Developing new therapeutic strategies for brain metastasis

开发脑转移的新治疗策略

基本信息

批准号：
10578405
负责人：
Eva Hernando
金额：
$ 54.01万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578405
关键词：
Acceleration Adenocarcinoma Adrenal Cortex Hormones Affect Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid beta-Protein Amyloid beta-Protein Precursor Antibodies Area Astrocytosis Autopsy Blood - brain barrier anatomy Brain Brain Edema Brain Neoplasms Breast Breast Adenocarcinoma Breast Carcinoma Cancer Patient Cells Cellular biology Cephalic Cessation of life Clinical Clinical Trials Combined Modality Therapy Computational Biology Disease Disease Progression Environment Excision Genetic Glioblastoma Growth Immune Immune checkpoint inhibitor Immunocompetent Immunotherapy Impairment Inflammatory Investigation Link Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator Metastatic malignant neoplasm to brain Microglia Modeling Molecular Mus Neoplasm Metastasis Nerve Degeneration Neurocognitive Deficit Nivolumab Organ Patient-Focused Outcomes Patients Phagocytosis Play Pre-Clinical Model Prognosis Proteins Proteomics Radiosurgery Resistance Resolution Role Safety Sampling Systemic Therapy Techniques Testing Therapeutic Therapeutic Effect Tropism Up-Regulation Xenograft Model anti-CTLA4 anti-PD-1 anti-PD1 therapy beta secretase brain dysfunction brain parenchyma cancer type chemotherapy efficacy evaluation efficacy testing experience gamma secretase humanized antibody improved in vitro Assay in vivo Model inhibitor insight ipilimumab lung Carcinoma malignant breast neoplasm melanoma neoplastic cell neuroinflammation neuropsychiatry neurosurgery new therapeutic target novel novel strategies novel therapeutic intervention objective response rate pharmacologic response single-cell RNA sequencing small molecule standard of care targeted treatment transcriptomics tumor tumor microenvironment tumorigenesis

项目摘要

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.

项目概要大多数发生脑转移的癌症患者死于这种疾病。在所有黑色素瘤患者中，黑色素瘤 (8-11%)、肺癌 (17-39%) 和乳腺癌 (5-17%) 是腺癌。转移性疾病中，40-50% 会发生脑转移，尸检研究中这一比例升至 70%。尽管它很重要，但介导脑转移的机制在很大程度上还是未知的。我们开发了一种新的患者来源短期培养物 (STC) BM 模型，其中包括脑转移瘤 (BM) 和来自同一患者的非脑转移 (NBM) 衍生的 STC，并显示匹配的 BM 通过蛋白质组学和体外测定，我们比 NBM STC 保留了更强的脑特异性转移能力。结果表明，BM STC 具有更高水平的 APP 特异性 γ 分泌酶活性，并且分泌更多的 Aβ 在异种移植模型中，Aβ 分泌的遗传或药理学抑制作用显着。抑制 BM 形成而不影响其他器官的转移，揭示了 Aβ 在 BM 中的关键作用。为治疗阿尔茨海默病而开发的针对 Aβ 的治疗药物可以重新利用用于治疗脑转移，作为单一药物或与已批准的疗法联合使用。该提案利用了 Hernando 博士（黑色素瘤的分子机制）的互补专业知识。和转移）、Schober（细胞生物学、单细胞 RNAseq）和 Ruggles（计算生物学）来：1) 评估临床级抗 Aβ 抗体和小分子在同基因临床前的治疗潜力脑转移模型，2）研究我们的发现是否适用于其他具有脑向性的肿瘤类型，例如肺癌和乳腺癌，以及脑肿瘤，如胶质母细胞瘤；3) 研究细胞自主性；使用单细胞分辨率研究靶向 Aβ 对大脑微环境的非细胞自主效应技术。我们的研究将详细描述 Aβ 是否/如何作为 BM 的关键介质发挥作用，并描述这种新机制的特征。提供对 BM 的重要见解，与神经变性建立有趣的联系，并提供证据 Aβ 抑制作为一种针对 BM 和可能的脑肿瘤的新型治疗策略。