Friday, May 3, 2024
5/3/2024
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-a (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 (ß-) vs. 225Ac (a) 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.
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