Elucidating the therapeutic tractability and functional role of SHP2 in ALK-driven high-risk neuroblastoma

阐明 SHP2 在 ALK 驱动的高危神经母细胞瘤中的治疗易处理性和功能作用

• 批准号: 10251917
• 负责人: Mark Gerelus
• 金额: $ 3.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251917
• 关键词: ALK gene; Age; Antitumor Response; Biological; CRISPR/Cas technology; Cell Death; Cell Line; Cell Survival; Cell model; Cells; Childhood; Clinic; Clinical; Clinical Trials Design; Combined Modality Therapy; Cytoplasm; Data; Diagnosis; Disease; Dose; Drug Targeting; Future; Gene Amplification; Gene Expression; Generations; Genetic Transcription; Genomics; Goals; Growth; Hot Spot; In Vitro; Knock-in; LEOPARD Syndrome; Ligands; Light; MAP Kinase Gene; MAPK3 gene; MYCN gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Minor; Modeling; Mutate; Mutation; Neural Crest Cell; Neuroblastoma; Non-Small-Cell Lung Carcinoma; Noonan Syndrome; Nuclear; Oncogenes; Oncogenic; Outcome; PTPN11 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Population; Prognosis; Protein Tyrosine Phosphatase; Proteins; Publishing; Receptor Protein-Tyrosine Kinases; Relapse; Research; Resistance; Risk; Role; Schedule; Series; Signal Transduction; Survival Rate; Testing; Therapeutic; Time; Transcriptional Regulation; Translating; Translations; anaplastic lymphoma kinase; base; clinical effect; clinically relevant; combat; crizotinib; drug development; early phase clinical trial; experimental study; genomic aberrations; high risk; improved; in vitro Model; inhibitor/antagonist; insight; kinase inhibitor; mutant; neoplastic cell; neuroblastoma cell; new therapeutic target; next generation; novel; novel therapeutics; patient derived xenograft model; patient population; pre-clinical; prevent; protein expression; protein protein interaction; resistance mechanism; response; risk stratification; small hairpin RNA; small molecule inhibitor; targeted treatment; therapeutic target; tumor; tumor heterogeneity

PROJECT SUMMARY: Neuroblastoma (NB), a predominantly pediatric cancer of neural crest cell origin, is a clinically challenging disease due to the genomic and intratumoral heterogeneity. There are three risk stratifications to characterize the disease - low-risk, intermediate-risk, and high-risk - which are based on several factors such as mutation burden and age at diagnosis. High-risk NB patients have a poor prognosis, with a 5- year survival rate of roughly 50% despite dose-intensive chemoradioimmunotherapy treatment. The few common genomic aberrations in high-risk NB include amplification of the MYCN oncogene in 40% of cases, aberrations in the receptor tyrosine kinase (RTK) Anaplastic Lymphoma Kinase (ALK) in 14% of cases such as ALK gene amplification and three hot spot mutations at the F1174, F1245, and R1275 residues conferring ligand- independent kinase activity, and mutations in the PTPN11 gene, which encodes the SHP2 protein, in 3.4% of cases. The only targeted therapy for high-risk NB treatment is ALK inhibition, and despite the fact that the third generation ALK inhibitor lorlatinib is more potent and superior than previous generation ALK inhibitors, relapse in patients on lorlatinib occurs. Thus, the discovery of new targeted therapies and dosing schedules to overcome the challenges endured in the clinic is paramount. A novel therapeutic drug target, the Src homology 2-containing tyrosine phosphatase (SHP2), is a non-receptor protein tyrosine phosphatase implicated in several disease states including Noonan Syndrome, LEOPARD Syndrome, and a variety of cancers. SHP2 plays a critical role in the full activation of the RAS/MAPK signaling cascade, as well as signal transduction from several RTKs to downstream pathways. Research aimed at understanding the role of SHP2 has largely been focused on the catalytic function with respect to signal transduction. I hypothesize that SHP2 is a tractable therapeutic vulnerability in ALK-driven high-risk NB. Recently, an allosteric small molecule inhibitor which targets SHP2, SHP099, has been discovered. While our preliminary data show that inhibiting SHP2 catalytic activity via SHP099 is not sufficient to prevent NB tumor cell viability, recent studies reveal that SHP2 inhibition shows translational promise in combination with other targeted therapies such as ALK inhibitors. It is imperative to define the functional effect of the SHP2 mutants observed in NB due to the mutations in PTPN11. Therefore, I will characterize the mutations in PTPN11 and investigate the phosphatase-independent role of SHP2 in high-risk NB. These studies will shed light on this overlooked potential role of SHP2 and allow for more rational drug development targeting SHP2 to result in a clinically impactful treatment option. In addition to defining the functional role of SHP2, I will study the combination of lorlatinib and SHP099 to determine anti-tumor activity and survival of ALK-driven high-risk NB upon combination treatment. These studies will provide evidence for which patient populations would benefit from this combination for future clinical trial design and translation to the clinic.

