Pancreatic cancer (PC) is a highly metastatic and therapy-resistant malignancy with patients presenting with local and distant metastases at the time of diagnosis. Immunotherapy has emerged as a viable alternative to conventional therapies. Immunotherapy tends to boost, direct, or restore the patient's immune system to fight cancer by proper recognition of specific antigens displayed by tumor cells on their surface, leading to an enhanced immune response. A major challenge in cancer immunotherapy is the development of vaccine formulations that can elicit a cell-mediated immune response in the face of immunological tolerance to the tumor antigen. The quest for new targets suitable for immunotherapy is an active area of research.'We have demonstrated that MUC4 mucin is overexpressed in PC. Preliminary studies from our group and others have also demonstrated the presence of circulating anfi-MUC4 antibodies in cancer patients where MUC4 is overexpressed (pancreatic and lung cancer). The presence of humoral immune response against MUC4 is evidence supporting the fact that MUC4 is immunogenic in cancer patients and together with the overexpression of this mucin in PC, supports the case of MUC4 as a promising vaccine candidate. The scientific rationale of this grant proposal is to evaluate the potential of MUC4 mucin for the immunotherapy of pancreatic cancer. The overall hypothesis of the proposal is that the encapsulation of MUC4 into amphiphilic polyanhydride nanospheres will provide superior adjuvanticity against PC. To test the hypothesis three specific aims are proposed.
Aim 1 : Formulation, optimization and ex vivo characterization of MUC4 nanovaccine.
Aim 2 : In vivo evaluation of MUC4 nanovaccine in syngeneic murine model of pancreatic cancer.
Aim 3 : Evaluation of MUC4 vaccine in MUC4 transgenic mouse model. Our proposed preclinical studies will establish whether MUC4 is a viable target to be pursued for vaccine development. Further, MUC4 nanovaccine will be evaluated in MUC4 transgenic mice which closely resemble the human situation i.e MUC4 is recognized as a self-antigen. If the results are encouraging, such formulations should be ready to be tested in human subjects within the next 3-4 years.

Public Health Relevance

High lethality, poor response to available therapeutic options and high relapse rates of pancreatic cancer mandate the development of effective therapeutic and preventive approaches. The proposed application is aimed at development and preclinical evaluation of an a novel cancer vaccine targeting one of the most differentially expressed mucins (MUC4) formulated in a non-toxic amphiphiliac polyanhydride nanospheres.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-TWD-Y (C2))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
United States
Zip Code
Macha, M A; Rachagani, S; Pai, P et al. (2015) MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene 34:1698-708
Macha, Muzafar A; Seshacharyulu, Parthasarathy; Krishn, Shiv Ram et al. (2014) MicroRNAs (miRNAs) as biomarker(s) for prognosis and diagnosis of gastrointestinal (GI) cancers. Curr Pharm Des 20:5287-97
Gutti, Tanuja L; Knibbe, Jaclyn S; Makarov, Edward et al. (2014) Human hepatocytes and hematolymphoid dual reconstitution in treosulfan-conditioned uPA-NOG mice. Am J Pathol 184:101-9
Yi, Xiang; Manickam, Devika S; Brynskikh, Anna et al. (2014) Agile delivery of protein therapeutics to CNS. J Control Release 190:637-63
Alakhova, Daria Y; Kabanov, Alexander V (2014) Pluronics and MDR reversal: an update. Mol Pharm 11:2566-78
Savalia, Krupa; Manickam, Devika S; Rosenbaugh, Erin G et al. (2014) Neuronal uptake of nanoformulated superoxide dismutase and attenuation of angiotensin II-dependent hypertension after central administration. Free Radic Biol Med 73:299-307
Shi, Wen; Ogbomo, Sunny M; Wagh, Nilesh K et al. (2014) The influence of linker length on the properties of cathepsin S cleavable (177)Lu-labeled HPMA copolymers for pancreatic cancer imaging. Biomaterials 35:5760-70
Gupta, Suprit; Batra, Surinder; Jain, Maneesh (2014) Antibody labeling with radioiodine and radiometals. Methods Mol Biol 1141:147-57
Nukolova, Natalia V; Oberoi, Hardeep S; Zhao, Yi et al. (2013) LHRH-targeted nanogels as a delivery system for cisplatin to ovarian cancer. Mol Pharm 10:3913-21
Zhou, Zhengyuan; Wagh, Nilesh K; Ogbomo, Sunny M et al. (2013) Synthesis and in vitro and in vivo evaluation of hypoxia-enhanced 111In-bombesin conjugates for prostate cancer imaging. J Nucl Med 54:1605-12

Showing the most recent 10 out of 16 publications