Center for Applied Preclinical Research (CAPR)

应用临床前研究中心 (CAPR)

• 批准号: 7970039
• 负责人: Terry van Dyke
• 金额: $ 181.74万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7970039
• 关键词: Address; Animal Model; Animal Testing; Animals; Antineoplastic Agents; Astrocytoma; Behavior; Biodistribution; Biological Markers; Cancer Model; Cancerous; Carcinogenesis Mechanism; Categories; Cell Culture Techniques; Cells; Characteristics; Charge; Clinical; Clinical Oncology; Clinical Trials; Collection; Commit; Communities; Country; Data; Derivation procedure; Development; Diagnostic; Disease model; Drug Delivery Systems; Drug usage; Engineering; Environment; Evaluation; Exhibits; Experimental Neoplasms; Fostering; Foundations; Future; Generations; Genetic; Genetically Engineered Mouse; Goals; Government; Human; Human Cell Line; Immunocompetent; Immunocompromised Host; Immunologic Surveillance; In Vitro; Inbred Strain; Individual; Industry; Injection of therapeutic agent; Investigation; Knowledge; Lead; Legitimacy; Lesion; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Marketing; Metabolic Pathway; Metabolism; Methodology; Modeling; Molecular; Molecular Profiling; Molecular Target; Mouse Strains; Mus; NCI Center for Cancer Research; Noise; Output; Ovary; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiological; Population; Primary carcinoma of the liver cells; Procedures; Process; Prognostic Marker; Prostate; Reproducibility; Research; Research Infrastructure; Research Personnel; Resources; Safety; Sampling; Source; Staging; Stratification; Technology; Therapeutic; Time; TimeLine; Tissues; Toxic effect; Transgenic Animals; Translating; Treatment Efficacy; Validation; Variant; Vascular System; Xenograft Model; Xenograft procedure; anti-cancer therapeutic; base; cancer therapy; cancer type; carcinogenesis; congenic; cost; design; design and construction; drug candidate; drug development; drug discovery; drug efficacy; drug testing; falls; innovation; knowledge base; mouse model; next generation; novel; pre-clinical; pre-clinical research; preclinical evaluation; preclinical study; prognostic; programs; research clinical testing; response; therapeutic evaluation; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenesis

At present, significant resources are committed by both academic research and industry to deliver groundbreaking therapeutic and diagnostic strategies aimed at curbing cancer occurrence. Despite the critical mass of available knowledge and technology platforms in the anti-cancer drug development field providing for the development of pathway-targeted therapies, only a few efficacious treatments have been developed. The major preclinical point of the government-regulated process for extensive animal testing of potential anti-cancer therapeutic compounds is directed towards safety assessment prior to the clinical introduction of any new anti-cancer drug. This analytical path of demonstrating the desired drug efficacy while proving it to be non-toxic has been implemented in a number of countries as multiphase clinical trial procedures. The initial stage in drug candidate evaluation demands routine investigation of future therapeutic compounds in animal and cell culture models, primarily to obtain knowledge of non-toxicity ranges, interaction with metabolic pathways, and systemic pharmacological behavior. This phase, termed preclinical characterization, may also provide a fair estimate point for the compounds therapeutic efficacy given the availability of appropriate disease model(s). In general, considering the extremely long (routinely >10 years) and expensive (often in excess of $700 million per drug lead) process to obtain the regulatory approval to market therapeutic compounds, the quality and the scope of efficacy data obtained during the preclinical stages may expedite clinical testing, dramatically increase affordability of downstream drug development steps, and advance the identification of effective cancer therapies. Currently, drug efficacy studies are conducted almost exclusively in xenograft models that employ transformed human cell lines to initiate tumor growth upon injection into immunocompromised animals. Though easily derived, the xenograft models feature multiple intrinsic limitations that jeopardize the predictability of drug testing output data. Xenograft tumors are developed from a genetically heterogeneous cell population that has been maintained <i>in vitro</i> for multiple passages. Moreover, the tumor growth occurs in an ectopic, non-physiological environment in the absence of immune surveillance and systemic interactions with the vascular system. As an alternative source of experimental tumors, animal models of spontaneous carcinogenesis may be also employed, but these models generally lack the reproducibility in timing of tumor onset and feature by heterogeneous tumor characteristics/drug response due to a considerable genetic "noise" caused by non-inbred strain background. The drawbacks of the xenograft and the spontaneous tumorigenesis models are largely ameliorated in genetically engineered mouse (GEM) tumor lines, which provide preclinical researchers with the ability to study naturally occurring tumors featuring pathway aberrations typical for similar human cancer types in the context of an appropriate tissue environment in immunocompetent animals. This approach finds ground in the rapidly expanding knowledge base for molecular mechanisms underlying carcinogenesis in human patients and is further fueled by the recent and rapid progress in the methodology and availability of resources to design and construct sophisticated animal models for a broad spectrum of human malignancies. At present, the GEM strategy not only provides an opportunity to combine in transgenic animals multiple genetic aberrations closely matching those detected in human patients, but also the potential to interfere with cancer-related molecular pathways in both a tissue-restricted and time-specific manner, providing genetic evidence for drug target legitimacy. This translates into a more accurate prediction of the dynamics of tumor progression while minimizing individual variations. In contrast to xenograft models, the cancerous lesions that occur in GEM animals exhibit a high degree of genetic similarity due to the availability of inbred and congenic lines for GEM generation. Among other benefits, this genetic similarity allows the decoding of individualized "tumor molecular signatures" that may be applicable for identifying cancer prognostic markers and developing personalized anti-tumor therapies based on predicting an individuals response to drug treatment known as the patient stratification principle. The CCR Center for Applied Preclinical Research (CAPR), will develop and implement a comprehensive preclinical trial framework for evaluating the anti-tumor efficacy and selectivity, safety, biodistribution, and metabolism of early stage candidate drugs using GEM models. CAPR will establish the infrastructure required for preclinical evaluation of anti-cancer drug leads in a recently derived collection of GEM models for high-occurrence cancers such as lung, ovary, and prostate gland tumors, as well as more rare cancer types that fall under the "unmet" demand category such as high-grade astrocytomas, hepatocellular carcinomas, and pancreatic cancers. CAPR will also be responsible for continuous sampling of the dynamic knowledge base on the mechanisms of carcinogenesis to seek additional molecular targets related to the tumor formation process. The appropriate GEM strains will be designed, derived, or adapted to address the CAPRs internal demand for novel mouse tumor models; however, these resources will also be shared with other scientific and industrial communities engaged in anti-cancer drug discovery and development.

