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有了许多了解，并取得了重大进展 尽管晚期黑色素瘤的治疗已经取得进展，但它仍然是最难治愈的癌症之一。 有很高的转移倾向。脑是各种肿瘤患者常见的转移部位。 包括黑色素瘤、乳腺癌、肺癌和结直肠癌。脑部治疗的中流砥柱 转移一直是放射治疗；有时还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 将受益于这样的团体，然而，最近有几项试验包括患有或不患有黑色素瘤的患者 脑转移瘤。这些试验的初步结果表明，观察到了类似的反应 对于有或没有脑转移的患者，还需要进一步的试验来证实这些结果。尽管如此 随着病情的改善，实体瘤多发性脑转移的患者通常表现为脑部进展。 导致神经恶化、生活质量下降和生存不良。 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 到临床治疗。然而，在过去几年里，快速发展的技术需要进一步完善 当前的方法使模型更适合于健壮的翻译应用程序，以提供 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%的人类 黑色素瘤细胞株和黑色素瘤活检组织表达非依赖的代谢性谷氨酸受体1(GRM1) N-RAS/B-RAF基因型别，而正常人黑素细胞则没有。基于这一发现，我们小组是 首次提出GRM1介导的谷氨酸能信号与黑色素瘤之间的联系。在最近的临床中 在试验中，我们观察到90%的入选患者在晚期黑色素瘤中表达GRM1。 然而，传统的黑色素瘤小鼠模型不能模仿这种常见的 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 以前正常的黑素细胞中的GRM1导致黑素细胞损伤持续、广泛的发展 并转移到包括肺和脑在内的各种器官，这是人类两个常见的转移部位 黑色素瘤。在本申请中，我们建议对这两种不同但互补的能力进行表征 模拟人类黑色素瘤脑转移并填补空白的创新模型，以扩大、改善和 转变哺乳动物肿瘤模型用于转译研究的效用。这项拟议工作的完成情况如下 朝着建立基本重要和相关的人类癌症动物模型迈出的重要一步 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.