Development and Preclinical Applications of Pancreatic Adenocarcinoma Models

胰腺癌模型的建立及临床前应用

基本信息

批准号：
10486946
负责人：
SHYAM SHARAN
金额：
$ 98.64万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10486946
关键词：
Adenocarcinoma Cell Adult Affect Alleles Allografting Animals Antibodies Binding Biological Availability CCR Cell Culture Techniques Cell Line Cells Characteristics Clinical Combined Modality Therapy Cre driver Cytotoxic T-Lymphocytes Data Development Disease Disease model Dose Drug Formulations Drug Kinetics Ductal Epithelium Engineering Epithelial Cells Epitopes Evaluation Fibroblasts Formulation Gene Expression Profile Generations Genetic Recombination Genetically Engineered Mouse Genomic DNA Goals Human Immune Targeting Immune system Immunocompetent Immunologics Immunotherapeutic agent Immunotoxins In Vitro Inflammatory Interleukin-15 Intervention Intraepithelial Neoplasia Invaded Investigation Joints Journals KPC model KRAS2 gene KRASG12D Laboratories Lesion Liver Liver Circulation Lung Malignant Neoplasms Malignant neoplasm of pancreas Manuscripts Mediating Minor Modeling Molecular Molecular Abnormality Mus Mutagenesis Mutation Neoplasm Metastasis Oncogenic Orthologous Gene Pancreas Pancreatic Adenocarcinoma Pancreatic Diseases Pancreatic duct Paper Pathway interactions Patients Peptides Pharmaceutical Preparations Phase Population Positioning Attribute Pre-Clinical Model Preclinical Drug Evaluation Preparation Primary Neoplasm Protein Isoforms Proteins Publications Publishing Recombinants Regimen Reporting Research Personnel Resources Scientist Series Single Nucleotide Polymorphism Site TP53 gene Therapeutic Thyroid Gland Tissues Toxic effect Transcriptional Regulation Transgenes Translational Research Tumor Tissue Up-Regulation Work anti-PD-1/PD-L1 anti-cancer clinical center cohort comparative cryogenics cytokine design drug development efficacy evaluation experimental study first-in-human gemcitabine humanized mouse immune checkpoint blockade immunogenic immunological intervention improved in silico in vivo macrophage mesothelin mouse model mutant neoantigens next generation novel novel strategies novel therapeutics pancreas development pancreatic cancer model pancreatic ductal adenocarcinoma model pancreatic neoplasm pre-clinical pre-clinical assessment pre-clinical research preclinical efficacy precursor cell premalignant preservation programs prototype rare cancer receptor research clinical testing screening small molecule standard of care tool transcriptome sequencing translational medicine transplant model treatment response tumor

