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.
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.
|Soni, Kruti S; Lei, Fan; Desale, Swapnil S et al. (2017) Tuning polypeptide-based micellar carrier for efficient combination therapy of ErbB2-positive breast cancer. J Control Release 264:276-287|
|Karuturi, Bala V K; Tallapaka, Shailendra B; Yeapuri, Pravin et al. (2017) Encapsulation of an EP67-Conjugated CTL Peptide Vaccine in Nanoscale Biodegradable Particles Increases the Efficacy of Respiratory Immunization and Affects the Magnitude and Memory Subsets of Vaccine-Generated Mucosal and Systemic CD8+ T Cells in a Diamet Mol Pharm 14:1469-1481|
|Fan, Wei; Zhang, Wenting; Jia, Yinnong et al. (2017) Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers. Mol Pharm 14:1405-1417|
|Chen, Shixuan; Ge, Liangpeng; Mueller, Aubrey et al. (2017) Twisting electrospun nanofiber fine strips into functional sutures for sustained co-delivery of gentamicin and silver. Nanomedicine 13:1435-1445|
|Chen, Shixuan; Ge, Liangpeng; Gombart, Adrian F et al. (2017) Nanofiber-based sutures induce endogenous antimicrobial peptide. Nanomedicine (Lond) 12:2597-2609|
|Jiang, Jiang; Chen, Shixuan; Wang, Hongjun et al. (2017) CO2-expanded nanofiber scaffolds maintain activity of encapsulated bioactive materials and promote cellular infiltration and positive host response. Acta Biomater :|
|Shrishrimal, Shashank; Kosmacek, Elizabeth A; Chatterjee, Arpita et al. (2017) The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues. Antioxidants (Basel) 6:|
|Souchek, Joshua J; Davis, Amanda L; Hill, Tanner K et al. (2017) Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells. Mol Cancer Ther 16:1819-1830|
|Smolsky, Joseph; Kaur, Sukhwinder; Hayashi, Chihiro et al. (2017) Surface-Enhanced Raman Scattering-Based Immunoassay Technologies for Detection of Disease Biomarkers. Biosensors (Basel) 7:|
|Lakshmanan, Imayavaramban; Salfity, Shereen; Seshacharyulu, Parthasarathy et al. (2017) MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53. Clin Cancer Res 23:3906-3917|
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