Illuminating the functions and translational potential of CDC42BP/MRCK kinases in ovarian cancer

阐明 CDC42BP/MRCK 激酶在卵巢癌中的功能和翻译潜力

• 批准号: 10216717
• 负责人: LAURIE G HUDSON
• 金额: $ 15.15万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2022-10-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216717
• 关键词: Address; Adhesions; Animal Model; Animals; Binding Proteins; Biological Assay; Biological Process; CRISPR/Cas technology; Cancer Model; Cancer Patient; Cancer cell line; Carcinoma; Cell Adhesion; Cell Survival; Cell model; Clinical Research; Combined Modality Therapy; Coupled; Critical Pathways; Data; Detection; Development; Disease; Disseminated Malignant Neoplasm; Engraftment; Enzymes; Epithelial; Evaluation; Family member; Future; Gap Junctions; Genes; Genome; Glioblastoma; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Hereditary Disease; Hyperactivity; In Vitro; Individual; Injections; Knock-out; Knowledge; Lighting; Literature; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Mediator of activation protein; Mesenchymal; Metastatic Neoplasm to the Bone; Modeling; Motivation; Mus; Neoplasm Metastasis; Neurodevelopmental Disorder; Normal Cell; Omentum; Outcome; Ovarian; Ovary; Pathway interactions; Patients; Peritoneum; Pharmacology; Phenotype; Phosphotransferases; Physiological; Protein Inhibition; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Psoriasis; Rare Diseases; Renal carcinoma; Role; Serous; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Skin; Structure of thyroid parafollicular cell; Study models; Sum; System; Testing; Therapeutic; Tumor Burden; Update; adverse outcome; anticancer activity; base; biochemical model; cGMP-dependent protein kinase Ibeta; cell behavior; cell motility; clinical translation; comparative; drug discovery; drug repurposing; human disease; improved; in vivo; inhibitor/antagonist; interest; meetings; metastatic process; migration; neoplastic cell; neurodevelopment; novel; online resource; osteosarcoma; ovarian neoplasm; overexpression; prospective; protein function; rac1 GTP-Binding Protein; response; small molecule; therapeutic development; three dimensional cell culture; tumor

PROJECT SUMMARY This proposal will examine the function and targeting potential of three related serine threonine kinases in the context of serous ovarian cancer – a rare disease with need for improved therapies. The selected kinases are significant because they are direct effector proteins and selective mediators of Rac1 and Cdc42 (not Rho A) GTPase signaling pathways with import in ovarian cancer metastasis and poor outcomes, as well as in normal neurodevelopment and inherited disorders. A large fraction of the over 8000 kinases curated by Pharos are involved in human disease, yet are understudied (6850 Tdark or Tbio targets) and have no small molecules meeting the criteria for clinical translation (activity at ≤ 30 nM). Among these kinases, the Cdc42 binding protein A, B and G kinases (MRCK α, β and γ) remain unrealized as targets due to the dearth of knowledge regarding their specific functions in biological processes and disease states. Our team first demonstrated hyperactivity and overexpression of Rac1 and Cdc42 in ovarian cancer patients, and the utility of a repurposed drug dually targeting Rac1 and Cdc42. Because the GTPases serve as a nexus for integrating multiple signaling cascades, we hypothesize that the Cdc42 binding protein kinases mediate the downstream adverse consequences of aberrant Rac1/Cdc42 activity in ovarian cancer. Our goals are to comparatively delineate the functions of Cdc42 binding proteins A, B and G in the ovarian cancer metastatic process (Aim1) and evaluate the therapeutic potential of individual Cdc42 binding protein inhibition, alone and in combination with selective Rac1/Cdc42 inhibition (Aim 2). In keeping with the RFA the planned studies will 1) increase biochemical, cellular, and animal model evidence of disease/physiological relevance for the selected proteins, 2) elucidate the functions of the understudied proteins in models that will inform normal functions and disruptions leading to human disease and 3) provide critical information on the therapeutic potential of Tbio kinase targets. Our selection of Cdc42 binding proteins A, B and G is based on their roles as direct effector proteins for Rac1/Cdc42 signaling, evidence for moderate to high expression in the ovary and frequent detection in ovarian cancer. Furthermore, our findings show that selective targeting of Rac1/Cdc42 provides anti-cancer activities in patient-derived ovarian tumor cells and survival benefit in animal models thereby supporting the potential significance of one or more of the Cdc42 binding proteins in this disease. In sum, it is expected that illumination of Cdc42 binding protein functions will be relevant to dysregulation in ovarian and other cancers as well as to neurodevelopmental and non-cancerous diseases. Delineation of the non-redundant functions of each family member are highly relevant to drug discovery and therapeutic development.

