MUC1 promoter-driven DTA as a targeted therapeutic strategy against pancreatic cancer

Renee M. Tholey, Shruti Lal, Masaya Jimbo, Richard A. Burkhart, Fernando F. Blanco, Joseph A. Cozzitorto, Josh D. Eisenberg, Wei Jiang, Christine A. Iacobuzio-Donahue, Agnieszka K. Witkiewicz, Melissa Glbert, Charles J. Yeo, Jonathan R. Brody, Janet A. Sawicki, Jordan M. Winter

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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 (+) cells had significantly elevated MUC1 mRNA expression compared with MUC1-negative (-) cells. Luciferase activity was significantly higher in MUC1+ cells when transfected with MUC1 promoter-driven luciferase and MUC1+ cells underwent enhanced cell death after transfection with a single dose of MUC1 promoter-driven DTA. IFNγ pretreatment enhanced MUC1 expression in MUC1- 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.

Original languageEnglish (US)
Pages (from-to)439-448
Number of pages10
JournalMolecular Cancer Research
Volume13
Issue number3
DOIs
StatePublished - Mar 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Tholey, R. M., Lal, S., Jimbo, M., Burkhart, R. A., Blanco, F. F., Cozzitorto, J. A., Eisenberg, J. D., Jiang, W., Iacobuzio-Donahue, C. A., Witkiewicz, A. K., Glbert, M., Yeo, C. J., Brody, J. R., Sawicki, J. A., & Winter, J. M. (2015). MUC1 promoter-driven DTA as a targeted therapeutic strategy against pancreatic cancer. Molecular Cancer Research, 13(3), 439-448. https://doi.org/10.1158/1541-7786.MCR-14-0199