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Detection, Radiosensitization and Theranostic Targeting of Metastatic Breast Cancer by PTPmu

Award Number: R01CA269816
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Detection, Radiosensitization and Theranostic Targeting of Metastatic Breast Cancer by PTPmu - Both inside the central nervous system and outside in the peripheral nervous system, cancer cells grow along nerves as routes of invasion and metastasis called neural invasion. This growth is common in several carcinomas including breast cancer and is associated with poor prognosis. Proteolysis of cell adhesion molecules (CAMs) occurs in development, and growing evidence suggests this post-translational modification may promote tumor migration and invasion on nerves that ultimately leads to metastasis to the brain in various tumor types including breast cancer. The receptor protein tyrosine phosphatase PTPµ is a CAM that is proteolyzed in cancer cells to generate an extracellular fragment that is a unique imaging biomarker of the tumor microenvironment. The PTPµ- targeted agents we developed bind to this biomarker and recognize human brain tumors as well as invasive primary breast cancer and breast cancer that has metastasized to the brain. Systemic delivery of the PTPµ- targeted agent results in binding to tumor cells within minutes in xenograft models. Using a 3D cryo-imaging system we analyzed the extent of cell migration and dispersal within the brain. We found that the PTPµ-targeted agent labels 99% of all dispersing tumor cells far away from the main tumor mass on nerves in mouse models. This proposal represents the convergence of our expertise in neuroscience, cell adhesion, imaging and cancer to test if the PTPµ biomarker can be used to detect tumor growth along nerves leading to brain metastases. Gold nanoparticles (AuNPs) have shown outstanding versatility in biomedical applications including imaging diagnostics, drug delivery, and radiation therapy. In this proposal, we describe the development of theranostic AuNPs for the detection and treatment of breast cancer metastases. We will achieve more sensitive detection and treatment of invasive and metastatic lesions through the use of a three component theranostic nanoparticle containing: 1) a highly specific targeting agent of the PTPµ biomarker in the tumor microenvironment; 2) a protease-sensitive quenched near infrared fluorophore for fluorescent imaging; and 3) a gold nanoparticle (AuNP) for sensitization to radiotherapy. We will test whether the PTPµ-targeted agents detects nerve associated growth using 3D single cell resolution cryo-imaging that precisely tracks migration of individual cancer cells on nerves. We will utilize our established human patient-derived xenograft models of metastatic breast cancer and models that metastasize from the breast to the brain. Metastatic tumors are resistant to almost all chemotherapeutics so “physical” killing strategies like radiation must be improved and employed for better therapeutic outcomes. By delivering PTPµ-targeted conjugated AuNPs directly to primary and metastatic breast cancer we will exploit the radiosensitization of AuNP to reduce the required dose of radiation needed for radiotherapy thereby reducing collateral damage to normal surrounding tissues. We expect that these studies will yield targeted nanoparticles that detect and treat nerve associated tumor growth while implicating CAM proteolysis as a generalizable mechanism for detecting and treating tumor invasion on nerves.


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 = $601,330 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	000	4	12/9/2025	NON-COMPETING CONTINUATION	$601,330
														Subtotal = $601,330

Issue Date FY: 2025 ( Subtotal = $668,144 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	002	3	8/28/2025	NON-COMPETING CONTINUATION	$0
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	001	3	6/25/2025	NON-COMPETING CONTINUATION	$66,814
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	000	3	11/6/2024	NON-COMPETING CONTINUATION	$601,330
														Subtotal = $668,144

Issue Date FY: 2024 ( Subtotal = $634,738 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$33,408
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	000	2	11/2/2023	NON-COMPETING CONTINUATION	$601,330
														Subtotal = $634,738

Issue Date FY: 2023 ( Subtotal = $668,144 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	000	1	11/21/2022	NEW	$668,144
														Subtotal = $668,144

Grand Total All Awards = $2,572,356

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Detection, Radiosensitization and Theranostic Targeting of Metastatic Breast Cancer by PTPmu

Award Number: R01CA269816

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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