Optimization and Characterization of "MYC Degraders" for Pediatric Medulloblastoma

小儿髓母细胞瘤“MYC 降解剂”的优化和表征

基本信息

批准号：
10612251
负责人：
Michael Jackson
金额：
$ 48.75万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
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：
2020-05-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10612251
关键词：
Affect Antineoplastic Agents Bioinformatics Biological Assay Biological Markers Bromodomain Cell Survival Cells Chemicals Chemotherapy and/or radiation Child Childhood Childhood Brain Neoplasm Childhood Medulloblastomas Collection Data Development Diagnosis Disease Exhibits Frequencies Gene Expression Genetic Markers Genetic Transcription Genomics Goals Hour Human Incidence Induced pluripotent stem cell derived neurons Lead Libraries MYC Family Protein MYC gene Malignant Neoplasms Malignant neoplasm of cerebellum Metabolic Molecular Profiling Monitor Mus Mutation Oncoproteins Operative Surgical Procedures Patient-Focused Outcomes Patients Permeability Pharmaceutical Chemistry Phase Phenotype Property Protein phosphatase Radiation Recurrence Route SHH gene Sampling Series Solubility Structure-Activity Relationship Subgroup Survival Rate Survivors Testing Therapeutic Therapeutic Agents Time Toxic effect analog aurora kinase A biomarker signature blood-brain barrier penetration c-myc Genes chemotherapy design drug discovery druggable target effective therapy experimental study immunohistochemical markers improved in vivo in vivo evaluation inhibitor lead optimization medulloblastoma molecular marker mouse model novel novel therapeutics overexpression patient derived xenograft model pharmacokinetics and pharmacodynamics pre-clinical protein activation scaffold scale up side effect small molecule targeted treatment therapeutically effective treatment group tumor tumor growth

项目摘要

PROJECT SUMMARY Medulloblastoma (MB) is a highly malignant tumor of the cerebellum that occurs most frequently in children. Despite advances in treatment – including surgery, radiation, and chemotherapy – approximately one-third of MB patients still die from the disease and survivors suffer severe side effects as a result of treatment. Genomic profiling and bioinformatic analyses of patient samples have identified four subgroups of MB – WNT, Sonic hedgehog (SHH), Group 3 (MYC-driven) and Group 4. These subgroups differ in terms of mutations, gene expression profiles and patient outcomes, and patients can be stratified using relevant genetic and immunohistochemical markers. Approximately one-quarter of MBs are Group 3 (G3) tumors, which exhibit overexpression or amplification of the c-Myc (MYC) oncogene. Patients with G3 MB are more likely to present with metastatic disease at time of diagnosis, have a higher incidence of recurrence and the poorest survival rate. Thus, more effective therapies for G3 MB are critically needed. To identify MYC inhibitors that would be effective in G3 MB, we developed a phenotypic, target-agnostic assay using disease-relevant cells isolated from G3 MB orthotopic patient-derived xenografts (PDXs). The assay was designed to identify small molecules that reduce endogenous MYC levels – the signature molecular marker of G3 MB – in 4 hours, to preferentially modulate targets directly affecting MYC stability and avoid indirect or off- target effects at later time points. We applied this assay to screen a 100,000 compound collection and identified small molecule scaffolds that robustly decrease cellular MYC levels. Hits were validated in a rigorous testing funnel designed to avoid undesired mechanisms of action, and initial SAR was explored for several scaffolds. From these studies the most promising series was prioritized with activities in the 100 nM potency range as well as compound properties indicative of good BBB penetration. We further confirmed that the compounds in this series decrease cell viability after 48 hours exposure and that this effect correlates with potency in the MYC assay. Preliminary data for the most active compound of this series, SBI1242, indicate that this decrease in cell viability of G3 MB patient cells is selective over iPSC-derived neurons, suggesting a possible therapeutic window. The goal of this proposal is to further optimize SBI1242 for preclinical in vivo testing and use the best analog to test our hypothesis that inhibitors of the G3 MB signature biomarker MYC identified in a highly disease-relevant context can safely and effectively arrest or reverse tumor growth in our G3 MB-specific orthotopic PDX mouse model. We anticipate that successful completion of these studies will be a significant step towards our long-term goal of identifying novel, safe, and effective treatments for MB and other MYC-driven cancers.

项目概要髓母细胞瘤（MB）是一种高度恶性的小脑肿瘤，最常见于儿童。尽管治疗方法取得了进展——包括手术、放疗和化疗——但仍有大约三分之一的患者 MB 患者仍然死于该疾病，而幸存者则因治疗而遭受严重的副作用。对患者样本的分析和生物信息学分析确定了 MB 的四个亚组——WNT、Sonic 刺猬 (SHH)、第 3 组（MYC 驱动）和第 4 组。这些亚组在突变、基因方面有所不同表达谱和患者结果，并且可以使用相关的遗传和患者对患者进行分层免疫组织化学标记物。大约四分之一的 MB 是第 3 组 (G3) 肿瘤，其表现出 c-Myc (MYC) 癌基因过度表达或扩增更有可能出现 G3 MB。诊断时患有转移性疾病，复发率较高，生存率最差。因此，迫切需要更有效的 G3 MB 疗法。为了鉴定对 G3 MB 有效的 MYC 抑制剂，我们开发了一种表型、靶点不可知的检测方法使用从 G3 MB 原位患者来源的异种移植物 (PDX) 中分离出的疾病相关细胞进行测定。旨在识别降低内源性 MYC 水平的小分子 - MYC 的标志性分子标记 G3 MB – 在 4 小时内，优先调节直接影响 MYC 稳定性的靶标，避免间接或偏离我们应用此测定法筛选了 100,000 个化合物集合并进行了鉴定。能够显着降低细胞 MYC 水平的小分子支架已在严格的测试中得到验证。漏斗旨在避免不良的作用机制，并针对几种支架探索了初始 SAR。从这些研究中，最有希望的系列优先考虑 100 nM 效力范围内的活性作为化合物特性，我们进一步证实了该化合物具有良好的 BBB 渗透性。系列暴露 48 小时后细胞活力下降，这种效应与 MYC 的效力相关该系列中最活跃的化合物 SBI1242 的初步数据表明细胞数量减少。 G3 MB 患者细胞的活力比 iPSC 衍生的神经元具有选择性，这表明可能的治疗窗口。该提案的目标是进一步优化 SBI1242 进行临床前体内测试，并使用最佳类似物检验我们的假设，即在与疾病高度相关的细胞中鉴定出 G3 MB 特征生物标志物 MYC 的抑制剂 context 可以安全有效地阻止或逆转我们的 G3 MB 特异性原位 PDX 小鼠的肿瘤生长我们预计这些研究的成功完成将是我们朝着长期目标迈出的重要一步。目标是确定针对 MB 和其他 MYC 驱动的癌症的新颖、安全且有效的治疗方法。