Inherent tropism and/or immune modulation in melanoma brain metastasis

大约一半的转移性黑色素瘤患者会发生脑转移。尽管最近在 对于转移性黑色素瘤的治疗，治疗脑转移患者仍然具有挑战性。这些病人 通常被排除在临床试验之外，因为从历史上看，黑色素瘤脑转移(MBM)是 很难控制，通常预示着预后很差。对MBMS患者的系统治疗是 由于缺乏知识，新的有效疗法的研究不足和临床前开发受到限制 关于脑转移的机制，加上缺乏关于药物通道的研究 穿过血脑屏障(BBB)。这强调了对MBMS的分子研究的迫切需要 开发新的药物靶点和有效和特定的系统疗法的目标。在我们的预赛中 我们对早期脑转移患者的肿瘤进行了基因表达谱研究。 并将其与不这样做的患者进行比较；PLEKHA5，一种已知的调节正常大脑发育的基因， 和CEACAM1，一种免疫检查点分子，是差异表达最大的基因。就地 对一组非重叠患者的蛋白质水平的评估表明，这两个分子的高水平是 与脑转移倾向显著相关，而早期发生MBMS的风险最高 当肿瘤中Ceacam1水平升高，肿瘤浸润性淋巴细胞密度降低时。此外， 以肌萎缩侧索硬化症为第一个远端病变部位的患者，两者的水平都高度升高。 生物标志物。PLEKHA5基因敲除降低了脑嗜性细胞的体外和体内增殖 抑制其血脑屏障迁移和侵袭。进一步的分析表明，PI3K可能存在相互作用 路径。在这里，我们建议1)进一步研究PLEKHA5和CEACAM1作为MBMS的可能介体 利用体细胞遗传学方法，结合体外细胞分析和体内实验小鼠 最近开发的模型，并同时研究CEACAM1定向免疫的作用 脑转移瘤的调控机制。拟议的研究具有很高的临床相关性：第一，PI3K通路 已被证明是重要的和可用于MBMS的药物，临床上可用的化合物跨越了 第二种是针对CEACAM1的新开发的免疫检查点抑制剂， 正在对包括黑色素瘤在内的实体肿瘤进行临床试验。我们的研究将提供有意义的 关于PLEKHA5、CEACAM1以及它们在脑转移中的联合作用的信息。如果 这些研究的成功将为PLEKHA5/PI3K和/或CEACAM1的未来开发奠定基础。 易转移至脑的黑色素瘤的靶向治疗。此外，他们还将提供 洞察这些试验中基于生物标记物的患者选择，从而改善治疗窗口。

Approximately half of the metastatic melanoma patients develop brain metastases. Despite recent advances in therapy for metastatic melanoma, treating patients with brain metastases remains challenging. These patients are typically excluded from clinical trials because historically, melanoma brain metastases (MBMs) were difficult to control and usually portended a poor prognosis. Systemic therapies for patients with MBMs are understudied and preclinical development of new effective therapies are limited by the lack of knowledge regarding mechanisms involved in brain metastasis, coupled with the lack of studies addressing drug passage across the blood brain barrier (BBB). This emphasizes the immediate need for molecular studies of MBMs with the goal of developing new drug targets and effective and specific systemic therapies. In our preliminary studies we conducted gene expression profiling of tumors of patients who developed early brain metastases and compared them to patients who did not; PLEKHA5, a gene known to regulate normal brain development, and CEACAM1, an immune checkpoint molecule, were among the most differentially expressed genes. In situ assessment of protein levels in a non-overlapping set of patients showed that high levels of both molecules are significantly associated with propensity for brain metastasis, while the risk of developing early MBMs is highest when tumors have elevated Ceacam1 levels and low density of tumor infiltrating lymphocytes. Moreover, patients who presented with MBM as their first distant site of disease had highly elevated levels of both biomarkers. Knock-down of PLEKHA5 decreased in vitro and in vivo proliferation of cerebrotropic cells and inhibited their BBB transmigration and invasion. Further analysis showed a possible interplay with the PI3K pathway. Here we propose to 1) further study PLEKHA5 and CEACAM1 as possible mediators of MBMs utilizing somatic cell genetic approaches along with in vitro cell based assays and in vivo experimental mouse models recently developed, and to 2) concurrently investigate the role of CEACAM1–directed immune modulation in brain metastasis. The proposed studies are of high clinical relevance: first, the PI3K pathway has been shown to be important and druggable in MBMs with clinically available compounds that cross the blood-brain-barrier and second, a newly developed immune check point inhibitor, directed against CEACAM1, is being investigated in clinical trials in solid tumors including melanoma. Our studies will provide meaningful information regarding the roles of PLEKHA5, CEACAM1 and their combined roles in brain metastasis. If successful, these studies will form the basis for future development of PLEKHA5/PI3K and/or CEACAM1- targeting therapies for treatment of melanomas prone to metastasize to the brain. Moreover, they will provide insight into biomarker-based patient selection for these trials, resulting in an improved therapeutic window.