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.
|Saraswathi, Viswanathan; Ganesan, Murali; Perriotte-Olson, Curtis et al. (2016) Nanoformulated copper/zinc superoxide dismutase attenuates vascular cell activation and aortic inflammation in obesity. Biochem Biophys Res Commun 469:495-500|
|Mahajan, Vivek; Gaymalov, Zagit; Alakhova, Daria et al. (2016) Horizontal gene transfer from macrophages to ischemic muscles upon delivery of naked DNA with Pluronic block copolymers. Biomaterials 75:58-70|
|Xie, Ying; Wehrkamp, Cody J; Li, Jing et al. (2016) Delivery of miR-200c Mimic with Poly(amido amine) CXCR4 Antagonists for Combined Inhibition of Cholangiocarcinoma Cell Invasiveness. Mol Pharm 13:1073-80|
|Fan, Wei; Shi, Wen; Zhang, Wenting et al. (2016) Cathepsin S-cleavable, multi-block HPMA copolymers for improved SPECT/CT imaging of pancreatic cancer. Biomaterials 103:101-15|
|Perriotte-Olson, Curtis; Adi, Nikhil; Manickam, Devika S et al. (2016) Nanoformulated copper/zinc superoxide dismutase reduces adipose inflammation in obesity. Obesity (Silver Spring) 24:148-56|
|Jiang, Jiang; Li, Zhuoran; Wang, Hongjun et al. (2016) Expanded 3D Nanofiber Scaffolds: Cell Penetration, Neovascularization, and Host Response. Adv Healthc Mater 5:2993-3003|
|Raja, Srikumar M; Desale, Swapnil S; Mohapatra, Bhopal et al. (2016) Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition. Oncotarget 7:10522-35|
|Mahajan, Vivek; Gaymalov, Zagit; Alakhova, Daria et al. (2016) Data on macrophage mediated muscle transfection upon delivery of naked plasmid DNA with block copolymers. Data Brief 7:1269-82|
|Jiang, Yuhang; Brynskikh, Anna M; S-Manickam, Devika et al. (2015) SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature. J Control Release 213:36-44|
|Wakaskar, Rajesh R; Bathena, Sai Praneeth R; Tallapaka, Shailendra B et al. (2015) Peripherally cross-linking the shell of core-shell polymer micelles decreases premature release of physically loaded combretastatin A4 in whole blood and increases its mean residence time and subsequent potency against primary murine breast tumors after I Pharm Res 32:1028-44|
Showing the most recent 10 out of 59 publications