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Principal Investigator: Jered C Garrison
Organization: UNIVERSITY OF NEBRASKA MEDICAL CENTER
Fiscal Year: 2024
Award: $621,119
Funding agency: National Cancer Institute
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a lethal, treatment-refractory malignancy characterized by
fibroblast-rich stroma. While external beam radiation therapy (EBRT) is a staple in the current treatment of PDAC,
its therapeutic efficacy is limited by normal tissue toxicities and its inability to target metastatic disease. Targeted
radionuclide therapeutics (TRTs), particularly low-molecular-weight carriers, offer an avenue to improve the
deliverable radiation dose and therapeutic efficacy compared to EBRT by selectively targeting tumors (both
primary and metastatic) and substantially reduce non-target toxicities. The fibroblast activation protein-α (FAP)
is selectively expressed on tumor-associated fibroblasts in the tumor microenvironment (TME) of PDAC (~75%)
and other malignancies. Several clinical imaging studies have validated the potential of small molecule, FAP-
targeted constructs (e.g., 68Ga-FAPI-46). However, the therapeutic translation of FAP-TRTs has failed mainly
due to their low tumor-residualization, which diminishes deliverable therapeutic doses, therapeutic efficacy, and
clinical potential. Recently, we have developed an endolysosomal trapping approach reliant on adduct formation
with cysteine protease to increase tumor residualization of TRTs substantially. Using this adduct formation
approach, the goals of this proposal are to optimize 177Lu- and 225Ac-FAP-targeted TRT constructs, obtain a
greater understanding of how PDAC biology impacts adduct formation, demonstrate our construct's therapeutic
efficacy and safety in PDAC models, understand the impact of FAP-TRTs on the PDAC tumor microenvironment
and compare and contrast the biological effect of 177Lu (β-) vs. 225Ac (α) based FAP-TRTs. Another challenge for
FAP-targeted therapies emerges from its heterogeneous expression and the inadequacy of preclinical models
to recapitulate variabilities in FAP expression. We have generated a panel of human immortalized patient-derived
pancreatic fibroblasts (iPDPFs) that recapitulate CAF heterogeneity and variable FAP expression. We have also
developed unique CAF-tumor cell co-implantation models that result in FAP high or FAP low tumors. We
hypothesize that incorporating cysteine protease trapping agents (CPTAs) into the structure of FAP-targeted
agents (FAPTAs) will allow the formation of intracellular adducts capable of delivering higher therapeutic efficacy
through enhanced PDAC-specific retention. To test this hypothesis, two specific aims are proposed. Aim 1
focuses on optimizing 177Lu/225Ac-CPTA-FAPTAs and examining adduct formation and distribution in PDAC
models. Studies in Aim 2 are designed to evaluate the therapeutic efficacy of 177Lu/225Ac-CPTA-FAPTAs and
investigate the impact of FAP-TRT therapy on CAF heterogeneity. We propose to employ cutting-edge
approaches and models to study the biodistribution, cellular uptake and trafficking, adduct formation, dosimetry,
and therapeutic efficacy of 177Lu/225Ac-CPTA-FAPTAs. Successful completion of the proposed studies will
provide the critical data required to progress the novel FAP-TRTs toward regulatory approval and initiation of
clinical trials in the future.
Terms: <170-kD Melanoma Membrane-Bound Gelatinase><Affinity><Alpha Subunit Fibroblast Activation Protein><Assay><Autoradiography><Bioassay><Biodistribution><Biological><Biological Assay><Biology><Biotin><Body Tissues><Cancer Cause><Cancer Etiology><Cancers><Caspase><Caspase Gene><Cell Body><Cell-Death Protease><Cells><Cessation of life><Chemicals><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clinical><Clinical Trials><Confocal Microscopy><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Data><Death><Definitive Radiation Therapy><Disease><Disorder><Dose><Drug or chemical Tissue Distribution><EBRT><Electrophoresis><Electrophoretic Fractionation><External Beam RT><External Beam Radiation Therapy><External Radiation><FAP-Alpha><FAPalpha><Fibroblasts><Fluorescence Light Microscopy><Fluorescence Microscopy><Future><Goals><Health><Heterogeneity><Human><ICE-like protease><Image><In Vitro><Integral Membrane Serine Protease><Investigation><Investigational Drugs><Investigational New Drugs><LC/MS><Label><Laboratories><Lysosomes><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Modeling><Modern Man><Molecular Weight><New Drug Approvals><Normal Tissue><Normal tissue morphology><Operative Procedures><Operative Surgical Procedures><PDA model><PDAC Model><PDAC cancer cell><PDAC cell><PanIN><Pancreas><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic><Pancreatic Cancer><Pancreatic Duct Dysplasia><Pancreatic Ductal Adenocarcinoma><Pancreatic Ductal Dysplasia><Pancreatic Intraepithelial Neoplasia><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Performance><Pre-Clinical Model><Preclinical Models><Radiation Dose><Radiation Dose Unit><Radioactive Isotopes><Radioautography><Radioisotopes><Radionuclide therapy><Radionuclides><Radiopharmaceutical Compound><Radiopharmaceuticals><Refractory><Role><Safety><Seprase><Strepavidin><Streptavidin><Structure><Surgical><Surgical Interventions><Surgical Procedure><Survival Rate><Testing><Therapeutic><Time><Tissue Distribution><Tissues><Toxic effect><Toxicities><Translations><Treatment Efficacy><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor Cell><Vitamin H><adduct><analog><biologic><cancer diagnosis><cancer microenvironment><chemo/radiation therapy><chemotherapy and radiotherapy><clinical imaging><clinical relevance><clinical translation><clinically relevant><clinically translatable><coenzyme R><comparable efficacy><comparative efficacy><compare efficacy><cystein protease><cystein proteinase><cysteine endopeptidase><design><designing><dosimetry><external-beam radiation><fibroblast activation protein alpha><human disease><imaging><imaging study><implantation><improved><in vitro Assay><in vivo><intervention efficacy><liquid chromatography mass spectrometry><malignancy><mouse model><murine model><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pancreas duct dysplasia><pancreas ductal dysplasia><pancreatic ductal adenocarcinoma cell><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pathway><patient oriented outcomes><radiation or chemotherapy><radioactive drugs><radiotherapeutic drugs><response to therapy><response to treatment><selective expression><selectively expressed><small molecule><social role><surface expressed protease><surgery><targeted agent><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><theranostics><therapeutic efficacy><therapeutic evaluation><therapeutic radionuclide><therapeutic response><therapeutic testing><therapy efficacy><therapy response><trafficking><translation><translational therapeutics><translational therapy><treatment response><treatment responsiveness><tumor><tumor microenvironment><uptake>