"Targeting the Plasminogen Activation System in Cancer for Imaging and Therapy"
Date
Aaron Matthew LeBeau, PhD
Postdoctoral Fellow
University of California, San Francisco
Department of Pharmaceutical Chemistry
Department of Radiology and Biomedical Imaging
Abstract: Cancer subtype-specific imaging probes and therapeutics have the potential to function as molecular stratification agents and targeted therapeutics in the clinic. Biomarkers that serve as molecular indicators of aggressive cancer subtypes need to be evaluated and targeted. The plasminogen activation system (PAS) is an attractive target for a biomarker-based imaging and therapeutic strategy. Over-expression of the PAS - which consists of the secreted serine protease urokinase plasminogen activator (uPA), the receptor of uPA (uPAR) and the inhibitor of uPA (PAI-1) - has been documented in triple-negative breast cancer (TNBC) and castration-resistant prostate cancer (CRPC). Using a human antibody phage display library, antagonistic human antibodies with low nanomolar affinities for uPAR and uPA were identified. The full length immunoglobulin antibodies were evaluated in vivo in TNBC and CRPC models. As SPECT imaging agents, the two antagonistic uPAR antibodies localized to TNBC xenografts with high tumor uptake values (%ID/g > 40%). The uPAR imaging probes accurately detected small disseminated lesions in a TNBC metastasis model, complementing the current clinical imaging standard FDG-PET at detecting non-glucose-avid metastatic lesions. Armed with the therapeutic radionuclide 177Lu, the uPAR antibodies were potent radioimmunotherapy agents yielding a complete reduction of tumor burden. In a CRPC model, the antagonistic uPA antibody was found to be internalized through a unique mechanism leading to high tumor uptake as a SPECT probe. This antibody was also able to image small osseous metastases in a metastatic CRPC model. Taken together, these results offer a preclinical proof-of-concept for PAS targeting as a strategy for cancer diagnosis and therapy.
Please note that Dr. Aaron LeBeau is an applicant for the Biomarker Imaging faculty position.
Type
Time Duration
Aaron Matthew LeBeau, PhD
Postdoctoral Fellow
University of California, San Francisco
Department of Pharmaceutical Chemistry
Department of Radiology and Biomedical Imaging
Abstract: Cancer subtype-specific imaging probes and therapeutics have the potential to function as molecular stratification agents and targeted therapeutics in the clinic. Biomarkers that serve as molecular indicators of aggressive cancer subtypes need to be evaluated and targeted. The plasminogen activation system (PAS) is an attractive target for a biomarker-based imaging and therapeutic strategy. Over-expression of the PAS - which consists of the secreted serine protease urokinase plasminogen activator (uPA), the receptor of uPA (uPAR) and the inhibitor of uPA (PAI-1) - has been documented in triple-negative breast cancer (TNBC) and castration-resistant prostate cancer (CRPC). Using a human antibody phage display library, antagonistic human antibodies with low nanomolar affinities for uPAR and uPA were identified. The full length immunoglobulin antibodies were evaluated in vivo in TNBC and CRPC models. As SPECT imaging agents, the two antagonistic uPAR antibodies localized to TNBC xenografts with high tumor uptake values (%ID/g > 40%). The uPAR imaging probes accurately detected small disseminated lesions in a TNBC metastasis model, complementing the current clinical imaging standard FDG-PET at detecting non-glucose-avid metastatic lesions. Armed with the therapeutic radionuclide 177Lu, the uPAR antibodies were potent radioimmunotherapy agents yielding a complete reduction of tumor burden. In a CRPC model, the antagonistic uPA antibody was found to be internalized through a unique mechanism leading to high tumor uptake as a SPECT probe. This antibody was also able to image small osseous metastases in a metastatic CRPC model. Taken together, these results offer a preclinical proof-of-concept for PAS targeting as a strategy for cancer diagnosis and therapy.
Please note that Dr. Aaron LeBeau is an applicant for the Biomarker Imaging faculty position.