Epithelial cell glycoprotein MUC1 is overexpressed and hypoglycosylated on all human adenocarcinomas and is recognized by the immune system as a tumor antigen. In basic and preclinical studies supported by the long-standing grant that this application aims to renew, we have deciphered numerous interactions of MUC1 and the adaptive immune system and this knowledge has been translated to MUC1 based vaccines for pancreatic, breast, colon and prostate cancer. We also made an unexpected observation that MUC1 interacts directly with the cells of the innate immune system and thus might play an important role in inflammation and cancer. Our hypothesis is that overexpression and aberrant glycosylation of MUC1 promotes first chronic inflammation and later progression to cancer and thus MUC1 should be targeted not only for tumor therapy, as studied so far, but also for therapy of chronic inflammation before tumors develop. We propose two specific aims:
Specific Aim 1. To define MUC1 related cellular and molecular events that regulate (induce, promote) chronic inflammation and cancer. We will use the new mouse model developed in the previous grant period as well as the information we obtained regarding the novel interactions of the MUC1 glycoprotein with the innate and the adaptive immune system.
Specific Aim 2. To test the ability of MUC1-specific or MUC1-related immunotherapy to prevent chronic inflammation and cancer. We will use vaccines based on immunogenic MUC1 glycopeptides defined in the last grant period as well as MUC1 specific TCR transgenic mice developed in the same period. We have preliminary evidence that inducing MUC1 specific adaptive immunity can prevent not only cancer but also chronic inflammation. Nobody has yet considered MUC1 as a target for therapy, and specifically immunotherapy, of chronic inflammatory diseases that carry increased risk of cancer.

Public Health Relevance

This is a long-standing project directed towards immunotherapy of cancer and cancer vaccines based on the tumor antigen MUC1. In this renewal application, work will be done to show that this form of immunotherapy and the same vaccines may be useful not only for cancer but also for treatment and prevention of chronic inflammations that increase risk for cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA056103-18
Application #
8196730
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Howcroft, Thomas K
Project Start
1991-06-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
18
Fiscal Year
2012
Total Cost
$312,611
Indirect Cost
$106,267
Name
University of Pittsburgh
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Cascio, Sandra; Zhang, Lixin; Finn, Olivera J (2011) MUC1 protein expression in tumor cells regulates transcription of proinflammatory cytokines by forming a complex with nuclear factor-ýýB p65 and binding to cytokine promoters: importance of extracellular domain. J Biol Chem 286:42248-56
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Ryan, Sean O; Vlad, Anda M; Islam, Kazi et al. (2009) Tumor-associated MUC1 glycopeptide epitopes are not subject to self-tolerance and improve responses to MUC1 peptide epitopes in MUC1 transgenic mice. Biol Chem 390:611-8
Chen, Xiaochuan; Gao, Wentao; Gambotto, Andrea et al. (2009) Lentiviral vectors encoding human MUC1-specific, MHC-unrestricted single-chain TCR and a fusion suicide gene: potential for universal and safe cancer immunotherapy. Cancer Immunol Immunother 58:977-87

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