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

Hedgehog EGF 通路相互作用：新型多靶点治疗胰腺癌

• 批准号: 8719562
• 负责人: Martin Ernesto Fernandez-Zapico
• 金额: $ 21.29万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719562
• 关键词: Address; Apoptotic; Attention; Award; Basic Science; Binding; Biochemical Pathway; Carcinogenesis Mechanism; Cell Survival; Cells; Clinic; Clinical Trials; Combined Modality Therapy; Complex; Cytotoxic agent; Data; Data Reporting; Development; Disease; Dose-Limiting; Epidermal Growth Factor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erinaceidae; Erlotinib; Excision; Foundations; GLI gene; Grant; Human; Image; Investigation; K-Series Research Career Programs; Knowledge; Laboratories; Link; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Mediating; Modality; Molecular; Monitor; Neoplasms; Oncogenic; Operative Surgical Procedures; Outcome; Pancreas; Pathway interactions; Patients; Phase I Clinical Trials; Phenotype; Preclinical Testing; Proto-Oncogene Proteins c-akt; Research Design; Research Personnel; Resistance; Resources; Survival Rate; Therapeutic Intervention; Time; Toxic effect; Translating; Work; Xenograft Model; Xenograft procedure; base; carcinogenesis; chemotherapeutic agent; chemotherapy; design; effective therapy; gemcitabine; improved; inhibitor/antagonist; insight; molecular imaging; molecular marker; novel; novel therapeutic intervention; pancreatic cancer cells; preclinical study; programs; receptor; research clinical testing; resistance mechanism; response; therapeutic target; therapy development; transcription factor; translational approach; treatment response; tumor

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.

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手段。 有效的治疗。因此，需要像我们实验室这样的转化研究人员来开发 针对与胰腺癌病理学相关的新生化途径的疗法 从未如此伟大。我们的目标是设计机械性和转化性的研究， 在职业生涯的支持下，利用我们实验室最近产生的知识 梅奥诊所胰腺 SPORE 授予 PI 开发奖。这份数据报告显示，对于 首次发现了一种新途径，将转录因子 GLH 识别为两者的共享效应子 胰腺致癌途径、Hedgehog (HH) 和表皮生长因子 (EGF)，产生促存活/ 胰腺癌细胞的抗凋亡功能。因此，与本次会议的主要目标相一致 SPORE 资助，我们的提案采用了全面的转化方法（从分子到细胞到动物） 对人类）用于该途径的分子和细胞表征以及临床前 及其靶向抑制的临床测试。我们的中心假设是一种新颖的功能 HH 和 EGF 通路之间的相互作用通过 GLI 1 介导的抗凋亡调节细胞存活 通过联合疗法对该途径的反应和靶向将对以下疾病的治疗产生积极影响： 胰腺癌。为了解决这个假设，我们提出以下独立的、相互关联的假设。 目标：AIM 1：表征胰腺癌的分子和细胞机制 通过新的 HH-EGF-GLI1 途径实现细胞存活；目标 2：描述转化意义 针对这种新的 HH-EGF-GLI1 生存途径，联合治疗胰腺癌 异种移植，通过使用分子和成像标记评估治疗反应（临床前试验）；和 目标 3：在人类中表征 HH-EGF-GLI1 生存途径的翻译意义 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研究 了解与胰腺癌发生有关的复杂网络，并作为 为开发胰腺癌新治疗方法奠定了基础。