目前，学术研究和工业界都投入了大量资源来提供旨在遏制癌症发生的突破性治疗和诊断策略。尽管抗癌药物开发领域拥有大量可用的知识和技术平台，可用于开发路径靶向疗法，但仅开发出少数有效的治疗方法。政府监管的潜在抗癌治疗化合物广泛动物试验过程的主要临床前要点是在任何新的抗癌药物临床引入之前进行安全性评估。这种展示所需药物功效同时证明其无毒的分析路径已在许多国家作为多阶段临床试验程序实施。候选药物评估的初始阶段需要在动物和细胞培养模型中对未来的治疗化合物进行常规研究，主要是为了了解非毒性范围、与代谢途径的相互作用以及全身药理学行为。这一阶段被称为临床前表征，鉴于适当的疾病模型的可用性，还可以为化合物的治疗功效提供公平的估计点。一般来说，考虑到获得监管部门批准上市治疗化合物的过程极其漫长（通常>10年）且昂贵（通常每个先导药物超过7亿美元），临床前阶段获得的疗效数据的质量和范围可以加快临床测试，显着提高下游药物开发步骤的负担能力，并促进有效癌症疗法的识别。目前，药效研究几乎全部在异种移植模型中进行，这些模型采用转化的人类细胞系在注射到免疫功能低下的动物体内后启动肿瘤生长。尽管很容易得出，但异种移植模型具有多种内在局限性，危及药物测试输出数据的可预测性。异种移植肿瘤是由遗传异质细胞群发展而来，该细胞群已在体外维持多次传代。此外，肿瘤生长发生在异位、非生理环境中，缺乏免疫监视和与血管系统的全身相互作用。作为实验肿瘤的替代来源，也可以采用自发癌变的动物模型，但这些模型通常缺乏肿瘤发病时间的可重复性以及异质性肿瘤特征/药物反应的特征，因为非自然因素引起的相当大的遗传“噪音”。 -近交系背景。异种移植和自发肿瘤发生模型的缺点在基因工程小鼠（GEM）肿瘤系中得到很大改善，这为临床前研究人员提供了在适当的背景下研究自然发生的肿瘤的能力，这些肿瘤具有类似人类癌症类型典型的通路畸变。免疫活性动物的组织环境。这种方法在人类患者致癌分子机制的快速扩展的知识库中找到了基础，并通过最近在为广泛的人类恶性肿瘤设计和构建复杂的动物模型的方法和资源可用性方面的快速进展而进一步推动。目前，GEM策略不仅提供了在转基因动物中结合与人类患者中检测到的多种遗传畸变密切匹配的机会，而且还具有以组织限制和时间特异性方式干扰癌症相关分子途径的潜力，为药物靶点的合法性提供遗传证据。这意味着可以更准确地预测肿瘤进展的动态，同时最大限度地减少个体差异。与异种移植模型相反，由于 GEM 产生的近交系和同源系的可用性，GEM 动物中发生的癌性病变表现出高度的遗传相似性。除其他好处外，这种遗传相似性允许解码个体化的“肿瘤分子特征”，这可能适用于识别癌症预后标志物，并基于预测个体对药物治疗的反应（称为患者分层原则）开发个体化抗肿瘤疗法。 CCR 应用临床前研究中心 (CAPR) 将开发和实施一个全面的临床前试验框架，使用 GEM 模型评估早期候选药物的抗肿瘤功效和选择性、安全性、生物分布和代谢。 CAPR 将在最近衍生的一系列 GEM 模型中建立抗癌药物先导化合物临床前评估所需的基础设施，这些模型适用于肺癌、卵巢癌和前列腺肿瘤等高发癌症，以及属于“未满足”的需求类别，如高级别星形细胞瘤、肝细胞癌和胰腺癌。 CAPR还将负责对致癌机制的动态知识库进行连续采样，以寻找与肿瘤形成过程相关的额外分子靶点。将设计、派生或调整适当的 GEM 菌株，以满足 CAPR 对新型小鼠肿瘤模型的内部需求；然而，这些资源也将与从事抗癌药物发现和开发的其他科学和工业界共享。