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

基本信息

批准号：
10470279
负责人：
Mark Gerelus
金额：
$ 3.41万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10470279
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 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

项目摘要

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.

项目摘要：神经母细胞瘤（NB），主要是神经rest细胞起源的儿科癌，是一种由于基因组和肿瘤内异质性，临床上具有挑战性的疾病。有三个风险表征疾病的分层 - 低风险，中等风险和高风险 - 基于几个突变负担和诊断年龄等因素。高危NB患者的预后较差，5- 尽管有剂量密集的化学adio疗疗法治疗，但年生存率约为50％。少数常见高风险NB中的基因组畸变包括在40％的病例中扩增MYCN癌基因在受体酪氨酸激酶（RTK）中性淋巴瘤激酶（ALK）中，诸如ALK基因等病例中有14％ F1174，F1245和R1275残基的扩增和三个热点突变，赋予配体 - 独立的激酶活性和编码SHP2蛋白的PTPN11基因中的突变，3.4％案例。高风险NB治疗的唯一有针对性的治疗是ALK抑制，尽管事实是第三一代ALK抑制剂Lorlatinib比上一代ALK抑制剂更有效和优越，复发在劳拉替尼的患者中发生。因此，发现新的目标疗法和剂量时间表以克服诊所所遇到的挑战至关重要。一种新型的治疗药物靶标，SRC同源2含酪氨酸磷酸酶（SHP2）是一种非受体蛋白质酪氨酸磷酸酶与几种疾病状态有关，包括Noonan综合征，豹子综合征和各种癌症。 SHP2在RAS/MAPK信号的完整激活中起着至关重要的作用级联以及从几个RTK到下游途径的信号转导。针对的研究了解SHP2的作用在很大程度上集中在信号上的催化功能上转导。我假设SHP2是ALK驱动的高风险NB的可拖动治疗脆弱性。最近，已经发现了一种靶向SHP2 SHP099的变构小分子抑制剂。而我们的初步数据表明，通过SHP099抑制SHP2催化活性不足以防止NB肿瘤细胞可行性，最近的研究表明，SHP2抑制作用显示了转化的前景，并结合其他目标诸如ALK抑制剂之类的疗法。必须定义在 NB由于PTPN11中的突变。因此，我将表征PTPN11中的突变并研究 SHP2在高危NB中的磷酸酶独立的作用。这些研究将阐明这种被忽视的潜力 SHP2的作用，并允许针对SHP2的更合理的药物开发导致临床影响力治疗选项。除了定义SHP2的功能作用外，我还将研究劳拉替尼和 SHP099确定组合处理后ALK驱动的高危NB的抗肿瘤活性和存活率。这些研究将提供证据证据，患者人群将从这种组合中受益于未来临床试验设计和转换为诊所。