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.

项目摘要 该建议将研究三种相关的丝氨酸/苏氨酸激酶的功能和靶向潜力， 浆液性卵巢癌-一种需要改进治疗的罕见疾病。选择的激酶是 因为它们是Rac 1和Cdc 42（而不是Rho A）的直接效应蛋白和选择性介质， GT3信号通路在卵巢癌转移和不良结局中的作用，以及在正常卵巢癌中的作用 神经发育和遗传性疾病。在Pharos管理的8000多种激酶中， 涉及人类疾病，但研究不足（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，Cdc 42结合 由于缺乏知识，蛋白A、B和G激酶（MRCK α、β和γ）仍未被认识为靶点 关于它们在生物过程和疾病状态中的特定功能。我们的团队首先展示了 卵巢癌患者中Rac 1和Cdc 42的过度活跃和过度表达，以及重新设计的 双靶向Rac 1和Cdc 42的药物。由于GTP酶是整合多种 信号级联，我们假设Cdc 42结合蛋白激酶介导下游不利的信号通路。 卵巢癌中Rac 1/Cdc 42活性异常的后果。我们的目标是比较性地描述 Cdc 42结合蛋白A、B和G在卵巢癌转移过程中的作用（Aim 1），并评估 单个Cdc 42结合蛋白抑制剂单独和与选择性Cdc 42结合蛋白抑制剂组合的治疗潜力 Rac 1/Cdc 42抑制（目的2）。为与RFA保持一致，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 模型中未充分研究的蛋白质的功能，将告知正常功能和中断， 人类疾病和3）提供关于Tbio激酶靶标的治疗潜力的关键信息。我们 Cdc 42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， Rac 1/Cdc 42信号传导，在卵巢中中度至高度表达的证据，以及在卵巢癌中频繁检测到的证据。 癌此外，我们的研究结果表明，Rac 1/Cdc 42的选择性靶向提供抗癌活性， 患者来源的卵巢肿瘤细胞和动物模型中的生存益处，从而支持 一种或多种Cdc 42结合蛋白在这种疾病中的意义。总而言之，预计照明 Cdc 42结合蛋白的功能与卵巢癌和其他癌症的失调有关， 神经发育和非癌症疾病。每个族的非冗余函数的描述 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.