PO.CL06.02 · 临床研究
具有独特p53突变的Sonic hedgehog型髓母细胞瘤中的拷贝数变异：用HDAC抑制剂抑制PI3K/AKT/mTOR通路可作为治疗选择
Copy number variation in Sonic hedgehog-medulloblastoma with unique p53 mutations: Inhibition of PI3K/AKT/mTOR pathways with HDAC inhibitors can serve as therapeutic options
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摘要 Abstract
中文摘要
髓母细胞瘤的Sonic hedgehog亚组（SHH-MB）起源于小脑颗粒神经元祖细胞（CGNP）群体，该群体依赖SHH通路信号进行其围产期扩增。拷贝数变异（CNV）是一种基因组结构变异，可导致基因拷贝数异常，包括基因扩增、增益和缺失。它是调控蛋白编码基因和非编码基因表达的重要因素，影响多种信号通路。基于p53突变，WHO已将SHH-MB分为两种不同的预后类别。在此，我们解析SHH-MB肿瘤的基因组模式，并评估PI3K和HDAC抑制剂作为治疗选择的应用价值。我们利用来自巴西人群的SHH-MB肿瘤（经IRB批准），使用OncoScan CNV Plus-Assay和ChAS 4.2软件评估基因组异常。通过FISH确定等臂染色体17q [i(17q)]的存在。通过细胞增殖、迁移、细胞周期和耐药性等功能实验，评估靶向PI3K（Buparlisib；BKM-120）和HDAC（LBH-589）的小分子抑制剂对SHH-MB细胞（Daoy）的影响。结果显示：1. 约30%的患者表现出i(17q)，并在该基因的热点区存在多个p53突变；2. 其他常见的遗传异常包括IDH2:p.R140Q:c.419G>A（40%）；PTEN:p.P248fs*5:c.741_742insA（60%）；以及KRAS:p.Q61H:c.183A>C（60%）；3. 部分患者表现出9号染色体异常；4. 用BKM-120或LBH-589单药或联合治疗可抑制SHH-MB细胞的细胞增殖、迁移、细胞周期进入和肿瘤形成；5. SHH-MB细胞对BKM-120治疗表现出耐药性；6. Western blot分析显示，BKM-120抑制了Akt及mTOR下游靶点S6K的活化，表现为磷酸化水平降低。总之，我们在一个特定人群中观察到SHH-MB中离散的遗传改变。i(17q)的存在可能预示不良预后，而p53异常可能是疾病进展导致治疗耐药的一个关键标准。此外，小分子PI3K和HDAC抑制剂抑制了PI3K/AKT/mTOR通路，从而抑制细胞增殖、迁移和肿瘤形成。这些研究为SHH-MB的基因组异常及治疗选择提供了证据。
查看英文原文 English abstract
The Sonic hedgehog subgroup of medulloblastoma (SHH-MB) originates from the cerebellar granule neuron progenitor (CGNP) population that relies on SHH pathway signaling for its perinatal expansion. Copy number variation (CNV) is a genomic structural variation that causes abnormal gene copy numbers including gene amplifications, gains, and losses. It is a vital factor regulating the expression of both protein-coding and non-coding genes, affecting various signaling pathways. Based on p53 mutations, the WHO has classified SHH-MB into two distinct prognostic categories. Here, we decipher the genomic patterns of SHH-MB tumors and evaluate the use of PI3K and HDAC inhibitors as therapeutic options. We utilized SHH-MB tumors (IRB-approved) from the Brazilian population to evaluate the genomic abnormalities using OncoScan CNV Plus-Assay and ChAS 4.2 software. Presence of isochromosome 17q [i(17q)] was determined by FISH. Effects of small molecule inhibitors targeting PI3K (Buparlisib; BKM-120) and HDAC (LBH-589) in SHH-MB cells (Daoy), were assessed via functional assays, such as cell proliferation, migration, cell cycle, and drug resistance. Results demonstrated: 1. Approximately 30% of patients exhibited i(17q) with multiple p53 mutations in the hotspot zone of the gene; 2. Other frequent genetic aberrations in IDH2:p.R140Q:c.419G>A (40%); PTEN:p.P248fs*5:c.741_742insA (60%); and KRAS:p.Q61H:c.183A>C (60%); 3. Some patients display aberrant chromosome 9; 4. Treatments with BKM-120 or LBH-589 or combined treatments inhibited cell proliferation, migration, cell cycle entry, and tumor formation of SHH-MB cells; 5. SHH-MB cells displayed resistance to BKM-120 treatments; 6. Western blotting analysis revealed that BKM-120 suppressed the activation of Akt and downstream target of mTOR, S6K, as evident by reduced levels of phosphorylation. In conclusion, we observed discrete genetic alterations in SHH-MB in a specialized population. The presence of i(17q) may define a poor prognosis and aberrant p53 is possibly an essential criterion for disease progression leading to therapy resistance. Furthermore, small molecule PI3K and HDAC inhibitors suppressed PI3K/AKT/mTOR pathways inhibiting cell proliferation, migration, and tumor formation. These studies provide evidence of genomic anomalies as well as treatment options for SHH-MB.
利益披露 Disclosure
A. Carpenter, None..
M. Das, None..
R. Salles S Medeiros, None..
S. Epelman,, None..
N. Zanon, None..
C. D. Gandhi, None..
M. Jhanwar-Uniyal, None.