Developing new therapeutic strategies for brain metastasis

项目摘要 大多数发生脑转移的癌症患者死于这种疾病。脑转移发生在患者 黑色素瘤（8-11%）、肺腺癌（17-39%）和乳腺癌（5-17%）。在所有黑色素瘤患者中 在转移性疾病中，40-50%发展为脑转移，并且在尸检研究中该百分比上升至70%。 尽管其重要性，介导脑转移的机制在很大程度上是未知的。 我们开发了一种新的患者来源的短期培养物（STC）的BM模型， (BM)和来自同一患者的非脑转移（NBM）来源的STC，并显示匹配对BM 保留比NBM STC更大的脑特异性转移能力。通过蛋白质组学和体外分析，我们 结果显示，BM STC具有更高水平的APP特异性γ分泌酶活性，并分泌比BMSC更多的Aβ。 他们的NBM同行。在异种移植模型中，Aβ分泌的遗传或药理学抑制显著 抑制BM形成而不影响转移到其他器官，暴露了Aβ在BM中的关键作用。我们 假设针对Aβ的治疗药物，开发用于治疗阿尔茨海默氏症，可以重新利用 用于治疗脑转移，作为单一药剂或与批准的疗法组合。 该提案利用了Hernando博士的互补专业知识（黑色素瘤的分子机制 和转移）、斯科贝尔（细胞生物学，单细胞RNAseq）和拉格尔斯（计算生物学）来：1）评估 临床级抗Aβ抗体和小分子药物在同基因临床前研究中的治疗潜力 脑转移瘤模型，2）研究我们的发现是否适用于其他向脑转移的肿瘤类型，如 肺和乳腺癌，以及脑肿瘤，如胶质母细胞瘤;和3）研究细胞自主 使用单细胞分辨率研究靶向Aβ对脑微环境的非细胞自主效应 技术. 我们的研究将详细说明Aβ是否/如何作为BM的关键介质发挥作用。描述这种新颖的机制将 为BM提供了重要的见解，建立了与神经变性的有趣联系，并提供了证据， Aβ抑制原理是一种新的治疗策略，可用于治疗BM和可能的脑肿瘤。

PROJECT SUMMARY Most cancer patients that develop brain metastasis succumb to the disease. Brain metastasis occurs in patients with melanoma (8-11%), lung (17-39%), and breast (5-17%) adenocarcinoma. Of all melanoma patients with metastatic disease, 40-50% develop brain metastasis and this percentage raises to 70% in autopsy studies. Despite its importance, mechanisms that mediate brain metastasis are largely unknown. We developed a new BM model of patient-derived short-term cultures (STCs), which consist of a brain metastasis (BM) and a non-brain metastasis (NBM)-derived STC from the same patient, and showed that matched pair BM retain greater brain-specific metastatic capability than NBM STCs. Through proteomics and in vitro assays, we showed that BM STCs have higher levels of APP-specific gamma secretase activity and secrete more Aβ than their NBM counterparts. In xenograft models, genetic or pharmacological inhibition of Aβ secretion dramatically inhibited BM formation without affecting metastasis to other organs, exposing a critical role for Aβ in BM. We hypothesize that therapeutic agents targeting Aβ, developed for the treatment of Alzheimer’s, can be repurposed for the treatment of brain metastasis, as single agents or combined with approved therapies. This proposal leverages the complementary expertise of Drs. Hernando (molecular mechanisms of melanoma and metastasis), Schober (cell biology, single cell RNAseq), and Ruggles (computational biology) to: 1) assess the therapeutic potential of clinical-grade antibodies and small molecules against Aβ in syngeneic preclinical models of brain metastasis, 2) investigate if our findings apply to other tumor types with tropism to the brain, like lung and breast adenocarcinoma, and brain tumors such as glioblastoma; and 3) investigate cell-autonomous and non-cell autonomous effects of targeting Aβ on the brain microenvironment using single-cell resolution techniques. Our studies will detail if/how Aβ functions as a critical mediator of BM. Characterizing this novel mechanism will provide important insights into BM, establish an intriguing link with neurodegeneration, and provide proof of principle of Aβ inhibition as a novel therapeutic strategy against BM and possibly brain tumors.