Targeting DCLK1 kinase activity in pancreatic cancer

描述（由申请人提供）：胰腺导管腺癌（PDAC）是美国癌症死亡的第四大原因。手术治疗是唯一的希望，传统的治疗方法，都未能提高总生存率。上皮间质转化（EMT）在肿瘤的侵袭和转移中起着关键作用。成功的PDAC治疗可能需要攻击多种细胞类型中的多种促肿瘤发生途径的治疗剂-即，治疗 目前还没有开发这些治疗PDAC的下一代药物是R21提案的总体目标。我们已经证明，推定的干细胞蛋白DCLK 1在各种实体瘤中过表达，并且是多能性、致癌PDAC通路和EMT的中心调节因子。DCLK 1的抑制导致肿瘤中内源性肿瘤抑制因子的激活，其进而调节参与癌症生长、多能性维持和EMT的癌基因。靶向过表达DCLK 1的细胞在动物模型中阻断肿瘤生长。该提案的目的是评估使用阻断DCLK 1激酶活性的小分子抑制剂（XMD 8 - 92）作为改善PDAC治疗结果的新治疗方法的可行性。我们将追求三个具体目标：（1）确定XMD 8 -92的有效剂量。(2)确定抑制原发性和转移性肿瘤形成的XMD 8 -92的有效剂量。(3)确定XMD 8 -92调节PDAC细胞中关键致癌下游通路的分子机制。总之，在完成本研究后，我们应该能够使用各种肿瘤模型证明XMD 8 -92针对PDAC的最小有效剂量。开发针对关键靶点（如DCLK 1）的小分子激酶抑制剂可能会导致更有效的治疗和潜在的PDAC治愈，并提高总生存率。

DESCRIPTION (provided by applicant): 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.