Characterization of the MUC1.Tg/MIN transgenic mouse as a model for studying antigen-specific immunotherapy of adenomas

Akporiaye, Emmanuel T.; Bradley-Dunlop, Deborah; Gendler, Sandra J.; Mukherjee, Pinku; Madsen, Cathy S.; Hahn, Tobias; Besselsen, David G.; Dial, Sharon M.; Cui, Haiyan; Trevor, Katrina T.

doi:10.1016/j.vaccine.2007.06.063

“…4), with results similar to reports from several human immunotherapy trials (51). However, this was a bit surprising because the same vaccine was shown by our own group to be highly effective in MUC1-tolerant colon cancer model (45, 47). Other vaccine strategy such as DC pulsed with the MUC1 peptides as well as DC pulsed with tumor lysate has been tested without success in this model (data not shown).…”

Section: Discussionmentioning

confidence: 98%

Regulation of T Cell Activation by Notch Ligand, DLL4, Promotes IL-17 Production and Rorc Activation

Mukherjee

¹

,

Schaller

²

,

Neupane

³

et al. 2009

The Journal of Immunology

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With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRASG12D mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E2 and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer.

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“…In the absence of MUC1, PanIN lesions do not progress. Similarly, in the APC min mouse of spontaneously developing colon polyps, MUC1 drives the polyps to become adenocarcinomas [101]. Thus, one can assume that MUC1 is crucial for the progression of the disease once an initiating oncogenic event has occurred.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

MUC1: a multifaceted oncoprotein with a key role in cancer progression

Nath

¹

,

Mukherjee

²

2014

Trends in Molecular Medicine

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The transmembrane glycoprotein Mucin 1 (MUC1) is aberrantly glycosylated and overexpressed in a variety of epithelial cancers, and plays a crucial role in progression of the disease. Tumor-associated MUC1 differs from the MUC1 expressed in normal cells with regard to its biochemical features, cellular distribution, and function. In cancer cells, MUC1 participates in intracellular signal transduction pathways and regulates the expression of its target genes at both the transcriptional and post-transcriptional levels. This review highlights the structural and functional differences that exist between normal and tumor-associated MUC1. We also discuss the recent advances made in the use of MUC1 as a biomarker and therapeutic target for cancer.

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“…2). This was indeed surprising because the same vaccine strategy was highly successful in preventing tumor formation in colon cancer models (45,47). However, when the MUC1 vaccine was combined with a COX-2 inhibitor, its efficacy was significantly enhanced (Fig.…”

Section: Immunization With Muc1-specific Vaccine Is Effective Only Inmentioning

confidence: 99%

Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition

Mukherjee¹,

Basu

²

,

Tinder³

et al. 2009

The Journal of Immunology

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With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRASG12D mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E2 and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer.

show abstract

Characterization of the MUC1.Tg/MIN transgenic mouse as a model for studying antigen-specific immunotherapy of adenomas

Cited by 16 publications

References 44 publications

Regulation of T Cell Activation by Notch Ligand, DLL4, Promotes IL-17 Production and Rorc Activation

Regulation of T Cell Activation by Notch Ligand, DLL4, Promotes IL-17 Production and Rorc Activation

MUC1: a multifaceted oncoprotein with a key role in cancer progression

Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition

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