项目摘要

CAPR recent progress in pursuing its internal development initiatives in pancreatic disease modelling includes generation and full characterization of three relevant Cre-inducible missense p53 GEM strains in which the non-recombined allele expresses wild type p53 prior to a Cre-driven conversion to a mutant isoform expressing one. The p53aa172 inducible mutant strain has been bred with PDX-Cre and KRASG12D-lsl mice to generate animals that are similar to the KPC model, with the exception that they harbor no null allele prior to expression of p53-172. Development of pancreatic malignancies in these mice (KPwt-172C) is similar to that of KPC mice, except that the ectopic tumors do not develop and PDAC develops with a somewhat shortened latency. Furthermore, orthotopic KPC-PDA GDA models have been established from several KPC-derived primary tumors and demonstrated to develop PDA with characteristics of the parental malignancy. As an intriguing observation, the metastatic rate in such KPC-GDA models has increased to about 70 %, thus potentially enabling studies on mechanisms and treatment of metastatic disease. This high metastatic rate makes this model ideal for evaluating therapies for metastatic disease. As one of the most visible preclinical resource for intramural CCR investigators, CAPR pancreatic program is involved in multiple collaborative initiatives with CCR PI labs. For example, the pancreatic team has recently finalized a large, multi-modular collaborative project with Dr. Udo Rudloff's lab pursuing a comprehensive IND-enabling characterization of metarrestin compound employing both de novo and syngeneic orthotopic transplant models of pancreatic adenocarcinoma (PDAC). Multiple integrated preclinical assessment studies interrogating bioavalability, in vivo toxicity, a spectrum of molecular responses to treatment, as well as efficacy as monotherapy and in combination with gemcitabine standard of care, have been completed and have been used to support the IND submission for metarrestin that has been recently successfully approved paving the way to launch clinical evaluation of metarrestin formulations in first-in-human trials interrogating metarrestin tolerability and anti-cancer efficacy. The results of this joint effort have been published as two collaborative publications co-authored by CAPR scientists. Expanding collaborative relations with Dr. Rudloff's section of the Rare Tumor initiative, CAPR also made significant progress with the second, CAPR Oversight Committee-approved PI initiated study to evaluate another molecule - a biosimilar peptide compound RP-182 - which has shown promise as a potential microenvironment re-modelling factor in PDAC. CAPR has conducted several pilot multi-organ PK studies to explore bioavailability in pancreatic tumors, other PDAC-affected tissues (e.g. lung and liver) and circulation. CAPR has also conducted preclinical efficacy evaluation experiments to assess the anti-tumor potency of RP-182 peptide in KPC model, as well as in orthotopic pancreatic cancer models established using wild-type and CD206-deficient syngeneic recipient animals to confirm the hypothesis of CD206 receptor being a specific target molecule for RP-182 peptide. The position paper reporting on this novel approach in targeting the tumor infiltrating macrophage population polarized by M2 type has been published earlier this year in Science Translational Medicine journal. CAPR pancreatic program has also completed the first part of a collaborative project with Dr. George Pavlakis' laboratory aimed at investigation of immunologic signatures in pancreatic tumors treated with recombinant hetIL-15 cytokine. Pancreatic tumor bearing animals have been subject to dosing with control vehicle compound or with IL-15 and gemcitabine as single drug regimens, or IL-15/Gemcitabine combination therapy. CAPR is currently evaluating the data from this study. Continuing to deliver on its extensive collaborative work with Dr. Christine Alewine, CAPR researchers established a broad allelic series of genetically modified mouse models expressing either chimeric mouse/human mesothelin (MSLN) protein under the transcriptional control of the endogenous mMSLN locus, or a fully human MSLN ortholog in a narrow expression domain in the thyroid gland. Upon extensive molecular characterization, these validated new tools offer immunocompetent models in which recipient animals are either immunologically 'tolerized' against orthologous human MSLN protein or lack MSLN expression in either a constitutive or a conditional manner. These models are currently used for syngeneic allografting studies with PDAC cells expressing "humanized" MSLN protein to prepare cohorts of tumor bearing animals to assess the efficacy of recombinant immunotoxins designed to recognize human MSLN protein by antibody binding to human MSLN-specific epitopes. To summarize the activities of CAPR pancreatic program, seven collaborative manuscripts have been published in 2019-2021, including two high-profile paper on metarrestin drug development and RP-182 peptide discovery and evaluation as potential therapeutic compound, both appearing in Science Translational Medicine. One of investigational compounds (metarrestin) is currently undergoing clinical testing in Phase I-II study conducted at the CCR Clinical Center. Another drug formulation (a small molecule candidate compound NCGC072) has been characterized in several single- and multi-dose administration pharmacokinetics experiments and is in preparation for the IND application filing.