项目总结：神经母细胞瘤（NB）是一种主要起源于神经嵴细胞的儿科癌症， 由于基因组和肿瘤内异质性，临床上具有挑战性的疾病。有三个风险 分层来表征疾病-低风险，中等风险和高风险-这是基于几个 突变负荷和诊断时的年龄等因素。高风险NB患者预后不良，5- 年生存率约为50%，尽管剂量密集的化学放射免疫治疗。少数常见的 高危NB的基因组畸变包括40%病例中MYCN癌基因扩增， 在受体酪氨酸激酶（RTK）、间变性淋巴瘤激酶（ALK）等ALK基因的病例中占14% 扩增和在F1174、F1245和R1275残基处的三个热点突变，赋予配体- 独立的激酶活性，以及编码SHP 2蛋白的PTPN 11基因突变，在3.4%的 例高危NB治疗的唯一靶向治疗是ALK抑制，尽管第三种治疗方法 第二代ALK抑制剂劳拉替尼比上一代ALK抑制剂更有效和上级，复发 发生于服用劳拉替尼的患者。因此，发现新的靶向治疗和给药方案，以克服 在临床上所经受的挑战是至关重要的。 一种新的治疗药物靶点，含Src同源2的酪氨酸磷酸酶（SHP 2），是一种非受体 蛋白质酪氨酸磷酸酶与努南综合征、LEOPARD等多种疾病状态有关 综合征，以及各种癌症。SHP 2在RAS/MAPK信号通路的完全激活中起关键作用 级联，以及从几个RTK到下游途径的信号转导。研究旨在 对SHP 2作用的理解主要集中在信号传导的催化功能上， 转导我假设SHP 2是ALK驱动的高风险NB中的易处理的治疗漏洞。 近年来，人们发现了一种靶向SHP 2的变构小分子抑制剂SHP 099。虽然我们的 初步数据显示，通过SHP 099抑制SHP 2催化活性不足以防止NB肿瘤细胞 最近的研究表明，SHP 2抑制显示出与其他靶向药物组合的翻译前景。 如ALK抑制剂。必须确定在细胞中观察到的SHP 2突变体的功能效应。 NB是由于PTPN 11中的突变。因此，我将描述PTPN 11中的突变，并研究PTPN 11中的突变。 SHP 2在高危NB中的磷酸酶非依赖性作用这些研究将揭示这种被忽视的潜力 SHP 2的作用，并允许更合理的药物开发靶向SHP 2，以产生临床上有影响的 治疗选择除了定义SHP 2的功能作用外，我还将研究劳拉替尼和 SHP 099，以确定联合治疗后ALK驱动的高风险NB的抗肿瘤活性和生存期。 这些研究将为将来哪些患者人群将从这种联合治疗中获益提供证据 临床试验设计和翻译到临床。