Translational application of mouse models of melanoma brain metastases

近年来，人们对黑色素瘤的分子病理学研究取得了很大进展 尽管已经有了很多治疗方法，但晚期黑色素瘤仍然是最难治愈的癌症之一， 具有高转移倾向。脑是各种肿瘤患者常见的转移部位 包括黑色素瘤、乳腺癌、肺癌和结肠直肠癌。治疗脑部疾病的主要方法 转移的治疗方法是放射治疗;有时也包括手术和化疗药物。 大多数临床试验通常排除脑转移患者，因为这些患者不太可能 然而，最近一些试验包括了黑色素瘤患者， 脑转移这些试验的初步结果表明，观察到了类似的反应性 对于有或没有脑转移的患者，需要进一步的试验来证实这些结果。尽管有这些 虽然有改善，但患有实体瘤多发性脑转移的患者通常表现出脑部进展， 导致神经功能恶化、生活质量下降和生存率低。 反映人类癌症的小鼠模型是转化基础科学发现的重要工具 临床治疗。然而，在过去几年中迅速发展的技术需要进一步完善 当前的方法使得模型更适合于鲁棒的翻译应用， 提供一致的信息，以满足患者的需求。在我们对黑色素瘤的研究中，我们发现>65%的人 黑色素瘤细胞系和黑色素瘤活检组织表达代谢型谷氨酸受体1（GRM 1），独立于 N-RAS/B-RAF基因型，而正常人黑素细胞没有。基于这一发现，我们的团队 第一个提出GRM 1介导的多巴胺能信号和黑色素瘤之间的联系。在最近的临床 在临床试验中，我们观察到>90%的所有入选患者在其晚期黑素瘤中表达GRM 1。 然而，传统的黑色素瘤小鼠模型不能模拟这种遗传改变， 黑色素瘤患者。因此，我们开发了小鼠模型（MASS和TGS），其中异位表达的 先前正常黑素细胞中的GRM 1导致黑素细胞病变的一致、广泛发展 以及转移到各种器官，包括肺和脑，这是人类两个常见的转移部位。 黑素瘤在本申请中，我们提出表征这两种不同但互补的能力 创新的模型，模拟人类黑色素瘤脑转移和填补差距，扩大，改善， 将哺乳动物肿瘤模型的效用转化为转化研究。完成这项拟议工作是 这是建立人类癌症的基本重要和相关动物模型的重要一步 这将改善和挽救癌症患者的生命。

Much has been learned about the molecular pathology of melanoma in recent years and significant progress has been made towards its treatment, yet late-stage melanoma still remains one of the least curable cancers with high metastatic propensity. The brain is a common site of metastasis for patients with various neoplasia including melanoma, breast cancer, lung cancer, and colorectal cancer. The mainstay for treatment of brain metastasis has been radiation therapy; sometimes surgery and chemotherapeutic agents have been included. Most clinical trials usually excluded patients with brain metastases because of the unlikelihood these patients will benefit from such regiment, however, recently a few trials have included melanoma patients with or without brain metastases. Preliminary results from these trials are suggestive that similar responsiveness was observed for patients with or without brain metastases, and further trials are needed to confirm these results. Despite these improvements, patients with multiple brain metastases from solid tumors often show progression in the brain contributing to neurological deterioration, decreased quality of life, and poor survival. Mouse models reflecting human cancers are important tools towards the translation of basic science discoveries to clinical therapies. However, rapidly evolving technologies within the last few years require further refining current approaches that enable models to be more suitable in robust translational applications to provide consistent information to meet patients’ needs. In our studies of melanoma, we discovered that >65% of human melanoma cell lines and melanoma biopsies express metabotropic glutamate receptor 1 (GRM1), independent of N-RAS/B-RAF genotypes, while normal human melanocytes do not. Based on this discovery, our group was the first to propose the link between GRM1-mediated glutamatergic signaling and melanoma. In recent clinical trials, we observed that >90% of all enrolled patients expressed GRM1 within their late-stage melanomas. However, the conventional mouse models of melanoma do not mimic this genetic alteration common to melanoma patients. Therefore, we developed mouse models (MASS and TGS) where the ectopic expression of GRM1 in previously normal melanocytes leads to consistent, wide-spread development of melanocytic lesions and metastasis to various organs including the lung and brain, two common metastatic sites for human melanoma. In this application, we propose to characterize the ability of these two different but complementary innovative models that mimic human melanoma with brain metastases and fill the gap, to expand, improve, and transform the utility of mammalian tumor models for translational research. Completion of this proposed work is an essential step towards establishing fundamentally important and relevant animal models of human cancer that will improve and save cancer patient lives.