Date FY: 2022 ( Subtotal = $436,990 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	2	3/10/2022	NON-COMPETING CONTINUATION	$401,315
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	001	2	5/11/2022	NON-COMPETING CONTINUATION	$35,675
														Subtotal = $436,990

Issue Date FY: 2021 ( Subtotal = $428,973 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	1	4/7/2021	NEW	$428,973
														Subtotal = $428,973

Grand Total All Awards = $2,187,404

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Developmental therapy for selectively targeting MEK-ERK pathway in cancer cells and tumor stromal compartment

Award Number: R01CA254938

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/07/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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