Simultaneous attack of epithelial and stromal compartments in pancreatic cancer

描述(申请人提供)：胰腺导管腺癌(PDA)是最致命的癌症形式之一，因为它具有侵袭性生长，而且通常在已经发生转移的阶段做出诊断。我们治疗PDA的能力受限于对支配细胞增殖的生物学机制的不完全了解，或者这些机制中的错乱允许原始器官内和转移部位的病理性增殖。在我们最近对小鼠的研究中，我们发现了上皮和间质之间的信号反馈电路，这似乎是控制内胚层器官增殖活动的中央控制机制。这个增殖控制回路涉及上皮和间质之间的相互信号，上皮中产生Hedgehog(HH)信号，间质中产生Wnt和其他信号。我们建议从遗传学和药理学上测试这种上皮/间质回路在动脉导管未闭中的作用，特别是测试药物治疗的效果，这些药物旨在同时扰乱上皮和间质间隔中的这一增殖控制回路。该方法可能为PDA的治疗提供一种新的模式。已知HH信号通路在PDA的病理生理学中起关键作用，肿瘤细胞表达Sonic hedgehog(Shh)信号蛋白，该信号激活胰腺间质中的HH通路反应，通过诱导间质细胞增殖来促进PDA典型的促结缔组织增生性反应。间质中对HH的反应也增加了其他几种信号的产生，包括Wnts，这些信号似乎通过激活WnT反应和刺激肿瘤细胞的增殖而在一个相互的旁分泌环路中起作用。在我们工作中选择的内源性PDA小鼠模型中，人PDA的促结缔组织增生反应和其他特征得到了忠实的概括，在该模型中，肿瘤的发生是由致癌K-ras的上皮表达驱动的。我们将测试HH途径拮抗剂与靶向上皮成分的药物，包括Wnt或致癌K-ras信号转导抑制剂。这一分析将通过使用新开发的能够以毫米分辨率在体内检测和测量胰腺肿瘤的超声波技术来简化，从而减少在药物治疗测试中测量存活率的冗长研究的需要。我们的目标是通过以下方式迅速改进PDA的治疗：(I)确定使用靶向药物组合同时攻击PDA的上皮和间质成分的策略的有效性；以及(Ii)为设计和实施FDA批准的药物或处于临床测试后期阶段的药物的早期临床试验提供具体基础。此外，这项工作也可作为治疗其他内胚层器官恶性疾病的范例。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of cancer because of its aggressive growth and because diagnosis typically is made at a stage by which metastasis has already occurred. We are limited in our ability to treat PDA by an incomplete understanding of the biological mechanisms that govern cell proliferation, or the derangements in these mechanisms that permit pathological proliferation within the primary organ and at metastatic sites. In our recent studies in the mouse we have discovered a signal feedback circuit between epithelium and stroma that appears to be a central control mechanism governing proliferative activity in endodermal organs. This proliferative control circuit involves reciprocal signaling between epithelium and stroma, with the Hedgehog (Hh) signal produced in the epithelium and Wnt and other signals in the stroma. We propose to test the role of this epithelial/stromal circuit genetically and pharmacologically in PDA and, in particular, the effects of drug treatments designed to simultaneously disrupt this proliferation control circuit in both the epithelial and stromal compartments. This approach may serve as a new model for therapy of PDA. The Hh signaling pathway is known to play a key role in the pathophysiology of PDA, as cells of the tumor express the Sonic hedgehog (Shh) signaling protein; this signal activates Hh pathway response in pancreatic stroma, contributing to the desmoplastic reaction typical of PDA by inducing proliferation of stromal cells. Response to Hh in the stroma also increases the production of several other signals, including Wnts, which appear to act in a reciprocal paracrine loop by activating Wnt response and stimulating proliferation of tumor cells. The desmoplastic reaction and other features of human PDA are faithfully recapitulated in the mouse model of endogenous PDA selected for our work, in which tumorigenesis is driven by epithelial expression of oncogenic K-ras. We will test Hh pathway antagonists in combination with agents that target the epithelial component, including Wnt or oncogenic K-ras signal transduction inhibitors. This analysis will be streamlined by the use of newly developed ultrasound techniques capable of detecting and measuring pancreatic tumors in vivo at millimeter resolution, thereby reducing the requirement for lengthy studies that measure survival in the testing of drug treatments. We aim to rapidly improve therapy for PDA by: (i) establishing the validity of a strategy that employs combinations of targeted agents to simultaneously attack epithelial and stromal components of PDA; and (ii) providing a concrete basis for design and implementation of early clinical trials with drugs that are FDA- approved or in advanced stages of clinical testing. In addition, this work may serve as a paradigm for treatment of malignant disease arising in other endodermal organs.