Radioimmunotherapy of human pancreatic cancer xenografts in NOD-scid mice with [Cu]Cu-NOTA-panitumumab F(ab') alone or combined with radiosensitizing gemcitabine and the PARP inhibitor, rucaparib.

Introduction: Our objective was to determine the feasibility of extending our previously reported PET imaging study of pancreatic cancer (PnCa) with [Cu]Cu-NOTA-panitumumab F(ab') to radioimmunotherapy (RIT) by exploiting the β-particle and Auger electron emissions of Cu (PET theranostic concept). To enhance the effectiveness of [Cu]Cu-NOTA-panitumumab F(ab'), we further combined RIT with radiosensitizing gemcitabine (GEM) and the poly(ADP)ribose polymerase inhibitor (PARPi), rucaparib.

Methods: Normal tissue toxicity was assessed in non-tumor-bearing NOD-scid mice injected i.

Whole genomes define concordance of matched primary, xenograft, and organoid models of pancreas cancer.

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities.

EGFR-Targeted Metal Chelating Polymers (MCPs) Harboring Multiple Pendant PEG Chains for MicroPET/CT Imaging of Patient-Derived Pancreatic Cancer Xenografts.

In this study, we developed a new generation of metal chelating polymer (MCP) reagents that carry multiple polyethylene glycol (PEG) pendant groups to provide stealth to MCP-based radioimmunoconjugates (RICs). We describe the MCP synthesis for covalent attachment to panitumumab F(ab') fragments (pmabF(ab')) in which different numbers of pendant methoxy-PEG chains [M = 2000, ∼45 ethylene glycol (EG) repeat units, referred to as PEG] are incorporated into the polymer backbone. The pendant PEG chains were designed to provide a protein-repellant corona so that metal chelators attached closer to the polymer backbone will be less apparent to the physiological environment.

MicroPET/CT imaging of patient-derived pancreatic cancer xenografts implanted subcutaneously or orthotopically in NOD-scid mice using (64)Cu-NOTA-panitumumab F(ab')2 fragments.

Introduction: Our objective was to study microPET/CT imaging of patient-derived pancreatic cancer xenografts in NOD-scid mice using F(ab')2 fragments of the fully-human anti-EGFR monoclonal antibody, panitumumab (Vectibix) labeled with (64)Cu. More than 90% of pancreatic cancers are EGFR-positive.

Methods: F(ab')2 fragments were produced by proteolytic digestion of panitumumab IgG or non-specific human IgG, purified by ultrafiltration then modified with NOTA chelators for complexing (64)Cu.

Activation of Src and Src-associated signaling pathways in relation to hypoxia in human cancer xenograft models.

The hypoxic response in vitro involves alterations in signaling proteins, including Src, STAT3 and AKT that are considered to be broadly pro-survival. The involvement of these signaling proteins in the hypoxic microenviroments that occur in solid tumors was investigated by the use of multicolor fluorescence image analysis to colocalize signaling proteins and regions of hypoxia in 4 human tumor xenografts, pancreatic carcinoma BxPC3 and PANC1 and cervical squamous cell carcinoma ME180 and SiHa. Expression levels of total Src protein (mean intensity x labeled region fraction) were higher in hypoxic regions, identified using the nitroimidazole probe EF5, relative to non-EF5 regions in all 4 tumor models.