Hedgehog and EGF interaction: a novel therapeutic approach for pancreatic cancer

胰腺癌是一种致命的疾病，其令人沮丧的结局主要归因于缺乏 有效的治疗。因此，翻译研究人员需要开发针对小说的治疗方法 与胰腺癌病理生物学相关的生化途径从未像现在这样强大。我们的目标是 利用最近的知识，设计既机械又可翻译的研究 在我们实验室里产生的。这一数据首次报告了识别转录的新途径 GLI1因子作为胰腺致癌途径Hedgehog(HH)和表皮的共同效应因子 生长因子(EGF)，在胰腺癌细胞中产生促进生存/抗凋亡的功能。因此，我们的 Proposal利用一种全面的翻译方法来描述这一现象的分子和细胞特征 途径相互作用以及其靶向抑制的临床前测试。我们的中心假设是 HH和EGF通路之间的一种新的功能相互作用通过GLI1- 介导的抗凋亡反应和通过联合治疗靶向该通路将产生积极的影响 关于胰腺癌的治疗。为了解决这一假设，我们提出了以下独立的、但 相互关联，目的：目的1：研究HH-EGF途径的分子机制(S)。我们 将检验PI3K-AKT轴通过特定的调制方式连接HH和EGF级联的假设 Gli1活性。具体地说，我们将确定AKT磷酸化对GLI1介导的转录的影响 在胰腺癌细胞中。目的2：研究HH-EGF途径相互作用在胰腺中的作用 癌细胞存活。我们将解决这样的假设，即HH-EGF-GLI1途径需要活性的PI3K- AKT轴调节胰腺癌生存。我们将研究这一途径相互作用在 GLI1介导的胰腺癌细胞中特异性抗凋亡分子激活的调控。目标3： 为了表征靶向这一新的HH-EGF-GLI1生存途径的翻译含义， 胰腺癌移植瘤的联合治疗，通过分子和分子生物学方法评估治疗反应 成像标记。因此，从这些研究中获得的知识将进一步加深我们对 复杂的网络与胰腺癌的发生有关，也是胰腺癌发生的基础 胰腺癌的新治疗方法。这些研究代表了一种明确的战略，以发现胰腺癌的新治疗策略，胰腺癌是一种痛苦的 和致命疾病，在美国癌症死亡原因中排名第四。受这种癌症影响的患者将在3到10年内死亡 确诊后6个月，目前尚无有效的治疗方法。然而，我们乐观地认为， 我们的研究将为未来治疗这种令人沮丧的疾病奠定基础。

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 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. This data reports, for the first time, a novel pathway that identifies the transcription factor GLI1 as a shared effector for both pancreatic oncogenic pathways, Hedgehog (HH) and Epidermal Growth Factor (EGF), engendering a pro-survival/anti-apoptotic function in pancreatic cancer cells. Thus, our proposal utilizes a comprehensive translational approach for the molecular and cellular characterization of this pathway interaction as well as the preclinical 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 GLI1- 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, yet interrelated, aims: AIM 1: To characterize the molecular mechanism(s) underlying the HH-EGF pathway. We will test the hypothesis that the PI3K-AKT axis links the HH and EGF cascades via specific modulation of GLI1 activity. Specifically, we will determine the effect of AKT phosphorylation on GLI1-mediated transcription in pancreatic cancer cells. AIM 2: To characterize the role of the HH-EGF pathway interaction in pancreatic cancer cell survival. We will address the hypothesis that the HH-EGF-GLI1 pathway requires an active PI3K- AKT axis to modulate pancreatic cancer survival. We will examine the role of this pathway interaction on the modulation of GLI1-mediated activation of specific anti-apoptotic molecules in pancreatic cancer cells. AIM 3: 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. 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. These investigations represent a defined strategy to discover novel therapeutic strategies for pancreatic cancer, a painful and deadly disease that ranks 4th as the cause of death by cancer in USA. Patients affected by this cancer die within 3 to 6 months after the diagnosis, and currently, no effective treatment exists for this disease. However, we are optimistic that our studies will build the foundation for future treatment of this dismal disease.