Developmental Signaling Pathways in Pancreatic Cancer

胰腺癌的发育信号通路

• 批准号: 7993590
• 负责人: ANIRBAN MAITRA
• 金额: $ 30.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993590
• 关键词: Address; Adult; Aftercare; Aldehydes; Bioavailable; Biological Markers; Biopsy Specimen; Cancer Etiology; Caring; Cause of Death; Cell Survival; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Cytomegalovirus; Development; Disease; Disease Progression; Elastases; Enzymes; Epithelial; Epithelial-Stromal Communication; Erinaceidae; Excision; Exocrine pancreas; Funding; Future; Genetic; Genetically Engineered Mouse; Human; Laboratories; Ligands; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metastatic to; Minor; Modality; Mus; Neoplasm Metastasis; Notch Signaling Pathway; Oncogenes; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase II Clinical Trials; Population; Pre-Clinical Model; Primary Neoplasm; Recurrence; Relative (related person); Research; Role; Series; Signal Pathway; Signal Transduction; Solid Neoplasm; Testing; Therapeutic; Transgenic Mice; Treatment Efficacy; Treatment Failure; Tumor Volume; United States; Xenograft Model; Xenograft procedure; aldehyde dehydrogenases; base; cancer stem cell; cellular targeting; clinical application; drug development; gamma secretase; gemcitabine; gemzar; improved; in vivo; inhibitor/antagonist; mortality; mouse model; mutant; notch protein; novel; oncology; outcome forecast; pancreatic neoplasm; pre-clinical; preclinical study; public health relevance; research clinical testing; response; self-renewal; small molecule; smoothened signaling pathway; therapeutic target; therapy development; translational study; tumor; tumor initiation; tumorigenic

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related mortality, with a five year survival less than 5%. The overwhelming majority of patients succumb to metastatic disease or tumor recurrence following apparently curative resection. Current treatment efforts in PDAC are focused almost entirely on reduction in "bulk" tumor size, rather than elimination of cells with tumor initiating and metastatic abilities. Research performed in our laboratory over the last funding cycle has identified a putative cancer stem cell (CSC) compartment in PDAC, delineated by high levels of expression of the enzyme aldehyde dehydrogenase. This minor subpopulation of ALDH "bright" cells is capable of self-renewal and tumor initiation, and is observed in elevated numbers in PDAC metastases. The ALDH "bright" cells are exquisitely dependent upon sustained Hedgehog (Hh) and Notch signals for their viability. Preferential elimination of the ALDH "bright" cells with small molecule Hh antagonists blocks systemic metastases and increases survival in PDAC preclinical models; conversely, gemcitabine enhances the relative proportion of ALDH "bright" cells, underscoring the pitfall of conventional anti-metabolite therapy. The current proposal will build upon these themes, by developing therapies that target the cellular compartment responsible for disease progression. In Aim 1, we propose the first Phase II clinical trial of an orally bioavailable Hh antagonist in combination with gemcitabine in patients with advanced PDAC, with the primary objective of improving overall survival. In Aim 2, we will study the emerging contribution Hh-dependent stromal responses to PDAC disease initiation and progression, including stromal interactions with the epithelial CSC compartment, using a newly developed conditional mouse model of Hh ligand misexpression. In Aim 3, we will initiate a comprehensive preclinical trial with an orally bioavailable inhibitor of Notch signaling in spontaneously metastatic orthotopic xenograft model of PDAC, as a prelude to future clinical application. We anticipate that developing parallel and complementary therapeutic approaches against two critical developmental signaling pathways that sustain CSC viability in PDAC provides an unprecedented opportunity for ameliorating the dismal prognosis of this malignancy. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth most common cause of death in the United States. The long-term objective of this proposal is to improve the dismal prognosis of pancreatic cancer by developing therapies that target metastatic disease and tumor recurrence, the two most important clinical parameters that determine survival. In order to address this objective, this proposal will conduct the first clinical trial of Hedgehog (Hh) antagonists in patients with advanced pancreatic cancer, explore the role of Hh-dependent epithelial stromal interactions in a new mouse model, and begin preclinical trials with a novel pharmacological inhibitor of the Notch pathway in preclinical models of pancreatic cancer.

描述（由申请人提供）：胰腺导管腺癌 (PDAC) 是癌症相关死亡的第四大常见原因，五年生存率低于 5%。绝大多数患者在明显治愈性切除后死于转移性疾病或肿瘤复发。目前 PDAC 的治疗工作几乎完全集中在减少“大块”肿瘤大小，而不是消除具有肿瘤起始和转移能力的细胞。我们实验室在上一个资助周期中进行的研究已经确定了 PDAC 中的一个假定的癌症干细胞 (CSC) 区室，该区室由醛脱氢酶的高水平表达所界定。这种 ALDH“明亮”细胞的小亚群能够自我更新和肿瘤起始，并且在 PDAC 转移中观察到数量增加。 ALDH“明亮”细胞的生存能力高度依赖于持续的 Hedgehog (Hh) 和 Notch 信号。在 PDAC 临床前模型中，用小分子 Hh 拮抗剂优先消除 ALDH“明亮”细胞可阻断全身转移并增加存活率；相反，吉西他滨提高了 ALDH“亮”细胞的相对比例，凸显了传统抗代谢药物治疗的缺陷。目前的提案将以这些主题为基础，开发针对负责疾病进展的细胞区室的疗法。在目标 1 中，我们建议在晚期 PDAC 患者中进行第一个口服生物可利用的 Hh 拮抗剂与吉西他滨联合的 II 期临床试验，主要目标是提高总体生存率。在目标 2 中，我们将使用新开发的 Hh 配体错误表达条件小鼠模型，研究 Hh 依赖性基质反应对 PDAC 疾病发生和进展的新兴贡献，包括基质与上皮 CSC 区室的相互作用。在目标 3 中，我们将在 PDAC 自发转移原位异种移植模型中启动一项全面的临床前试验，使用口服生物可利用的 Notch 信号抑制剂，作为未来临床应用的前奏。我们预计，针对维持 PDAC 中 CSC 活力的两条关键发育信号通路开发并行和互补的治疗方法，将为改善这种恶性肿瘤的不良预后提供前所未有的机会。 公共卫生相关性：胰腺癌是美国第四大常见死因。该提案的长期目标是通过开发针对转移性疾病和肿瘤复发（决定生存的两个最重要的临床参数）的疗法来改善胰腺癌的不良预后。为了实现这一目标，该提案将在晚期胰腺癌患者中进行首次 Hedgehog (Hh) 拮抗剂临床试验，探索 Hh 依赖性上皮基质相互作用在新小鼠模型中的作用，并开始临床前试验胰腺癌临床前模型中Notch通路的新型药理学抑制剂。