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Urokinase-type plasminogen activator receptor (uPAR)-targeted imaging and therapy in aggressive thyroid cancers

Award Number: R21CA317608
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/06/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Urokinase-type plasminogen activator receptor (uPAR)-targeted imaging and therapy in aggressive thyroid cancers - PROJECT SUMMARY Most types of thyroid cancer have an excellent prognosis with good outcomes. However, two significant exceptions are poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), both of which are rare but highly aggressive with a similar clinical course. While the mean survival of patients with PDTC is 3.2 years the ATC mean survival is only 6 months. Moreover, ATC is considered the most lethal hu¬man malignancy. Management of PDTC and ATC is cha¬llenging as neither of these thyroid cancers take up radioactive iodine, and tradi¬tional chemotherapy and radio¬the¬rapy are of limited benefit. Thus, treatment options for the ino¬pe¬rable ATC and PDTC are still limited and new targeted therapeutic approaches capable of managing both local and metastatic PDTC and ATC are needed. We have demonstrated that PDTC and ATC cell lines and patients’ tissue ex¬press cell membrane receptor, uro¬kinase-type pla¬smi¬nogen activator receptor (uPAR). It has been shown that uPAR is minimally expressed in normal organs but becomes overexpressed in cancers and is correlated with poor outcomes and severity of different types of neoplasms. We propose here inno¬va¬tive, and precise detection of PDTC and ATC using radio¬¬phar¬-ma¬¬ceutical [89Zr]Zr-ATN615 targeting uPAR. Our preliminary data demonstrated significant uptake of this radiopharmaceutical in the uPAR positive PDTC and ATC cells and xenografts. The over¬ar¬ching goal of this proposal is to iden¬tify and validate a novel detection stra¬tegy which will set a stage for future clinical therapy studies to reduce mor¬bi¬di¬ty and mortality of PDTC and ATC pa¬tients. To reveal the utility of uPAR in imaging and potential treat¬ment of aggressive thyroid can¬¬cers we propose to conduct experiments in two Aims. In Aim 1 we will assess the clinical and translational relevance of uPAR expre¬ssion in PDTC and ATC cell lines and patient-derived speci¬mens via qualitative and quantitative immunohistochemistry. The goal of the Aim 2 is to optimize the radiolabeling of ATN615 antibody with 89Zr and perform in vitro and in vivo uPAR targeting and imaging experiments using multiple preclinical models: (i) subcutaneous with cell line derived xenografts (CDXs), (ii) subcutaneous with patient derived xenograft (PDXs), and (iii) orthotopic with cell line derived xenograft (OCDXs). Unlike in vitro cultures, animal models provide a complex, living circulatory system necessary to evaluate how the radiopharmaceutical circulates, clears from healthy organs, and targets tumors. Subcutaneous models allow to observe, measure, and image tumor growth in a simple location whereas orthotopic models (in the thyroid) place the cancer in its natural microenvironment to precisely test the radiopharmaceutical's imaging accuracy and diagnostic performance. These [89Zr]Zr-ATN615 uptake experiments in uPAR positive PDTC and ATC models will provide a foundation for future clinical imaging studies and research on ATN615 radiolabeled with the alternative isotopes, for possible therapeutic applications.


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 = $383,116 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	1	8/6/2026	NEW	$383,116
														Subtotal = $383,116

Grand Total All Awards = $383,116

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Urokinase-type plasminogen activator receptor (uPAR)-targeted imaging and therapy in aggressive thyroid cancers

Award Number: R21CA317608

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/06/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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