WP1066 induces cell death in a schwannomatosis patient-derived schwannoma cell line.

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Cold Spring Harbor Molecular Case Studies Pub Date : 2022-06-22 Print Date: 2022-06-01 DOI:10.1101/mcs.a006178
Abdulrahman Allaf, Berta Victoria, Rosa Rosario, Carly Misztal, Sakir Humayun Gultekin, Christine T Dinh, Cristina Fernandez-Valle
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引用次数: 1

Abstract

Schwannomatosis is a rare genetic disorder that predisposes individuals to development of multiple schwannomas mainly in spinal and peripheral nerves and to debilitating chronic pain often unrelated to any schwannoma. Pathogenic variants of two genes, SMARCB1 and LZTR1, are causal in familial cases. However, many schwannomatosis patients lack mutations in these genes. Surgery is the standard treatment for schwannomas but leaves patients with increasing neurological deficits. Pain management is a daily struggle controlled by the use of multiple analgesic and anti-inflammatory drugs. There is a need for both nonsurgical treatment to manage tumor growth and nonaddictive, nonsedative pain control. Because standard clinical trials are exceedingly difficult for patients with rare disorders, precision medicine approaches offer the possibility of bespoke therapeutic regimens to control tumor growth. As a proof of principle, we obtained a bio-specimen of paraspinal schwannoma from a schwannomatosis patient with a germline point mutation in the SMARCB1/INI gene. We created an hTERT immortalized cell line and tested the ability of targeted small molecules with efficacy in neurofibromatosis type 2-related schwannomas to reduce cell viability and induce cell death. We identified WP1066, a STAT3 inhibitor, currently in phase 2 clinical trials for pediatric and adult brain tumors as a lead compound. It reduced cell viability and STAT-3 phosphorylation and induced expression of markers for both necroptosis and caspase-dependent cell death. The results demonstrate feasibility in creating patient-derived cell lines for use in precision medicine studies.

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WP1066诱导神经鞘瘤患者源性神经鞘瘤细胞系细胞死亡
神经鞘瘤病是一种罕见的遗传性疾病,使个体易患多发性神经鞘瘤,主要发生在脊髓和周围神经,并导致与任何神经鞘瘤无关的慢性疼痛。SMARCB1和LZTR1这两个基因的致病变异在家族病例中是因果关系。然而,许多神经鞘瘤患者缺乏这些基因的突变。手术是神经鞘瘤的标准治疗方法,但会使患者的神经功能缺陷增加。疼痛管理是一种日常斗争,通过使用多种镇痛和抗炎药物来控制。需要非手术治疗来控制肿瘤生长和非成瘾性、非镇静性疼痛控制。由于标准的临床试验对患有罕见疾病的患者来说极其困难,精准医学方法提供了定制治疗方案来控制肿瘤生长的可能性。为了证明这一原理,我们从一位SMARCB1/INI基因发生种系点突变的神经鞘瘤患者身上获得了脊髓旁神经鞘瘤的生物标本。我们创建了一个hTERT永生化细胞系,并测试了靶向小分子在2型神经纤维瘤病相关神经鞘瘤中降低细胞活力和诱导细胞死亡的能力。我们确定了STAT3抑制剂WP1066作为先导化合物,目前正处于儿童和成人脑肿瘤的2期临床试验中。它降低细胞活力和STAT-3磷酸化,诱导坏死下垂和caspase依赖性细胞死亡标志物的表达。结果表明,在创建患者来源的细胞系用于精密医学研究的可行性。
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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