Osteopontin-targeted therapy for primary CNS lymphoma

原发性中枢神经系统淋巴瘤的骨桥蛋白靶向治疗

• 批准号: 9342631
• 负责人: John A. Copland
• 金额: $ 28.4万
• 依托单位: MODULATION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-28 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9342631
• 关键词: Alkaloids; Alpha Cell; Apoptosis; Autopsy; Blood; Body Weight; Brain; Brain Neoplasms; Cell Line; Cell Proliferation; Cells; Central Nervous System Lymphoma; Chemistry; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Complete Blood Count; Control Groups; Data; Data Set; Development; Dimethyl Sulfoxide; Disseminated Malignant Neoplasm; Dose; Dose-Limiting; Down-Regulation; Frequencies; Gene Expression Profiling; Genes; Glioblastoma; Goals; Harvest; Immunohistochemistry; Incidence; Laboratories; Legal patent; Lymphoma; Malignant Neoplasms; Malignant neoplasm of brain; Marines; Maximum Tolerated Dose; Measures; Mediating; Metastatic breast cancer; Methotrexate; Modification; Molecular; Molecular Abnormality; Orphan Drugs; Patients; Penetrance; Penetration; Persons; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Play; Porifera; Rare Diseases; Rattus; Refractory; Relapse; Role; Schedule; Scientist; Secure; Signal Transduction; Small Business Technology Transfer Research; Survival Analysis; Therapeutic; Therapeutic Agents; Therapeutic Uses; Tissues; Toxic effect; Translating; Translational Research; Treatment Efficacy; Tumorigenicity; Xenograft Model; Xenograft procedure; analog; base; cytotoxicity; design; experience; food consumption; functional genomics; histopathological examination; immunoregulation; in vivo; innovation; large cell Diffuse non-Hodgkin' s lymphoma; meetings; mouse model; novel; osteopontin; overexpression; preclinical development; programs; response; standard of care; targeted treatment; therapeutic evaluation; trial design; tumor growth; tumorigenic

Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive brain tumor with a dire unmet therapeutic need. It has an overall incidence of 0.47 per 100,000 person-years and is regarded as an orphan disease with potential for fast track approval. Our group made a discovery via gene expression analysis that osteopontin (OPN) is the most upregulated gene in PCNSL compared to its non-CNS counterpart. By immunohistochemistry analysis, OPN is expressed heavily by all the lymphoma cells in 92% of PCNSL cases. Functional genomic studies identified OPN as an important pro-tumorigenic driver with multifaceted role in CNS lymphoma including intracerebral tumor growth, invasion, and dissemination via a unique mechanistic activation of NF-κB signaling. High OPN expression in PCNSL patients has a strong correlation with poor progression-free and overall survival. To target OPN, we have developed a novel compound, Chloro-ethyl agelastatin A (CEAA), with excellent CNS penetration (~27%), which demonstrates robust therapeutic activity against CNS lymphoma in a cell line-derived murine model. We have secured a patent for composition of matter of agelastatin A analogues and their therapeutic use in primary and secondary brain tumors such as primary and secondary CNS lymphoma, glioblastoma multiforme, and metastatic breast cancer of the brain. We are proposing to further develop CEAA for PCNSL with two specific aims. In Aim 1 (Copland/Hazlehurst, Modulation Therapeutics Inc.), the dose limiting toxicity (DLT) of CEAA will be determined in rats. In Aim 2, the Tun Laboratory will evaluate the therapeutic activity of CEAA against PCNSL in two novel patient derived xenograft (PDX) mouse models with high OPN expression in comparison to two control groups – standard of care control with high-dose Methotrexate and no-treatment vehicle control. The dose and frequency will be varied, as guided by results from Aim 1, to inform the Phase I clinical trial design. The generated dataset will provide the necessary data to i) initiate a pre-IND meeting with the FDA ii) design of the GLP studies required for the IND application and iii) design of the phase I clinical trial. CEAA represents a first in class agent, which targets a specific molecular abnormality in PCNSL. We believe that due to high penetrance to the brain, and robust in vivo activity of CEAA that further pre-clinical development of CEAA for the treatment of PCNSL is warranted. As OPN is ubiquitously over-expressed in many aggressive cancers including other brain tumors, we anticipate that the study results will have ramifications and applications for many other cancers.

抽象的 原发性中枢神经系统淋巴瘤（PCNSL）是一种侵袭性脑肿瘤，具有可怕的 未满足的治疗需求的总发病率为每 10 万人年 0.47 例，并且 我们的团队被视为一种孤儿疾病，有可能获得快速批准。 通过基因表达分析发现骨桥蛋白（OPN）是上调最多的基因 通过免疫组织化学分析，PCNSL 与其非 CNS 对应物相比。 在 92% 的 PCNSL 功能基因组病例中，所有淋巴瘤细胞均大量表达。 研究发现 OPN 是一种重要的促肿瘤驱动因素，在中枢神经系统中具有多方面的作用 淋巴瘤包括脑内肿瘤通过独特的生长、侵袭和传播 PCNSL 患者中 NF-κB 信号传导的高表达与机制有关。 与较差的无进展生存期和总生存期有很强的相关性。 开发了一种新型化合物氯乙基阿吉司他汀 A (CEAA)，具有优异的中枢神经系统作用 渗透率（~27%），这表明对中枢神经系统淋巴瘤具有强大的治疗活性 我们已获得细胞系衍生的小鼠模型的物质组合物专利。 阿吉拉斯汀 A 类似物及其在原发性和继发性脑肿瘤中的治疗用途，例如 原发性和继发性中枢神经系统淋巴瘤、多形性胶质母细胞瘤和转移性乳腺癌 我们建议进一步开发用于 PCNSL 的 CEAA，具有两个特定的功能。 目标 1（Copland/Hazlehurst，Modulation Therapeutics Inc.），剂量限制毒性。 在目标 2 中，Tun 实验室将在大鼠中测定 CEAA 的 DLT（DLT）。 CEAA 在两种新型患者来源的异种移植物 (PDX) 中对 PCNSL 的治疗活性 与两个对照组相比，具有高 OPN 表达的小鼠模型 – 标准 高剂量甲氨蝶呤护理控制和无治疗载体控制。 根据目标 1 结果的指导，频率将有所不同，以便为 I 期临床试验提供信息 生成的数据集将为 i) 启动 IND 前会议提供必要的数据。 ii) IND 申请所需的 GLP 研究设计和 iii) 设计 CEAA 是针对特定分子的一流药物。 我们认为，PCNSL 的异常是由于对大脑的高外显性，并且在体内强健。 CEAA 的活性表明 CEAA 治疗 PCNSL 的进一步临床前开发是 OPN 在许多侵袭性癌症（包括其他癌症）中普遍过度表达。 脑肿瘤，我们预计该研究结果将产生影响和应用 许多其他癌症。