Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma: A Review of the Current Status of Literature

Hull, Ashleigh; Li, Yanrui; Bartholomeusz, Dylan; Hsieh, William; Allen, Barry J.; Bezak, Eva

doi:10.3390/cancers12020481

Cited by 11 publications

(5 citation statements)

References 78 publications

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“…Radioimmunotherapy with b-emitters may be less influenced by dense tumor stroma, as cross-fire radiation can treat regions of the tumor unbound by drug. Indeed, radioimmunotherapy research has been vibrant with the recent reemergence of nuclear theranostics, and over 15 preclinical trials testing discrete therapies against targets like CA19.9, MUC1, and integrin a6b4 have shown considerable promise in reducing tumor burden and/or extending overall survival (28). More rigorous comparisons between 4A06 and other experimental therapeutics are warranted to assess the relative strengths and weaknesses of each drug target.…”

Section: Discussionmentioning

confidence: 99%

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

Moroz

Wang

Sharib

et al. 2020

Clinical Cancer Research

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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.

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Section: Discussionmentioning

confidence: 99%

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

Moroz

Wang

Sharib

et al. 2020

Clinical Cancer Research

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“…Astatine-211-OTSA101, an α-emitting anti-FZD10 RIC, suppressed tumor growth of SS mouse xenografts more efficiently than the same dose of the Yttrium-90-OTSA101, a β-emitting anti FZD10 RIC, without remarkable toxic side effects [110]. This confirmed that α-RIT is superior to β-RIT in treating solid tumors because α-particles, with higher linear energy transfer, may have more advantages in terms of cytotoxicity compared to β-particles, with lower linear energy transfer [111].…”

Section: Radioimmunoconjugates For Sarcomamentioning

confidence: 59%

Antibody Conjugates for Sarcoma Therapy: How Far along Are We?

et al. 2021

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Sarcomas are one of the most difficult type of cancer to manage and treat because of their extremely heterogeneous molecular and morphological features. Despite the progress made over the years in the establishment of standard protocols for high and low grading/staging sarcoma patients, mostly with chemotherapy and/or radiotherapy, 50% of treated patients experience relapse episodes. Because of this, in the last 20 years, new therapeutic approaches for sarcoma treatment have been evaluated in preclinical and clinical studies. Among them, antibody-based therapies have been the most studied. Immunoconjugates consist of a carrier portion, frequently represented by an antibody, linked to a toxic moiety, i.e., a drug, toxin, or radionuclide. While the efficacy of immunoconjugates is well demonstrated in the therapy of hematological tumors and more recently also of epithelial ones, their potential as therapeutic agents against sarcomas is still not completely explored. In this paper, we summarize the results obtained with immunoconjugates targeting sarcoma surface antigens, considering both preclinical and clinical studies. To date, the encouraging results obtained in preclinical studies allowed nine immunoconjugates to enter clinical trials, demonstrating the validity of immunotherapy as a promising pharmacological tool also for sarcoma therapy.

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“…A wide range of antibodies have been developed to target MUC1-CE including PAM4, Gatipotuzumab, TAB004, MA5 and C595 (Danielczyk et al 2006 ; Gold et al 2013 ; Wu et al 2018a ; Price et al 1990 ). Radiolabelling of these antibodies to a therapeutic radionuclide which emits alpha particles, beta particles or auger electrons has been shown to elicit a cytotoxic effect (Hull et al 2020b ). This radioimmunotherapy (RIT) approach allows for systemic yet localised targeting of MUC1-CE expressing cells which can be harnessed to treat metastatic disease including micro-metastases.…”

Section: Introductionmentioning

confidence: 99%

In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer

Hull

Hsieh

Tieu

et al. 2023

EJNMMI radiopharm. chem.

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Background Pancreatic ductal adenocarcinoma (PDAC) continues to be a malignancy with an unmet clinical demand. Development of radioimmunoconjugates which target cancer-specific receptors provides an opportunity for radioimmunotherapy of both metastatic and primary PDAC. In this study, we characterised the in vitro behaviour of a novel beta-emitting radioimmunoconjugate [177Lu]Lu-DOTA-C595 as a therapeutic agent against PDAC. [177Lu]Lu-DOTA-C595 is designed to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on most epithelial cancers, including PDAC. Results A series of in vitro experiments were performed on PDAC cell lines (PANC-1, CAPAN-1, BxPC-3 and AsPC-1) exhibiting strong to weak MUC1-CE expression. [177Lu]Lu-DOTA-C595 bound to all cell lines relative to their expression of MUC1-CE. [177Lu]Lu-DOTA-C595 was also rapidly internalised across all cell lines, with a maximum of 75.4% of activity internalised within the PANC-1 cell line at 48 h. The expression of γH2AX foci and clonogenic survival of PANC-1 and AsPC-1 cell lines after exposure to [177Lu]Lu-DOTA-C595 were used to quantify the in vitro cytotoxicity of [177Lu]Lu-DOTA-C595. At 1 h post treatment, the expression of γH2AX foci exceeded 97% in both cell lines. The expression of γH2AX foci continued to increase in PANC-1 cells at 24 h, although expression reduced in AsPC-1. Clonogenic assays showed a high level of cell kill induced by [177Lu]Lu-DOTA-C595. Conclusion [177Lu]Lu-DOTA-C595 has favourable in vitro characteristics to target and treat MUC1-CE positive PDAC. Further investigations to characterise the in vivo effects and potential value of [177Lu]Lu-DOTA-C595 in other MUC1-CE expressing malignancies such as lung, ovarian and colorectal adenocarcinoma are warranted.

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Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma: A Review of the Current Status of Literature

Cited by 11 publications

References 78 publications

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

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

Antibody Conjugates for Sarcoma Therapy: How Far along Are We?

In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer

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