Theranostic Targeting of CUB Domain Containing Protein 1 (CDCP1) in Pancreatic Cancer

Abstract

Purpose: The recent emergence of radioligand therapies for cancer treatment has increased enthusiasm for developing new theranostic strategies coupling both imaging and cytotoxicity in the same entity. In this study, we evaluated whether CUB domain containing protein 1 (CDCP1), a single-pass transmembrane protein highly overexpressed in diverse human cancers, might be a target for cancer theranostics.Experimental Design: The ectodomain of CDCP1 was targeted using radiolabeled forms of 4A06, a potent and specific recombinant human antibody that we developed. Imaging and antitumor assessment studies were performed in animal models of pancreatic cancer, including two patient-derived xenograft models we developed for this study. For antitumor assessment studies, the endpoints were death due to tumor volume >3,000 mm 3 or ≥20% loss in body weight. Specific tracer binding or antitumor effects were assessed with an unpaired, two-tailed Student t test and survival advantages were assessed with a log rank (Mantel-Cox) test. Differences at the 95% confidence level were interpreted to be significant.Results: 89 Zr-4A06 detected a broad dynamic range of full length or cleaved CDCP1 expression on seven human pancreatic cancer tumors (n ¼ 4/tumor). Treating mice with single or fractionated doses of 177 Lu-4A06 significantly reduced pancreatic cancer tumor volume compared with mice receiving vehicle or unlabeled 4A06 (n ¼ 8; P < 0.01). A single dose of 225 Ac-4A06 also inhibited tumor growth, although the effect was less profound compared with 177 Lu-4A06 (n ¼ 8; P < 0.01). A significant survival advantage was imparted by 225 Ac-4A06 (HR ¼ 2.56; P < 0.05).Conclusions: These data establish that CDCP1 can be exploited for theranostics, a finding with widespread implications given its breadth of overexpression in cancer.

Comparative Microsomal Proteomics of A Model Lung Cancer Cell Line NCI-H23 Reveals Distinct Differences Between Molecular Profiles of 3D and 2D Cultured Cells

“…[17] Importantly, subsequent investigations established CD318 as a viable target for radiological staging and treatment of pancreatic cancer. [47,64] In this study, we confirmed exclusive expression of CD146, CD99 and CD239 on the surface of 3D-grown NCI-H23 cells ( Figure 4B) and showed their potential interaction through the activation of protein networks facilitated by PI3K, NFkB, and IFN-beta signaling ( Figure 4A). A recent study focused on the evaluation of the KRas G12C direct covalent inhibitor ARS1620 using patient-derived xenograft (PDX) models and found that intrinsic resistance of NSCLC to ARS1620 monotherapy, driven by nongenetic adaptive mechanisms, can be alleviated by concomitant application of PI3K inhibitors.…”

Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities

“…and Dammes & Peer for further detail [ 206 , 207 ]. Antibody-based theranostic pairs have been developed targeting a variety of antigens including carcinoembrionic antigen (CEA) [ 208 ], tissue factor [ 35 ], CUB domain containing protein 1 (CDCP1) [ 209 ] and Met [ 210 ]. For instance, Knutson and colleagues have reported the development of a theranostic monoclonal antibody specific for CEA, conjugated to paclitaxel and a PEGylated near-infrared fluorophore (DyLight™ 680-4xPEG, Thermo Fisher Scientific, #46603, Rockford, IL, USA).…”

CUB domain containing protein 1 (CDPC1) is a target for radioligand therapy in castration resistant prostate cancer

“…We next evaluated if CDCP1 expression can be detected on PET using 89 Zr-labeled 4A06. 4A06 was functionalized with desferrioxamine B and radiolabeled to high yield with Zr-89 as previously reported (13). A cohort of mice (n = 4/tumor type) bearing one of the following tumors were studied: TRAMP C2, DU145, 22Rv1, LTL-545 and LTL-331.…”

“…We chose this dosing regimen as we previously showed it to be more efficacious that a single fraction of an equivalent total radioactive dose (i.e. 800 μCi) (13). SPECT/CT imaging showed effective tumor targeting at 72 hours after the first injection (Figure 4A).…”

“…This restricted expression distinguishes CDCP1 from PSMA which is broadly expressed in the salivary gland, liver, kidney, and other tissues. Lastly, we recently established proof of concept for CDCP1 directed RLT by showing that that pancreatic cancer tumors can be effectively treated with an anti-CDCP1 antibody termed 4A06 coupled to βor α emitters (13).…”