MYC is a critical downstream effector in KRAS-driven pancreatic cancer

 描述(申请人提供)：胰腺癌是美国癌症相关死亡的第四大原因。胰腺癌患者的5年生存率只有6%，这表明迫切需要更好地了解胰腺癌的发展和确定新的治疗靶点。MYC是一种蛋白质，在多种组织中强烈促进癌症的进展，并调节在癌症发展过程中被破坏的几种细胞功能。重要的是，在小鼠肿瘤模型中，MYC功能的丧失可以导致癌细胞死亡和肿瘤形成的减少。对MYC功能的研究已经确定了MYC的一种修饰形式，它具有更高的稳定性和活性。这种形式在几种类型的癌细胞中含量很高，并导致细胞生长失控。重要的是，MYC在几个已知在胰腺癌中被解除调控的因子的下游被激活。具体地说，KRAS通路在所有胰腺导管肿瘤中占95%，已被证明在其他类型的细胞中有助于MYC的激活。然而，MYC在胰腺癌中的作用还知之甚少。这项建议的总体目标是确定KRAS介导的MYC激活是否显著促进胰腺肿瘤的进展。为了实现这一目标，拟议的AIMS将利用一种新的胰腺癌、患者组织和胰腺癌细胞的小鼠模型来研究MYC如何改变胰腺癌的发生和发展。具体地说，目标1将确定在一种新的小鼠模型中结合异常的KRAS和MYC活性是否概括了人类胰腺疾病的特征。目的2，将确定在人类和小鼠肿瘤中MYC向更稳定、更活跃的形式过渡的阶段。最后，Aim 3将确定MYC的激活是否显著促进了正常胰腺细胞向KRAS信号下游的癌细胞的转化。胰腺癌仍然对癌症治疗具有很高的抵抗力。KRAS通路的改变发生在大多数胰腺癌患者中，然而，针对该蛋白开发成功的临床药物一直不成功。这项拟议的研究将增加我们对KRAS下游驱动胰腺癌的途径的理解，并有可能确定控制MYC激活修饰的蛋白质作为胰腺癌的治疗靶点。

 DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States. The 5-year survival rate for pancreatic cancer patients is only 6%, indicating a critical need for an improved understanding of pancreatic cancer development and identification of new therapeutic targets. MYC is a protein that strongly contributes to cancer progression in a wide variety of tissues and regulates several cellular functions that are corrupted during cancer development. Importantly, loss of MYC function can lead to cancer cell death and decreased tumor formation in mouse tumor models. Studies of MYC function have identified a modified form of MYC that has increased stability and activity. This form is found at high levels in several cancer cell types and leads to uncontrolled cell growth. Importantly, MYC is activated downstream of several factors known to be deregulated in pancreatic cancer. Specifically, the KRAS pathway, which is constitutively on in ~95% of all pancreatic ductal tumors, has been shown to contribute to MYC activation in other cell types. The role of MYC in pancreatic cancer, however, is poorly understood. The overall goal of this proposal is to determine if KRAS-mediated activation of MYC significantly contributes to pancreatic tumor progression. To achieve this goal, the proposed aims will utilize a novel mouse model of pancreatic cancer, patient tissue, and pancreatic cancer cells to investigate how MYC alters the initiation and progression of pancreatic cancer. Specifically, Aim 1 will determine if combining aberrant KRAS and MYC activity in a novel mouse model recapitulates the hallmarks of human pancreatic disease. Aim 2, will identify the stage at which MYC transitions to the more stable, active form in both human and mouse tumors. Finally, Aim 3 will determine if activation of MYC significantly contributes to the transformation of normal pancreatic cells to cancer cells downstream of KRAS signals. Pancreatic cancer remains highly resistant to cancer therapies. Alterations in the KRAS pathway occur in the majority of pancreatic cancer patients, however developing successful clinical drugs that target this protein has been unsuccessful. The proposed research will increase our understanding of the pathways that drive pancreatic cancer downstream of KRAS and potentially identify the proteins that control the activating modification of MYC as therapeutic targets in pancreatic cancer.