Hedgehog EGF Pathway Interaction: Novel Multi-Target Therapy Pancreatic Cancer

胰腺癌是一种致命的疾病，其令人沮丧的结果主要归因于缺乏治疗。 有效治疗。因此，需要翻译研究人员，如我们的实验室，开发 靶向与胰腺癌病理生物学相关的新生化途径的疗法， 从未如此伟大我们的目标是设计既机械又转化的研究， 利用我们实验室最近在职业生涯的支持下产生的知识 马约诊所胰腺孢子开发奖授予PI。该数据报告，对于 第一次，一种新的途径，确定转录因子GLH作为一个共同的效应，为双方 胰腺致癌途径，刺猬（HH）和表皮生长因子（EGF），产生促生存/ 胰腺癌细胞中的抗凋亡功能。因此，与《公约》的主要目标一致， 我们的提案利用了一种全面的翻译方法（从分子到细胞到动物， 对人）的分子和细胞表征的这一途径，以及临床前 以及其靶向抑制作用的临床试验。我们的中心假设是， HH和EGF途径之间的相互作用通过GLI 1介导的抗凋亡调节细胞存活 通过联合治疗对该途径的应答和靶向将对治疗产生积极影响， 胰腺癌为了解决这个假设，我们提出了以下独立的，相互关联的。 目的：目的1：研究胰腺癌的分子和细胞机制 通过一种新的HH-EGF-GLI 1途径的细胞存活;目的2：表征 靶向这一新的HH-EGF-GLI 1生存通路，联合治疗胰腺癌 异种移植物，通过使用分子和成像标志物评估治疗反应（临床前试验）;和 目的3：在人类中表征HH-EGF-GLI 1存活途径的翻译意义， 使用HH抑制剂GDC-0449与EGFR联合的多靶点方法的联合治疗 抑制剂，厄洛替尼（I期试验）。因此，从这些研究中获得的知识将进一步促进我们的 了解胰腺癌发生中涉及的复杂网络，以及作为一个 为胰腺癌新治疗方法的发展奠定了基础。

Pancreatic cancer is a deadly disease in which the dismal outcome is primarily attributed to the lack of an effective treatment. Therefore, the need of translational researchers, such as our laboratory, to develop therapies targeting novel biochemical pathways relevant to the pathobiology of pancreatic cancer has never been greater. Our GOAL is to design studies that are both mechanistic and translational, taking advantage of the knowledge recently generated in our laboratory with the support of the Career Development Award from the Mayo Clinic Pancreatic SPORE awarded to the PI. This data reports, for the first time, a novel pathway that identifies the transcription factor GLH as a shared effector for both pancreatic oncogenic pathways, Hedgehog (HH) and Epidermal Growth Factor (EGF), engendering a prosurvival/ anti-apoptotic function in pancreatic cancer cells. Thus, congruent with the major objective of the SPORE grant, our proposal utilizes a comprehensive translational approach (from molecules-to-cells-toanimals- to-human) for the molecular and cellular characterization of this pathway as well as the preclinical and clinical testing of its targeted inhibition. Our CENTRAL HYPOTHESIS is that a novel functional interaction between the HH and EGF pathways regulates cell survival via a GLI 1-mediated anti-apoptotic response and targeting of this pathway by a combination therapy will positively impact on the treatment of pancreatic cancer. To address this hypothesis we propose the following independent, vet interrelated. aims: AIM 1: To characterize both, the molecular and cellular mechanism(s) underlying pancreatic cancer cell survival via a novel HH-EGF-GLI1 pathway; AIM 2: To characterize the translational implications of targeting this novel HH-EGF-GLI1 survival pathway, with a combination therapy in pancreatic cancer xenografts, by assessing treatment response using molecular and imaging markers (Preclinical Trial); and AIM 3: To characterize, in humans, the translational implications of HH-EGF-GLI1 survival pathway through combination therapy using a multi-target approach with the HH inhibitor, GDC-0449, combined with EGFR inhibitor, Erlotinib (Phase I Trial). Thus, the knowledge derived from these studies will further our understanding of the complex network implicated in pancreatic carcinogenesis, as well as serve as a foundation for the development of new therapeutic approaches for pancreatic cancer.