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.

虽然化疗仍然是标准治疗，但对开发新的化疗药物的兴趣越来越大。 胰腺导管腺癌（PDAC）的治疗方案。新的治疗方案，如BET和 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，老鼠 模型有几个局限性。随着越来越多的癌症药物被开发出来， 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，也是相当令人生畏的。 最近，人肿瘤的离体组织切片已被用于治疗研究，但其中一个研究领域是肿瘤细胞。 人PDAC肿瘤切片培养的重大挑战是新鲜人PDAC的可用性有限 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， 在转基因小鼠模型中发展的PDAC肿瘤的培养物可以克服两种小鼠模型的局限性， 人PDAC肿瘤的模型和离体切片培养。此应用程序的主要目标是验证 在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物将 很容易允许测试胰腺癌的新方案。拟议研究的理由是， 验证小鼠PDAC肿瘤的切片培养物将加速筛选和鉴定新的 治疗PDAC患者。提出了两个具体的目标：1）从以下建立离体切片培养物： 小鼠PDAC肿瘤通过测试批准的化疗。2)体外切片培养物建立自 通过测试BET和HDAC抑制剂的组合来治疗小鼠PDAC肿瘤。第一个目标是化疗 先前已显示在小鼠模型和人PDAC肿瘤中体内有效的方案 将在从三种不同的转基因小鼠模型建立的肿瘤的离体切片培养物中进行测试， PDAC。此外，我们还将评估在体外化疗中加入靶向抑制剂的有效性 来自转基因小鼠的PDAC肿瘤的切片培养物。在第二个目标中，BET和HDAC的组合 将在从三种不同的转基因小鼠建立的肿瘤的离体切片培养物中测试抑制剂 PDAC模型此外，我们将评估BET抑制剂与化疗联合使用的相对疗效。 在离体肿瘤切片培养物中。这份提案中有几个创新的元素，包括小说 使用小鼠肿瘤的离体切片培养物来测试PDAC的各种组合疗法的概念。这 提出的研究是重要的，因为验证小鼠肿瘤的离体切片培养，以确定新的 治疗方案将对PDAC患者具有重要的临床转化意义。