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.
|Chini, Claudia C S; Espindola-Netto, Jair M; Mondal, Gourish et al. (2016) SIRT1-Activating Compounds (STAC) Negatively Regulate Pancreatic Cancer Cell Growth and Viability Through a SIRT1 Lysosomal-Dependent Pathway. Clin Cancer Res 22:2496-507|
|Murphy, Stephen J; Hart, Steven N; Halling, Geoffrey C et al. (2016) Integrated Genomic Analysis of Pancreatic Ductal Adenocarcinomas Reveals Genomic Rearrangement Events as Significant Drivers of Disease. Cancer Res 76:749-61|
|Chaiteerakij, Roongruedee; Petersen, Gloria M; Bamlet, William R et al. (2016) Metformin Use and Survival of Patients With Pancreatic Cancer: A Cautionary Lesson. J Clin Oncol 34:1898-904|
|Cao, H; Eppinga, R D; Razidlo, G L et al. (2016) Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process. Oncogene 35:1099-110|
|Hu, Chunling; Hart, Steven N; Bamlet, William R et al. (2016) Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. Cancer Epidemiol Biomarkers Prev 25:207-11|
|McWilliams, Robert R; Maisonneuve, Patrick; Bamlet, William R et al. (2016) Risk Factors for Early-Onset and Very-Early-Onset Pancreatic Adenocarcinoma: A Pancreatic Cancer Case-Control Consortium (PanC4) Analysis. Pancreas 45:311-6|
|Carr, Ryan M; Fernandez-Zapico, Martin E (2016) Pancreatic cancer microenvironment, to target or not to target? EMBO Mol Med 8:80-2|
|Wang, Jianbo; Galvao, Joana; Beach, Krista M et al. (2016) Novel Roles and Mechanism for KrÃ¼ppel-like Factor 16 (KLF16) Regulation of Neurite Outgrowth and Ephrin Receptor A5 (EphA5) Expression in Retinal Ganglion Cells. J Biol Chem 291:18084-95|
|Lopez, Angelica P; Kugelman, Jeffrey R; Garcia-Rivera, Jose et al. (2016) The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium-Derived Growth Factor Proteins and Modulates HIV-1 Replication. J Mol Biol 428:2814-31|
|Lakshminarayanan, Vani; Supekar, Nitin T; Wei, Jie et al. (2016) MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice. PLoS One 11:e0145920|
Showing the most recent 10 out of 242 publications