项目概要 该提案将检查三种相关丝氨酸苏氨酸激酶的功能和靶向潜力 浆液性卵巢癌是一种罕见疾病，需要改进的治疗方法。所选激酶是 意义重大，因为它们是 Rac1 和 Cdc42（不是 Rho A）的直接效应蛋白和选择性介体 GTPase 信号通路在卵巢癌转移和不良预后以及正常情况中具有重要意义 神经发育和遗传性疾病。 Pharos 管理的 8000 多种激酶中，很大一部分是 与人类疾病有关，但尚未得到充分研究（6850 个 Tdark 或 Tbio 靶标）并且没有小分子 符合临床转化标准（活性≤30 nM）。在这些激酶中，Cdc42 结合 由于缺乏知识，蛋白 A、B 和 G 激酶（MRCK α、β 和 γ）仍未成为靶标 关于它们在生物过程和疾病状态中的特定功能。我们团队首先展示了 卵巢癌患者中 Rac1 和 Cdc42 的过度活跃和过度表达，以及重新利用的用途 双重靶向 Rac1 和 Cdc42 的药物。因为 GTPases 是整合多个 信号级联，我们假设 Cdc42 结合蛋白激酶介导下游不利 Rac1/Cdc42 活性异常对卵巢癌的影响。我们的目标是比较地描绘 Cdc42结合蛋白A、B和G在卵巢癌转移过程（Aim1）中的功能并评估 单个 Cdc42 结合蛋白抑制单独或与选择性结合的治疗潜力 Rac1/Cdc42 抑制（目标 2）。根据 RFA，计划的研究将 1) 增加生化、 所选蛋白质的疾病/生理相关性的细胞和动物模型证据，2) 阐明 模型中待研究蛋白质的功能将告知正常功能和导致的破坏 人类疾病；3) 提供有关 Tbio 激酶靶点治疗潜力的关键信息。我们的 Cdc42 结合蛋白 A、B 和 G 的选择是基于它们作为直接效应蛋白的作用 Rac1/Cdc42 信号传导，卵巢中中度至高表达以及卵巢中频繁检测的证据 癌症。此外，我们的研究结果表明，选择性靶向 Rac1/Cdc42 可在以下方面提供抗癌活性： 患者来源的卵巢肿瘤细胞和动物模型中的生存​​获益，从而支持了潜在的 一种或多种 Cdc42 结合蛋白在此疾病中的重要性。总而言之，预计照明 Cdc42 结合蛋白功能的变化与卵巢癌和其他癌症的失调以及 神经发育和非癌症疾病。划分各家族的非冗余功能 成员与药物发现和治疗开发高度相关。

项目成果

Agent-based modeling predicts RAC1 is critical for ovarian cancer metastasis.

• DOI: 10.1091/mbc.e21-11-0540
• 发表时间: 2022-12-01
• 期刊: MOLECULAR BIOLOGY OF THE CELL
• 影响因子: 3.3
• 作者: Rivera, Melanie;Toledo-Jacobo, Leslie;Romero, Elsa;Oprea, Tudor, I;Moses, Melanie E.;Hudson, Laurie G.;Wandinger-Ness, Angela;Grimes, Martha M.
• 通讯作者: Grimes, Martha M.