This indicated that IMCRON8 is functional for inhibiting MSP-mediated signaling pathways and exhibits strong efficacy with respect to blocking the PI3K/Akt pathway. Previous work from our lab and others has demonstrated that Akt activation is linked to members of the inhibitor of apoptosis family such as XIAP and survivin, which are overexpressed and dysregulated in many human cancers. Akt phosphorylation of XIAP led to increased stability and decreased cell apoptosis in ovarian cancer treated with cisplatin. The PI3K/Akt pathway mediated by many growth factors was reported to upregulate survivin expression. Our Carfilzomib experiment found that MSP induced Ron activation increased survivin but not XIAP mRNA expression. The protein level did not significantly change. Pancreatic cancer is a highly aggressive disease with a propensity for early invasion and metastasis. Ron is rarely expressed in normal pancreatic ducts or early pancreatic intraepithelial neoplasia. The expression level of Ron is increased in invasive and metastatic cancer and correlates with tumor progression in pancreatic cancer patient samples. Studies showed that MSP-mediated Ron activation significantly increased cell migration and invasion. The PI3K/Akt pathway is required for epithelial cell migration activated by MSP. Substantial cell migration and invasion was also seen in pancreatic cancer with Ron-overexpression and was associated with EMT. The effect of IMC-RON8 on Ronmediated cell migration was evaluated in our studies by transwell and wound healing assays. IMC-RON8 LY2835219 strongly inhibited MSPdependent cell migration in transwell assays. Wound healing assays showed that a robust healing response to MSP was blocked by IMC-RON8 before MSP stimulation. It is reasonable to postulate that IMC-RON8 treatment in pancreatic cancer may reduce the invasive and metastatic phenotype activated by circulating MSP. The PI3K/Akt and MAPK signaling pathways have been reported to be involved in Ron-mediated anchorage independent growth in colon epithelial cells. Ron KD resulted in reduced cell transformation in colon cancer cells. Although IMCRON8 had no effects on cell proliferation and apoptosis as assessed by MTT, PARP and caspase 9 cleavage in pancreatic cancer cells, anchorage independent growth was significantly impaired with IMC-RON8 treatment. The same reduction could also be seen in Ron KD L3.6pl cell clones, where Ron KD resulted in reduced colony formation compared to Ron SC cells. HDACs play an important role in the epigenetic regulation of gene expression in human cancers, including pancreatic cancer. Recently, development of HDAC inhibitors and their usage in combination therapy has emerged as a promising strategy. The HDACi TSA, Vorinostat, Panobinostat and Belinostat have been a focus for recent cancer studies. TSA treatment of pancreatic cancer cells inhibited cell proliferation amd induced cell apoptosis through cell cycle arrest and altered expression of proapoptotic gene versus anti-apoptotic genes. Vorinostat was reported to induce growth inhibition in pancreatic cancer cell lines through p21 induction.