Preclinical GEM and GDA Models of Primary and Metastatic Melanoma

原发性和转移性黑色素瘤的临床前 GEM 和 GDA 模型

• 批准号: 10262429
• 负责人: SHYAM SHARAN
• 金额: $ 132.74万
• 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/10262429
• 关键词: Adjuvant; Allografting; Anatomy; Animals; BRAF gene; Biotechnology; CCR; CTLA4 gene; Clinical; Clinical Management; Collaborations; Cutaneous Melanoma; Diagnostic; Disease; Disease model; Dose; Drug resistance; Evaluation; Excision; Foundations; Generations; Goals; Growth; HGF gene; Image; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunomodulators; Immunotherapeutic agent; Immunotherapy; Journals; Laboratories; Lesion; Luciferases; Malignant Neoplasms; Medicine; Metastatic Melanoma; Modeling; Molecular; Molecular Abnormality; Monitor; Mutation; Nature; Neoadjuvant Therapy; Neoplasm Metastasis; Oncogenic; Outcome; PD-1/PD-L1; Paper; Patients; Pattern; Privatization; Procedures; Proteins; Publishing; Regimen; Reporting; Research Personnel; Resected; Resistance; Resistance development; Resources; Scientist; Therapeutic; Therapeutic Intervention; Treatment Protocols; Tumor-infiltrating immune cells; cancer cell; checkpoint modulation; cohort; comparative; comparative efficacy; conventional therapy; drug development; experimental study; imaging probe; immune checkpoint; immune checkpoint blockade; immunomodulatory therapies; inhibitor/antagonist; melanoma; mouse model; multidisciplinary; mutant; novel; patient subsets; pre-clinical; programmed cell death protein 1; response; targeted treatment; therapeutic development; translational impact; tumor

Metastatic cutaneous melanoma is featured by predominant resistance to conventional therapies, resulting in poor prognoses and almost uniformly high lethality due to this disease. About 60% of all melanoma clinical cases harbor the BrafV600E mutation, and most are responsive to the recently approved therapies that target the mutant Braf protein. However, disease generally recurs within 12-15 months displaying the acquires resistance to Braf inhibitors, aggressive growth and enhanced metastatic potential. Additional promising results that demonstrate the possibility of durable responses in a subset of patients have recently been achieved with immune checkpoint modulation therapy that targets PD1/PDL1 or CTLA4 or the combination, and further immunomodulation therapies are being developed. However, it is not clear why some patients respond so well, while others don't respond at all. In addition, it will be critical to determine dosing regimens, effective combinations of multiple immunotherapies and their combination with cancer cells or other components of the cancer stroma. The metastatic melanoma GDA models developed in this project has been demonstrated as a highly valuable preclinical resource in determining potential mechanisms of drug resistance and the development of effective combination treatments, dosing regimens and diagnostic strategies for evaluation in patients. The established and validated GDA models include HGF/MET-driven primary and metastatic melanoma, including models in which tumors express luciferase. In addition, primary Braf driven and primary and metastatic HGF/MET/Braf driven models have been established. These models have been actively employed during a broad-scope collaboration study aimed at a comparative assessment of the effects of checkpoint inhibitors in BRAF or HGF-driven mouse models of melanoma in collaboration with Dr. Glenn Merlino's CCR laboratory. CAPR scientists in collaboration with Dr. Merlino's melanoma researchers completed recently an impressive continuum of experimental activities aimed at description and molecular characterization of multiple melanoma models featuring metastatic spread post-resection and is currently advancing studies to model the outcomes of checkpoint blockade therapies in adjuvant vs. neo-adjuvant settings for melanoma therapy. These experiments, conducted in HGF/SF- and Cdkn2a-driven melanoma models, allowed to establish conditions and therapeutic schedules for treatment of tumor-bearing animals with PD-1 checkpoint inhibitor, in both adjuvant and neoadjuvant settings following tumor resection this preparing the foundation for a large scale comparative efficacy experiment. As one of the additional key goals of this study, the melanoma disease response to such therapeutic intervention will be compared across at least three different melanoma models driven by a combination of distinct oncogenic molecular aberrations. A high-profile collaborative paper in Nature Medicine journal has been recently published to report on these valuable discoveries broadly expected to have a significant translational impact for melanoma therapeutic development.

转移性皮肤黑色素瘤的特点是对传统疗法具有显着的耐药性，导致预后不良，并且由于这种疾病几乎一致具有高致死率。大约 60% 的黑色素瘤临床病例带有 BrafV600E 突变，并且大多数对最近批准的针对突变 Braf 蛋白的疗法有反应。然而，疾病通常在 12-15 个月内复发，表现出对 Braf 抑制剂的获得性耐药性、侵袭性生长和增强的转移潜力。最近，通过针对 PD1/PDL1 或 CTLA4 或其组合的免疫检查点调节疗法取得了其他有希望的结果，证明了在部分患者中出现持久反应的可能性，并且正在开发进一步的免疫调节疗法。然而，尚不清楚为什么有些患者反应如此良好，而另一些患者则根本没有反应。此外，确定给药方案、多种免疫疗法的有效组合以及它们与癌细胞或癌基质其他成分的组合也至关重要。该项目开发的转移性黑色素瘤 GDA 模型已被证明是一种非常有价值的临床前资源，可用于确定潜在的耐药机制以及开发有效的联合治疗、给药方案和患者评估的诊断策略。已建立和验证的 GDA 模型包括 HGF/MET 驱动的原发性和转移性黑色素瘤，包括肿瘤表达荧光素酶的模型。此外，还建立了原发性 Braf 驱动模型以及原发性和转移性 HGF/MET/Braf 驱动模型。这些模型已在一项广泛的合作研究中得到积极应用，该研究旨在与 Glenn Merlino 博士的 CCR 实验室合作，比较评估检查点抑制剂在 BRAF 或 HGF 驱动的黑色素瘤小鼠模型中的效果。 CAPR 科学家与 Merlino 博士的黑色素瘤研究人员合作，最近完成了一系列令人印象深刻的实验活动，旨在描述和分子表征具有切除后转移扩散的多种黑色素瘤模型，目前正在推进研究，以模拟检查点阻断疗法在辅助治疗与. 黑色素瘤治疗的新辅助设置。这些实验在 HGF/SF 和 Cdkn2a 驱动的黑色素瘤模型中进行，允许建立在肿瘤切除后的辅助和新辅助环境中用 PD-1 检查点抑制剂治疗荷瘤动物的条件和治疗方案，这奠定了基础用于大规模比较功效实验。作为这项研究的额外关键目标之一，将在至少三种由不同致癌分子畸变组合驱动的不同黑色素瘤模型中比较黑色素瘤疾病对此类治疗干预的反应。最近在《自然医学》杂志上发表了一篇备受瞩目的合作论文，报告了这些有价值的发现，人们普遍认为这些发现将对黑色素瘤治疗的发展产生重大的转化影响。