MUC1: A target molecule for cancer therapy

Singh, Ravibhushan; Bandyopadhyay, Dilip

doi:10.4161/cbt.6.4.4201

Cited by 148 publications

(146 citation statements)

References 45 publications

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“…In previous reports, MUC1 antibody was developed and used in tumor-specific drug delivery systems (Singh and Bandyopadhyay, 2007;Moase, et al, 2011). Recently, MUC1…”

Section: Discussionmentioning

confidence: 99%

Self-assemble gene delivery system for molecular targeting using nucleic acid aptamer

Kurosaki

Higuchi

Kawakami

et al. 2012

Gene

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We have developed a novel vector constructed with pDNA, polyethylenimine (PEI), and mucin 1 (MUC1) aptamer for tumor-targeted gene delivery. The MUC1 aptamer and non-specific aptamer were employed to coat the pDNA/PEI complexes electrostatically and stable nanoparticles were formed. The addition of a non-specific aptamer to the pDNA/PEI complex decreased gene expression in the human lung cancer cell line, A549 cells expressing MUC1 regularly. At the same time, the pDNA/PEI/MUC1 aptamer complex showed higher gene expression than pDNA/PEI/non-specific aptamer complex. Furthermore, the pDNA/PEI/MUC1 aptamer complex showed markedly high gene expression in tumor-bearing mice; thus, pDNA/PEI/MUC1 aptamer complexes are useful as a tumor-targeted gene delivery system with high transfection efficiency.

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“…In previous reports, MUC1 antibody was developed and used in tumor-specific drug delivery systems (Singh and Bandyopadhyay, 2007;Moase, et al, 2011). Recently, MUC1…”

Section: Discussionmentioning

confidence: 99%

Self-assemble gene delivery system for molecular targeting using nucleic acid aptamer

Kurosaki

Higuchi

Kawakami

et al. 2012

Gene

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“…It was engineered by grafting the complementary determining regions of the parental murine antibody (HMFG1) into the consensus framework of a human IgG1. Unlike the low expression rate of antigens such as HER2 (20 -25%), polymorphic epithelial mucin or MUC1 expression is considered to be universal (490%) in breast cancer, as well as in other common epithelial cancers (Singh and Bandyopadhyay, 2007).…”

mentioning

confidence: 99%

Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

Royer

Wu²,

Pegram

et al. 2010

Br J Cancer

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BACKGROUND: HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model. METHOD: Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16 mg kg À1 . Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set. RESULTS: A linear two-compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion. CONCLUSION: A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody.

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“…Thus, MUC1 meets the key criteria for DTA promoter-driven therapy: It is expressed at low levels in normal cells (15)(16)(17), it is overexpressed in pancreatic cancer (particularly in the most aggressive pancreatic cancer subpopulations associated with early cancer-specific mortality), and its expression is predominantly governed at the transcriptional level (highlighted in this study). Herein, we are the first to develop and report MUC1 promoterdriven DTA therapy in any cancer type, and demonstrate targeted specificity against MUC1-positive (þ) pancreatic cancer cells.…”

Section: Introductionmentioning

confidence: 87%

MUC1 Promoter–Driven DTA as a Targeted Therapeutic Strategy against Pancreatic Cancer

Tholey

Lal

Jimbo

et al. 2015

Molecular Cancer Research

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Mucin1 (MUC1) is overexpressed in pancreatic ductal adenocarcinoma (PDA) and is associated with tumor aggressiveness, suggesting that MUC1 is a promising therapeutic target for promoter-driven diphtheria toxin A (DTA). Endogenous MUC1 transcript levels were analyzed by quantitative PCR (qPCR) in multiple PDA cells (Capan1, HPAFII, Su.86.86, Capan2, Hs766T, MiaPaCa2, and Panc1). Expression levels were correlated with luciferase activity and cell death after transfection with MUC1 promoter-driven luciferase and DTA constructs. MUC1-positive (þ) cells had significantly elevated MUC1 mRNA expression compared with MUC1-negative (À) cells. Luciferase activity was significantly higher in MUC1 þ cells when transfected with MUC1 promoter-driven luciferase and MUC1 þ cells underwent enhanced cell death after transfection with a single dose of MUC1 promoter-driven DTA. IFNg pretreatment enhanced MUC1 expression in MUC1 À cells and induced sensitivity to MUC1-DTA therapy. Matched primary and metastatic tumor lesions from clinical specimens revealed similar MUC1 IHC labeling patterns, and a tissue microarray of human PDA biopsies revealed increased immunolabeling with a combination of MUC1 and mesothelin (MSLN) antibodies, compared with either antibody alone. Combining MUC1 with MSLN-targeted DTA enhanced drug efficacy in an in vitro model of heterogeneous PDA. These data demonstrate that MUC1 promoter-driven DTA preferentially kills MUC1-expressing PDA cells and drugs that enhance MUC1 expression sensitize PDA cells with low MUC1 expression.Implications: MUC1 expression in primary and metastatic lesions provides a rationale for the development of a systemic MUC1 promoter-driven DTA therapy that may be further enhanced by combination with other promoter-driven DTA constructs. Mol Cancer Res; 13(3); 439-48. Ó2014 AACR.

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MUC1: A target molecule for cancer therapy

Cited by 148 publications

References 45 publications

Self-assemble gene delivery system for molecular targeting using nucleic acid aptamer

Self-assemble gene delivery system for molecular targeting using nucleic acid aptamer

Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

MUC1 Promoter–Driven DTA as a Targeted Therapeutic Strategy against Pancreatic Cancer

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