Phenotypic marker-guided development of selective antimetastasis therapeutic leads

表型标记引导选择性抗转移治疗先导药物的开发

• 批准号: 10420845
• 负责人: Kevin J. Frankowski
• 金额: $ 65.78万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420845
• 关键词: Address; Adverse effects; Animals; Antineoplastic Agents; Behavior; Binding; Biological Availability; Cancer cell line; Cause of Death; Cell Line; Cells; Cessation of life; Characteristics; Chemicals; Clinic; Complex; Cytology; DNA Binding; Development; Disease; Disease Progression; Disseminated Malignant Neoplasm; Drug Kinetics; Evaluation; Event; Exhibits; Genes; Goals; Growth; In Vitro; Knowledge; Libraries; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Metastatic to; Modeling; Molecular Target; Morphology; Mus; Nature; Neoplasm Metastasis; Normal Cell; Nuclear; Nude Mice; Oncogenic; Oral; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Phase I Clinical Trials; Phenotype; Prevalence; Primary Neoplasm; Process; Property; Proteins; Reducing Agents; Ribosomes; Role; Structure; Surrogate Markers; Therapeutic; Tissues; Toxic effect; Tumor Tissue; United States National Institutes of Health; Validation; Xenograft Model; Xenograft procedure; analog; anti-cancer; base; cancer biomarkers; cancer cell; cancer clinical trial; cancer survival; carcinogenesis; clinical candidate; clinical practice; cytotoxicity; drug development; drug discovery; effective therapy; experimental study; falls; gene product; high throughput screening; human cancer mouse model; improved; in vitro Assay; in vivo; inhibitor; malignant breast neoplasm; migration; neoplastic cell; next generation; novel; novel therapeutics; pancreas xenograft; phenotypic biomarker; pre-clinical; prognostic; prostate cancer model; scaffold; screening; small molecule; targeted agent; tool; tumor; tumor growth

The lack of effective treatment against cancer metastasis is in large part due to the complexity of the metastatic transformation process and incomplete understanding of the key underlying mechanisms. The list of genes and pathways associated with carcinogenesis is growing and anti-cancer agents targeting single gene activities have reached clinics and shown primary tumor growth inhibition. However, these agents fall short in effectively treating metastasis, leading to poor long-term patient survival and reinforcing the challenge of cancer complexity. It has long been a clinical practice to grade the levels of malignancy based on morphological changes of tumor cells and tissues, where a high-grade cancer generally correlates with poor patient outcomes, suggesting cancer specific pathognomonic features can be used as readouts for the malignant potential of cancer tissues. Here we utilize a “top-down” approach, in which specific subcellular pathognomonic structures unique to metastatic potential are used as surrogate markers for malignancy. We reason that such cellular substructures should reflect the complex and unique malignant properties better than any single gene or gene product. These structures not only provide an in vitro experimental platform (cell lines) to investigate the key factors important for cancer metastasis (and subsequent in vivo validations), but also serve as a phenotypic marker for anti-cancer drug development. To this end, we have validated the perinucleolar compartment (PNC), a nuclear body, as such a marker for cancer cell malignant behavior. PNCs are highly prevalent in metastatic tumors and PNC prevalence positively correlates with disease progression and inversely correlates with patient outcomes in several cancers. Using PNC prevalence reduction as a phenotypic marker for metastasis in a high-content screen, we developed the phase I clinical candidate metarrestin, a potent PNC inhibitor for a large array of cancer cell lines. Metarrestin inhibits invasion in vitro, blocks metastatic development in three mouse models of human cancers, and extends survival of mice in a metastatic pancreatic cancer xenograft model without discernable adverse effects. This proposal describes a two-pronged approach for the development new anti-metastasis therapeutic leads. We have identified eEF1A2 as a molecular target for metarrestin and will use inter-disciplinary, complementary approaches to leverage interactions with eEF1A2 to develop more potent PNC prevalence inhibitors as next generation therapeutic leads. In parallel, we will use PNC prevalence as a phenotypic readout to interrogate additional structurally distinct high-throughput screening hits. These hits have been vetted for PNC activity, counterscreened for cytoxicity and DNA binding, and confirmed to possess efficacy in in vitro migration and invasion experiments. Both complementary approaches capitalize on the knowledge gained from the development of metarrestin and facilitate the development of new therapeutic leads and chemical tools for investigating the role of eEF1A2 and PNCs in metastasis.

缺乏针对癌症转移的有效治疗很大程度上是由于转移的复杂性 转换过程和对关键基础机制的不完全理解。基因和 与癌变相关的途径正在增长，靶向单基因活性的抗癌药具有 到达诊所并显示了原发性肿瘤生长抑制作用。但是，这些代理在有效治疗时缺乏 转移，导致长期患者生存不足并加强癌症复杂性的挑战。它有 长期以来一直是基于肿瘤细胞形态变化的恶性肿瘤水平的临床实践 和组织，高度癌症通常与患者的结局不佳相关，表明癌症 特定的病理特征可以用作癌症组织恶性潜力的读数。我们在这里 利用一种“自上而下”的方法，其中特定的亚细胞病理性结构是转移性的独特 潜力用作恶性肿瘤的替代标记。我们认为这种细胞子结构应 比任何单个基因或基因产物更好地反映复杂而独特的恶性特性。这些 结构不仅提供了体外实验平台（细胞系）来研究重要因素 用于癌症转移（随后的体内验证），但也可以作为抗癌的表型标记 药物开发。为此，我们已经验证了核体的核能室（PNC），作为 这种标记是癌细胞恶性行为。 PNC在转移性肿瘤中高度普遍，PNC患病率与疾病正相关 进展和成反比与几种癌症的患者结局相关。使用PNC患病率降低 作为在高含量屏幕中转移的表型标记，我们开发了I期临床候选者 Metarrestin，一种潜在的PNC抑制剂，用于大量癌细胞系。 Metarrestin抑制体外入侵， 阻断三种人类癌症小鼠模型中的转移性发展，并扩展了小鼠在A中的存活率 转移性胰腺癌特征模型没有明显的不良反应。 该提案描述了开发新的抗晶状体治疗铅的两管齐下的方法。 我们已经将EEF1A2确定为Metarrestin的分子靶标，并将使用跨学科的完整性 利用与EEF1A2相互作用以开发更多潜在的PNC患病率抑制剂的方法 一代理论领导。同时，我们将使用PNC患病率作为表型读数来询问 其他结构上不同的高通量筛选命中。这些热门人已被审查以进行PNC活动， 针对细胞毒性和DNA结合而进行了筛选，并确认在体外迁移和 入侵实验。两种完整的方法都利用了从 开发Metarrestin并支持开发新的治疗铅和化学工具 研究EEF1A2和PNC在转移中的作用。