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在很大程度上是由于转移的复杂性 转化过程和关键潜在机制的不完全理解。 与癌发生相关的途径正在不断增加，针对单基因活性的抗癌药物已经出现 临床上已达到并显示出原发性肿瘤生长抑制作用，但这些药物在有效治疗方面仍存在不足。 转移，导致患者长期生存不佳并加剧癌症复杂性的挑战。 长期以来根据肿瘤细胞形态变化对恶性程度进行分级的临床实践 和组织，其中高级癌症通常与患者预后不良相关，这表明癌症 特定的病理特征可以用作癌症组织恶性潜力的读数。 利用“自上而下”的方法，其中转移性特有的特定亚细胞特征结构 我们认为这种细胞亚结构应该被用作恶性肿瘤的替代标记。 比任何单个基因或基因产物都能更好地反映复杂且独特的恶性特性。 结构不仅提供了体外实验平台（细胞系）来研究重要的关键因素 用于癌症转移（以及随后的体内验证），也可作为抗癌的表型标记 为此，我们验证了核周室（PNC），即核体。 这种癌细胞恶性行为的标记。 PNC 在转移性肿瘤中非常普遍，并且 PNC 患病率与疾病呈正相关 PNC 患病率的降低与进展呈负相关。 作为高内涵筛选中转移的表型标记物，我们开发了 I 期临床候选药物 Metarrestin 是一种有效的 PNC 抑制剂，可抑制多种癌细胞系的体外侵袭， 阻断三种人类癌症小鼠模型的转移发展，并延长小鼠的生存期 转移性胰腺癌异种移植模型没有明显的副作用。 该提案描述了开发新的抗转移治疗药物的双管齐下的方法。 我们已确定 eEF1A2 作为 Metalrestin 的分子靶标，并将利用跨学科、互补的方法 利用与 eEF1A2 的相互作用来开发更有效的 PNC 流行抑制剂的方法 同时，我们将使用 PNC 患病率作为表型读数来询问。 其他结构独特的高通量筛选命中这些命中已经过 PNC 活性审查， 反筛选细胞毒性和 DNA 结合，并证实具有体外迁移和 两种互补的方法都利用了从入侵实验中获得的知识。 开发metarrestin并促进新的治疗药物和化学工具的开发 研究 eEF1A2 和 PNC 在转移中的作用。