Ex vivo slice cultures of mouse pancreatic tumors to test novel regimens

小鼠胰腺肿瘤的离体切片培养物测试新疗法

• 批准号: 10361971
• 负责人: Hidayatullah G. Munshi
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361971
• 关键词: Architecture; Awareness; Cell Line; Chemotherapy-Oncologic Procedure; Clinical; Colon Carcinoma; Combined Modality Therapy; Development; Elements; Epigenetic Process; Excision; Fibrosis; Genetic Engineering; Goals; Health; Histone Deacetylase Inhibitor; Human; Human Characteristics; Immunocompetent; Immunotherapy; In Vitro; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mission; Modeling; Monitor; Morphology; Mus; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Pharmaceutical Preparations; Reaction; Regimen; Reporting; Research; Resected; Slice; TP53 gene; Testing; Therapeutic Studies; Therapeutic Use Study; Tissues; Transgenic Mice; Transgenic Model; Transgenic Organisms; Treatment Protocols; United States Department of Veterans Affairs; Veterans; base; cancer therapy; chemotherapy; effectiveness evaluation; efficacy evaluation; expectation; human disease; implantation; improved; in vivo; inhibitor; innovation; interest; mouse model; mutant; novel; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pre-clinical; preservation; rapid testing; research study; response; screening; standard care; tumor; tumor microenvironment; tumorigenesis

While chemotherapy remains the standard treatment, there is an increasing interest in developing novel regimens for pancreatic ductal adenocarcinoma (PDAC). Novel regimens, such as the combination of BET and HDAC inhibitors targeting epigenetic changes, are often tested initially in mouse models. However, mouse models have several limitations. With an ever-increasing number of drugs being developed for cancer, how best to evaluate these drugs in mouse models, either alone or in combination regimens, can also be quite daunting. Recently, ex vivo tissue slices of human tumors have been utilized for therapeutic studies, but one of the significant challenges of slice cultures with human PDAC tumors is the limited availability of fresh human PDAC tumors for research studies. As there is an urgent need to identify effective regimens for PDAC patients, slice cultures from PDAC tumors developing in transgenic mouse models may overcome the limitations of both mouse models and ex vivo slice cultures of human PDAC tumors. The main objective in this application is to validate slice cultures from PDAC tumors developing in transgenic mouse models as a means of testing novel regimens for pancreatic cancer. The central hypothesis is that slice cultures established from mouse PDAC tumors will readily allow the testing of novel regimens for pancreatic cancer. The rationale for the proposed research is that validating slice cultures from mouse PDAC tumors will accelerate the screening and identification of novel regimens for PDAC patients. Two specific aims are proposed: 1) Validate ex vivo slice cultures established from mouse PDAC tumors by testing approved chemotherapies. 2) Validate ex vivo slice cultures established from mouse PDAC tumors by testing the combination of BET and HDAC inhibitors. Under the first aim, chemotherapy regimens that have previously been shown to be effective in vivo in mouse models and human PDAC tumors will be tested in ex vivo slice cultures of tumors established from three different transgenic mouse models of PDAC. In addition, we will evaluate the effectiveness of adding targeted inhibitors to chemotherapy in ex vivo slice cultures of PDAC tumors from transgenic mice. In the second aim, the combination of BET and HDAC inhibitors will be tested in ex vivo slice cultures of tumors established from three different transgenic mouse models of PDAC. In addition, we will evaluate the relative efficacy of combining BET inhibitors with chemotherapy in the ex vivo tumor slice cultures. There are several innovative elements in this proposal, including the novel concept of using ex vivo slice cultures of mouse tumors to test various combination therapies for PDAC. This proposed research is significant because validating ex vivo slice cultures of mouse tumors to identify novel regimens will have important clinical-translational implications for PDAC patients.

虽然化学疗法仍然是标准治疗方法，但对发展新颖的兴趣越来越多 胰腺导管腺癌（PDAC）的方案。新型方案，例如赌注和 靶向表观遗传变化的HDAC抑制剂通常在小鼠模型中进行测试。但是，鼠标 模型有几个局限性。随着为癌症开发数量不断增加的药物，如何最好 要在小鼠模型中评估这些药物，无论是单独还是组合方案中的这些药物，也可能令人生畏。 最近，人类肿瘤的离体组织切片已用于治疗研究，但其中之一是 人类PDAC肿瘤的切片培养物的重大挑战是新鲜人类PDAC的有限可用性 研究研究的肿瘤。由于迫切需要确定PDAC患者有效方案，因此切片 来自转基因小鼠模型中PDAC肿瘤的培养物可能会克服两只小鼠的局限性 模型和离体切片人类PDAC肿瘤的培养物。此应用程序的主要目的是验证 从转基因小鼠模型中发展的PDAC肿瘤的切片培养物作为测试新方案的一种手段 用于胰腺癌。中心假设是从小鼠PDAC肿瘤建立的切片培养物将 很容易允许对胰腺癌的新型治疗疗法进行测试。拟议研究的理由是 从小鼠PDAC肿瘤中验证切片培养物将加速筛查和鉴定。 PDAC患者的方案。提出了两个具体目标：1）验证从 小鼠PDAC肿瘤通过测试认可的化学疗法。 2）验证从 小鼠PDAC肿瘤通过测试BET和HDAC抑制剂的组合。在第一个目标下，化学疗法 以前已证明在小鼠模型和人PDAC肿瘤中在体内有效的方案 将在从三种不同的转基因小鼠模型中建立的肿瘤的离体切片中进行测试 PDAC。此外，我们将评估在离体中将靶向抑制剂添加到化学疗法中的有效性 来自转基因小鼠的PDAC肿瘤的切片。在第二个目标中，BET和HDAC的结合 抑制剂将在从三种不同的转基因小鼠建立的肿瘤的离体切片中进行测试 PDAC的模型。此外，我们将评估将BET抑制剂与化学疗法相结合的相对功效 在离体肿瘤切片培养物中。该提案中有几个创新元素，包括小说 使用小鼠肿瘤的离体切片培养物测试PDAC的各种组合疗法的概念。这 拟议的研究很重要，因为验证了小鼠肿瘤的离体切片培养物以鉴定新型 方案将对PDAC患者具有重要的临床翻译意义。