WP1066 induces cell death in a schwannomatosis patient-derived schwannoma cell line.
WP1066 induces cell death in a schwannomatosis patient-derived schwannoma cell line.
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DOI：
10.1101/mcs.a006178
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发表时间：
2022-06
影响因子：
1.8
通讯作者：
Fernandez-Valle, Cristina
中科院分区：
文献类型：
--
作者：
Allaf, Abdulrahman;Victoria, Berta;Rosario, Rosa;Misztal, Carly;Gultekin, Sakir Humayun;Dinh, Christine T.;Fernandez-Valle, Cristina
神经鞘瘤病是一种罕见的遗传性疾病，易使个体发生多发性神经鞘瘤，主要发生在脊髓和周围神经，并使人衰弱的慢性疼痛，通常与任何神经鞘瘤无关。SMARCB 1和LZTR 1两个基因的致病性变体在家族性病例中是致病性的。然而，许多神经鞘瘤病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损增加。疼痛管理是通过使用多种镇痛和抗炎药物控制的日常斗争。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于罕见疾病患者来说非常困难，精确医学方法提供了定制治疗方案来控制肿瘤生长的可能性。作为原理的证明，我们从一个SMARCB 1/INI基因发生种系点突变的神经鞘瘤病患者身上获得了一个椎旁神经鞘瘤的生物标本。我们建立了hTERT永生化细胞系，并测试了靶向小分子在神经纤维瘤病2型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WP1066，一种STAT 3抑制剂，目前在儿童和成人脑肿瘤的2期临床试验中作为先导化合物。它降低细胞活力和STAT-3磷酸化，并诱导坏死性凋亡和半胱天冬酶依赖性细胞死亡的标志物的表达。结果证明了创建用于精密医学研究的患者源性细胞系的可行性。
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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影响因子：
2.6
作者：
Chang, Long-Sheng;Abraham, Jacob;Welling, D. Bradley
通讯作者：
Welling, D. Bradley
影响因子：
11.2
作者：
Hussain, S. Farzana;Kong, Ling-Yuan;Heimberger, Amy B.
通讯作者：
Heimberger, Amy B.
DOI：
10.1007/s00262-008-0618-y
发表时间：
2009-07
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
--
作者：
Kong LY;Wei J;Sharma AK;Barr J;Abou-Ghazal MK;Fokt I;Weinberg J;Rao G;Grimm E;Priebe W;Heimberger AB
通讯作者：
Heimberger AB
Schwannomatosis的分子发病机理，这是多种肿瘤抑制基因在肿瘤发生中共同参与的范例。
影响因子：
5.3
作者：
Kehrer-Sawatzki H;Farschtschi S;Mautner VF;Cooper DN
通讯作者：
Cooper DN
影响因子：
11
作者：
Evans, D. Gareth;Bowers, Naomi L.;Smith, Miriam J.
通讯作者：
Smith, Miriam J.