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: 10653683
• 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/10653683
• 关键词: Acceleration; Architecture; Awareness; Bromodomains and extra-terminal domain inhibitor; 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; cancer therapy; chemotherapy; clinical translation; 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; treatment response; 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.

虽然化疗仍然是标准治疗方法，但人们对开发新的治疗方法越来越感兴趣 胰腺导管腺癌(PDAC)的治疗方案。新方案，如BET和BET的组合 针对表观遗传变化的HDAC抑制剂通常最初在小鼠模型中进行测试。然而，鼠标 模型有几个限制。随着治疗癌症的药物数量不断增加，如何最好地 在小鼠模型中评估这些药物，无论是单独使用还是联合使用，也可能相当令人望而生畏。 最近，人类肿瘤的体外组织切片已被用于治疗研究，但其中一个 人PDAC肿瘤切片培养的主要挑战是新鲜人PDAC的可获得性有限 用于研究的肿瘤。由于迫切需要为PDAC患者确定有效的治疗方案，Slice 在转基因小鼠模型中生长的PDAC肿瘤的培养可以克服这两种小鼠的局限性 人PDAC肿瘤模型及体外切片培养。此应用程序的主要目标是验证 转基因小鼠模型中PDAC肿瘤的切片培养作为测试新方案的手段 治疗胰腺癌。中心假设是，从小鼠PDAC肿瘤建立的切片培养将 容易地允许测试治疗胰腺癌的新方案。建议进行这项研究的理由是 验证小鼠PDAC肿瘤切片培养将加速新基因的筛选和鉴定 PDAC患者的治疗方案。提出了两个具体的目标：1)验证从 小鼠PDAC肿瘤通过测试批准的化疗方法。2)验证建立的体外切片培养 通过测试BET和HDAC抑制剂的组合来检测小鼠PDAC肿瘤。在第一个目标下，化疗 先前已被证明对小鼠模型和人类PDAC肿瘤有效的治疗方案 将在三种不同的转基因小鼠模型建立的肿瘤的体外切片培养中进行测试 PDAC。此外，我们还将评估在体外化疗中添加靶向抑制剂的效果。 转基因小鼠PDAC肿瘤切片培养。在第二个目标中，BET和HDAC的结合 抑制剂将在三种不同转基因小鼠建立的肿瘤的体外切片培养中进行测试 PDAC的模型。此外，我们还将评估联合应用BET抑制剂和化疗的相对疗效。 在体外肿瘤切片培养中。这份提案有几个创新的元素，包括小说 利用小鼠肿瘤体外切片培养的概念来测试PDAC的各种联合治疗方法。这 拟议的研究具有重要意义，因为验证了小鼠肿瘤的体外切片培养以识别新的 这些方案将对PDAC患者具有重要的临床转译意义。