CAPR 在胰腺疾病模型方面的内部开发计划的最新进展包括三种相关 Cre 诱导错义 p53 GEM 菌株的生成和完整表征，其中非重组等位基因在 Cre 驱动的突变同工型转化之前表达野生型 p53表达一. p53aa172 诱导突变株已与 PDX-Cre 和 KRASG12D-lsl 小鼠一起培育，产生与 KPC 模型相似的动物，不同之处在于它们在表达 p53-172 之前不存在无效等位基因。这些小鼠 (KPwt-172C) 中胰腺恶性肿瘤的发展与 KPC 小鼠相似，不同之处在于异位肿瘤不发展并且 PDAC 发展的潜伏期稍短。此外，已经从几个 KPC 衍生的原发性肿瘤中建立了原位 KPC-PDA GDA 模型，并证明可以发展出具有亲本恶性肿瘤特征的 PDA。一个有趣的观察结果是，此类 KPC-GDA 模型中的转移率已增加至约 70%，因此有可能使研究转移性疾病的机制和治疗成为可能。这种高转移率使该模型成为评估转移性疾病治疗的理想选择。作为壁内 CCR 研究人员最明显的临床前资源之一，CAPR 胰腺项目参与了与 CCR PI 实验室的多项合作计划。例如，胰腺团队最近与 Udo Rudloff 博士的实验室完成了一个大型、多模块合作项目，旨在利用胰腺腺癌 (PDAC) 的从头和同基因原位移植模型对metarrestin 化合物进行全面的 IND 表征。多项综合临床前评估研究已经完成，包括生物利用度、体内毒性、治疗的一系列分子反应以及单一疗法和与吉西他滨护理标准相结合的疗效，并已用于支持metarrestin的IND提交，最近已成功获得批准，为在首次人体试验中启动 Metarrestin 制剂的临床评估铺平了道路，以探讨 Metarrestin 的耐受性和抗癌功效。这项共同努力的结果已作为两份由 CAPR 科学家共同撰写的合作出版物发表。 CAPR 扩大了与 Rudloff 博士罕见肿瘤计划部门的合作关系，并取得了重大进展，CAPR 监督委员会批准的 PI 发起的第二项研究评估了另一种分子 - 生物类似肽化合物 RP-182 - 该分子已显示出作为一种药物的前景。 PDAC 中潜在的微环境重塑因子。 CAPR 进行了多项试点多器官 PK 研究，以探索胰腺肿瘤、其他 PDAC 影响的组织（例如肺和肝）和循环中的生物利用度。 CAPR还进行了临床前疗效评估实验，以评估RP-182肽在KPC模型以及使用野生型和CD206缺陷同系受体动物建立的原位胰腺癌模型中的抗肿瘤效力，以证实CD206的假设受体是 RP-182 肽的特异性靶分子。今年早些时候，《科学转化医学》杂志发表了关于这种针对 M2 型极化肿瘤浸润巨噬细胞群的新方法的立场文件。 CAPR 胰腺项目还完成了与 George Pavlakis 博士实验室合作项目的第一部分，旨在研究重组 hetIL-15 细胞因子治疗的胰腺肿瘤的免疫特征。患有胰腺肿瘤的动物已经接受了对照媒介物化合物或IL-15和吉西他滨作为单一药物方案的给药，或IL-15/吉西他滨联合治疗。 CAPR 目前正在评估这项研究的数据。 CAPR 研究人员继续与 Christine Alewine 博士开展广泛的合作工作，建立了一系列广泛的等位基因转基因小鼠模型，这些模型在内源性 mMSLN 基因座的转录控制下表达嵌合小鼠/人间皮素 (MSLN) 蛋白，或者表达完全表达的小鼠/人间皮素 (MSLN) 蛋白。人类 MSLN 直系同源物，位于甲状腺的狭窄表达域中。经过广泛的分子表征，这些经过验证的新工具提供了免疫活性模型，其中受体动物要么对直系同源人类 MSLN 蛋白进行免疫“耐受”，要么以组成型或条件性方式缺乏 MSLN 表达。这些模型目前用于使用表达“人源化”MSLN 蛋白的 PDAC 细胞进行同基因同种异体移植研究，以制备荷瘤动物群，以评估重组免疫毒素的功效，该重组免疫毒素旨在通过与人 MSLN 特异性表位结合的抗体来识别人 MSLN 蛋白。为了总结 CAPR 胰腺项目的活动，2019-2021 年已发表了 7 份合作手稿，其中包括两篇关于metarrestin 药物开发和 RP-182 肽发现和评估作为潜在治疗化合物的备受瞩目的论文，这两篇论文均发表在《科学转化医学》杂志上。其中一种研究化合物（metarrestin）目前正在 CCR 临床中心进行 I-II 期研究的临床测试。另一种药物制剂（小分子候选化合物NCGC072）已在多个单剂量和多剂量给药药代动力学实验中进行了表征，并正在准备提交IND申请。