Our goal is to target novel immune-modulating agents directly to the pancreatic tumor site using a tumorspecific MUC1 antibody as a carrier. This will be administered in combination with the MUC1/KRAS peptide vaccine and low-dose gemcitabine. MUC1 and Kras are over expressed in 90% of pancreatic ductal adenocarcinomas (PDA) and have long been targets for therapeutic interventions. Thus far, cancer vaccines have not been clinically as successful as one had hoped for. Vaccines have failed to generate long-term immune memory against the tumor antigens because tumors have adopted ways to escape immune recognition and killing. Several new agents that can reverse immune evasion have been tested with modest clinical responses probably because the agents were administered systemically and may have never reached the tumor site. We hypothesize that by directly delivering the immune modulating agents to the pancreatic tumor site and combining this with a multi-peptide MUC1/Kras vaccine, we can generate a robust anti-tumor response with a strong memory response. The treatment will affect both localized and disseminated tumors, and strong memory responses will prevent recurrence. We will test the hypothesis in an appropriate mouse model of spontaneous PDA that clearly resembles the human disease.
Our specific aims are: 1) To optimize a MUC1/Kras-based vaccine in the PDA X MUCLTg mice by immobilizing four immune modulating agents directly to the tumor site by chemically conjugating the agents to a tumor-specific MUC1 monoclonal antibody. This antibody will home not only to the primary pancreas tumor but also to the metastatic tumor sites that over express MUC1;2) To assess immune status and naturally occurring MUC1 - specific cellular and humoral immune responses in pancreatic cancer patients.
This aim will provide a solid database as to the roles of tumor-associated tolerizing factors and anti-MUCI responses in tumor progression, metastasis, survival, and prognosis and 3) A Phase I trial for the treatment of pancreas cancer. This trial utilizes a MUC1-pep1ide based vaccine, celecoxib, gemcitabine, and external beam radiation in patients with locally advanced pancreatic cancer. We will monitor the immune tolerance mechanisms, and the immune responses before, during, and after treatment. Future: This study could lead to development of a new combination modality for the treatment of localized and disseminated pancreas tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
3P50CA102701-10W1
Application #
8719563
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
2013-09-12
Project End
2014-08-31
Budget Start
2013-09-12
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$128,024
Indirect Cost
$43,024
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Liou, Geou-Yarh; Döppler, Heike; Necela, Brian et al. (2015) Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov 5:52-63
Zhen, David B; Rabe, Kari G; Gallinger, Steven et al. (2015) BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med 17:569-77
Delgiorno, Kathleen E; Hall, Jason C; Takeuchi, Kenneth K et al. (2014) Identification and manipulation of biliary metaplasia in pancreatic tumors. Gastroenterology 146:233-44.e5
Li, Liang; Fridley, Brooke L; Kalari, Krishna et al. (2014) Discovery of genetic biomarkers contributing to variation in drug response of cytidine analogues using human lymphoblastoid cell lines. BMC Genomics 15:93
Halfdanarson, Thorvardur R; Bamlet, William R; McWilliams, Robert R et al. (2014) Risk factors for pancreatic neuroendocrine tumors: a clinic-based case-control study. Pancreas 43:1219-22
Mills, Lisa D; Zhang, Lizhi; Marler, Ronald et al. (2014) Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression. J Biol Chem 289:16516-25
Chini, Claudia C S; Guerrico, Anatilde M Gonzalez; Nin, Veronica et al. (2014) Targeting of NAD metabolism in pancreatic cancer cells: potential novel therapy for pancreatic tumors. Clin Cancer Res 20:120-30
Wu, Lang; Goldstein, Alisa M; Yu, Kai et al. (2014) Variants associated with susceptibility to pancreatic cancer and melanoma do not reciprocally affect risk. Cancer Epidemiol Biomarkers Prev 23:1121-4
Calvo, Ezequiel; Grzenda, Adrienne; Lomberk, Gwen et al. (2014) Single and combinatorial chromatin coupling events underlies the function of transcript factor Krüppel-like factor 11 in the regulation of gene networks. BMC Mol Biol 15:10
Urrutia, Raul; Velez, Gabriel; Lin, Marisa et al. (2014) Evidence supporting the existence of a NUPR1-like family of helix-loop-helix chromatin proteins related to, yet distinct from, AT hook-containing HMG proteins. J Mol Model 20:2357

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