Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of U.S. cancer deaths. Surgical therapy is the only hope as traditional therapy, have failed to improve overall survival. Epithelial-to-mesenchymal transition (EMT) plays a key role in cancer invasion and metastasis. Successful PDAC treatment likely requires therapeutics that attacks multiple pro-tumorigenic pathways in multiple cell types-i.e., treatments that are not yet available. Development of these next-generation agents to treat PDAC is the overall goal of this R21 proposal. We have demonstrated that the putative stem cell protein DCLK1 is overexpressed in various solid tumors and is a central regulator of pluripotency, oncogenic PDAC pathways, and EMT. Inhibition of DCLK1 leads to activation of endogenous tumor-suppressors in the tumor, which in turn regulate oncogenes involved in cancer growth, pluripotency maintenance, and EMT. Targeting cells that overexpress DCLK1 blocks tumor growth in animal models. The goal for this proposal is to assess the feasibility of using small molecule inhibitor (XMD8- 92) that block DCLK1 kinase activity as a new therapeutic approach to improve PDAC treatment outcomes. We will pursue three Specific Aims: (1) Determine an effective dose of XMD8-92. (2) Determine an effective dose of XMD8-92 that will suppress primary and metastatic tumor formation. (3) Determine the molecular mechanism by which XMD8-92 regulates key oncogenic downstream pathways in PDAC cells. Overall, upon completion of this study, we should be able to demonstrate a minimal effective dose of XMD8-92 against PDAC using various tumor models. Development of an small molecule kinase inhibitor directed at critical targets such as DCLK1 could lead more effective treatment and potential cure of PDAC and improve overall survival.
Pancreatic cancer is one of the most deadly cancers, and it defeats our best efforts to cure it about 95% of the time. In this R21 grant application, we proposes to pursue an innovative treatment (based on highly promising preliminary work) that has the potential to produce a new class of drug for pancreatic cancer eradication that will address the drawbacks of current therapies. Ultimately the development of novel therapeutic will establish an advanced class of chemotherapy agents that will substantially improve the treatment of pancreatic cancer and possibly other deadly cancers to greatly improve health for millions.
| Weygant, Nathaniel; Ge, Yang; Qu, Dongfeng et al. (2016) Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem-like Cells Marked by DCLK1 Kinase. Cancer Res 76:4090-9 |
| Sureban, Sripathi M; Qu, Dongfeng; Houchen, Courtney W (2015) Regulation of miRNAs by agents targeting the tumor stem cell markers DCLK1, MSI1, LGR5, and BMI1. Curr Pharmacol Rep 1:217-222 |
| Sureban, Sripathi M; May, Randal; Weygant, Nathaniel et al. (2014) XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism. Cancer Lett 351:151-61 |
