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: 10650784
• 负责人: Kevin J. Frankowski
• 金额: $ 62.95万
• 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/10650784
• 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; Invaded; Knowledge; Libraries; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Measures; Metastasis Induction; Metastatic Neoplasm to the Lung; Metastatic breast cancer; 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; Productivity; 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; cancer biomarkers; cancer cell; cancer clinical trial; cancer survival; carcinogenesis; clinical candidate; clinical practice; counterscreen; 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; 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.

癌症转移缺乏有效的治疗在很大程度上是由于转移的复杂性