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Targeting mechanosignaling in pediatric brain cancer

Award Number: R01CA263216
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/14/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Targeting mechanosignaling in pediatric brain cancer - Project Summary Despite multimodal treatment, cancer-related mortality in pediatric brain cancers remains high and survivors often suffer from serious, life-long, therapy-related side effects and secondary malignancies. There is a clear need for more effective therapies, including for the most common malignant pediatric brain cancer medullo- blastoma, a tumor that originates in the cerebellum. Mechanosensitive signaling pathways have emerged as powerful targets in cancer drug discovery, including for the treatment of medulloblastoma. Yet, when targeting signaling pathways that serve as sensors for a tumor cell's microenvironment, traditional monolayer cultures that are most commonly used in cell-based high-throughput drug discovery, do not accurately recapitulate critical environmental cues such as tissue stiffness or extracellular matrix composition. Drug discovery aimed at key mediators of mechanosensitive signaling require cell-based screening assays in a cell culture environment that more closely resembles in vivo tissue. Three-dimensional (3D) cell cultures have moved to the forefront in the effort to create more in vivo-like experimental environments that can mimic intricate cell-cell and cell-extracellular matrix interactions found in tissue. Our previous collaborative work demonstrated the suitability of the self- assembling and hydrogelating MAX8 β-hairpin peptide as a 3D cell culture scaffold for automated high- throughput drug discovery. We demonstrated that MAX8 combines biocompatibility and tunability in function and stiffness with unique mechanical properties (e.g., shear-thinning, injectable solid with immediate rehealing) that allow automatic handling with standard high-throughput screening (HTS) liquid handling equipment commonly found in a drug discovery laboratory. The primary objective of this proposal is to use the versatile and tunable MAX8 peptide to develop a 3D cell culture scaffold that mimics key features of brain extracellular matrix while also retaining material properties critical for use with automated liquid handling equipment, all for a high- throughput drug discovery approach targeting mechanosignaling. Aim 1 will establish a targeted assay for a well- characterized mechanosensitive signaling pathway that is compatible with MAX8 peptide hydrogel scaffold- based 3D cell cultures in a high throughput-compatible setup. Aim 2 will examine how tuning hydrogel stiffness and peptide functionalization with brain extracellular matrix components affects assay performance and phenotype of cerebellar neurons and pediatric brain cancer cells. Aim 3 will validate the newly developed assay platform by performing a pilot drug screen and in vivo efficacy testing of candidate compounds. The outcome of these studies will be a 3D cell culture platform that will provide fundamental understanding of how extracellular matrix composition and tissue stiffness regulate mechanosignaling in both normal neurons and pediatric brain cancer cells. Additionally, these studies will lay the foundation for a future high-throughput drug discovery approach targeting mechanosignaling in scaffold-based 3D cultures optimized for pediatric brain tumors.


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 = $329,013 )
2025	2025	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Cancer Biology Research	000	4	1/27/2025	NON-COMPETING CONTINUATION	$296,112
2025	2025	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Cancer Biology Research	001	4	5/22/2025	NON-COMPETING CONTINUATION	$32,901
														Subtotal = $329,013

Issue Date FY: 2024 ( Subtotal = $313,090 )
2024	2024	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Cancer Biology Research	001	3	4/18/2024	NON-COMPETING CONTINUATION	$16,478
2024	2024	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Cancer Biology Research	000	3	2/12/2024	NON-COMPETING CONTINUATION	$296,612
														Subtotal = $313,090

Issue Date FY: 2023 ( Subtotal = $323,494 )
2023	2023	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Cancer Biology Research	000	2	2/23/2023	NON-COMPETING CONTINUATION	$323,494
														Subtotal = $323,494

Issue Date FY: 2022 ( Subtotal = $340,209 )
2022	2022	NEMOURS FOUNDATION, THE	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Cancer Biology Research	000	1	2/14/2022	NEW	$340,209
														Subtotal = $340,209

Grand Total All Awards = $1,305,806

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Targeting mechanosignaling in pediatric brain cancer

Award Number: R01CA263216

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/14/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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