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

基本信息

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
项目类别：
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

项目摘要

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。新颖的治疗方案，例如 BET 和针对表观遗传变化的 HDAC 抑制剂通常首先在小鼠模型中进行测试。然而，鼠标模型有几个限制。随着越来越多的癌症药物被开发出来，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，都是相当艰巨的。最近，人类肿瘤的离体组织切片已被用于治疗研究，但其中之一人类 PDAC 肿瘤切片培养的重大挑战是新鲜人类 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，因此在转基因小鼠模型中开发的 PDAC 肿瘤培养物可能会克服两种小鼠的局限性人类 PDAC 肿瘤模型和离体切片培养物。该应用程序的主要目标是验证在转基因小鼠模型中开发的 PDAC 肿瘤切片培养物作为测试新疗法的手段用于胰腺癌。核心假设是，从小鼠 PDAC 肿瘤中建立的切片培养物将很容易测试胰腺癌的新疗法。拟议研究的理由是验证小鼠 PDAC 肿瘤切片培养物将加速新型肿瘤的筛选和鉴定 PDAC 患者的治疗方案。提出了两个具体目标：1）验证从以下来源建立的离体切片培养物：通过测试批准的化疗来治疗小鼠 PDAC 肿瘤。 2) 验证建立的离体切片培养物通过测试 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被证明在小鼠模型和人类 PDAC 肿瘤体内有效的治疗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，我们将评估在离体化疗中添加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。第二个目标是BET和HDAC的结合抑制剂将在由三种不同转基因小鼠建立的肿瘤的离体切片培养物中进行测试 PDAC 模型。此外，我们将评估BET抑制剂与化疗相结合的相对疗效在离体肿瘤切片培养物中。这个提案有几个创新元素，包括新颖的使用小鼠肿瘤的离体切片培养物来测试 PDAC 的各种联合疗法的概念。这拟议的研究意义重大，因为验证小鼠肿瘤的离体切片培养物以识别新的治疗方案将对 PDAC 患者产生重要的临床转化意义。