Pancreatic cancer (PaCa) carries a poor survival due to lack of effective drug treatment. This project will address this barrier through the development of new therapeutic strategies for drug treatment of PaCa based upon the targeting of newly identified molecules as targets for maintaining the survival of PaCa cells using emerging novel drugs. We will test these emerging drugs in human pancreatic cancer cells grown in immunosuppressed mice to demonstrate the feasibility that effective combination strategies tailored for the Smad4 wild type (WT) and mutant (MT) subgroups of PaCa, respectively, can be developed. The strategies are based upon description of a cell survival mechanism in which a pro-survival protein complex consisting of survivin and XIAP inhibits the executioner caspase enzymes that would normally kill cancer cells undergoing the stress of the cancer micro-environment. Our laboratory has found that the mutation of Smad4 leads to the overproduction of a cell surface protein called RonK that in turn generates the activation of enzymes that modify the survivin/XIAP complex to enhance its stability and thereby make the inhibition of caspases more efficient. Consequently, one arm of the strategy for the Smad4 MT subgroup (approximately 50% of PaCa) will be the inhibition of the Met family tyrosine kinase receptor RonK by a newly developed monoclonal antibody from Imclone (IMC-Ron8). Treatment will be coupled with YM155, a first-in-its-class inhibitor of survivin, which has been shown to disrupt the stabilization of survivin/XIAP complexes that then permits the function of caspases in generating cell death. The second subgroup is Smad4 WT, which represents the other half of the disease, will be addressed by a strategy that takes advantage of Smad4 function using a drug that cause re-expression of a tumor suppressor gene called TGF? receptor II. The drug, Belinostat, a histone deacetylase inhibitor reverses the epigenetic signaling pathway that stabilizes both survivin and XIAP. The Smad4 WT subgroup will also be treated in combination with YM155 to directly attack the expression of survivin. Both strategies will be tested in immunosuppressed mice using pancreatic cancer xenografts in order to learn how best to administrate these drugs to pancreatic cancer patients.
Pancreatic cancer is known to have the highest fatality rate among the solid tumors. More than 80% of the patients died within 1 year of diagnosis. The major barrier to improving survival rates is the lack of effective drug treatments for this disease. This project will address this barrier through the development of new therapeutic strategies for drug treatment by using emerging novel drugs on newly identified molecules essential in maintaining the survival of pancreatic cancer cells.
|Banerjee, Kasturi; Kumar, Sushil; Ross, Kathleen A et al. (2018) Emerging trends in the immunotherapy of pancreatic cancer. Cancer Lett 417:35-46|
|Wiest, Edwin J; Smith, Heather Jensen; Hollingsworth, Michael A (2018) Met receptor inhibitor SU11274 localizes in the endoplasmic reticulum. Biochem Biophys Res Commun 501:858-862|
|Chugh, Seema; Barkeer, Srikanth; Rachagani, Satyanarayana et al. (2018) Disruption of C1galt1 Gene Promotes Development and Metastasis of Pancreatic Adenocarcinomas in Mice. Gastroenterology 155:1608-1624|
|Jahan, Rahat; Macha, Muzafar A; Rachagani, Satyanarayana et al. (2018) Axed MUC4 (MUC4/X) aggravates pancreatic malignant phenotype by activating integrin-?1/FAK/ERK pathway. Biochim Biophys Acta Mol Basis Dis 1864:2538-2549|
|Qazi, Asif Khurshid; Siddiqui, Jawed A; Jahan, Rahat et al. (2018) Emerging therapeutic potential of graviola and its constituents in cancers. Carcinogenesis 39:522-533|
|Tiriac, Hervé; Belleau, Pascal; Engle, Dannielle D et al. (2018) Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov 8:1112-1129|
|Qi, Bowen; Crawford, Ayrianne J; Wojtynek, Nicholas E et al. (2018) Indocyanine green loaded hyaluronan-derived nanoparticles for fluorescence-enhanced surgical imaging of pancreatic cancer. Nanomedicine 14:769-780|
|Goodwin, Justin; Choi, Hyunsung; Hsieh, Meng-Hsiung et al. (2018) Targeting Hypoxia-Inducible Factor-1?/Pyruvate Dehydrogenase Kinase 1 Axis by Dichloroacetate Suppresses Bleomycin-induced Pulmonary Fibrosis. Am J Respir Cell Mol Biol 58:216-231|
|Coelho, Sílvia Castro; Reis, Daniel Pires; Pereira, Maria Carmo et al. (2018) Gold Nanoparticles for Targeting Varlitinib to Human Pancreatic Cancer Cells. Pharmaceutics 10:|
|Krishn, Shiv Ram; Ganguly, Koelina; Kaur, Sukhwinder et al. (2018) Ramifications of secreted mucin MUC5AC in malignant journey: a holistic view. Carcinogenesis 39:633-651|
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