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.

项目摘要大多数发展脑转移的癌症患者屈服于该疾病。患者发生脑转移黑色素瘤（8-11％），肺（17-39％）和乳腺癌（5-17％）腺癌。所有黑色素瘤患者转移性疾病，40-50％的脑转移发展，这一百分比在尸检研究中提高了70％。尽管其重要性，但介导脑转移的机制在很大程度上是未知的。我们开发了一种由患者衍生的短期培养物（STC）的新的BM模型，该模型由脑转移组成（BM）和非脑转移（NBM）来自同一患者的STC，并显示了匹配的PAIR BM 与NBM STC保持更大的大脑特异性转移能力。通过蛋白质组学和体外测定，我们表明BM STC具有更高水平的APP特异性伽马神分泌酶活性，并且分泌Aβ大于他们的NBM同行。在异种移植模型中，Aβ分泌的遗传学或药理抑制抑制BM的形成而不会影响其他器官转移，从而暴露了Aβ在BM中的关键作用。我们假设靶向Aβ的治疗剂可用于治疗阿尔茨海默氏症的治疗为了治疗脑转移，作为单一药物或与批准的疗法结合使用。该提案利用Drs的完善专业知识。 Hernando（黑色素瘤的分子机制和转移），Schober（细胞生物学，单细胞RNASEQ）和RUGGLES（计算生物学）至：1）评估临床级抗体和针对Aβ的小分子的治疗潜力脑转移模型，2）调查我们的发现是否适用于对大脑的其他肿瘤类型，例如肺和乳腺癌腺癌，以及诸如胶质母细胞瘤等脑肿瘤； 3）研究细胞自主使用单细胞分辨率靶向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如何作为BM的关键介体功能。表征这种新型机制将向BM提供重要的见解，与神经变性建立有趣的联系，并提供证明 Aβ的原理是针对BM和可能的脑肿瘤的新型治疗策略。