Kinases as therapeutic targets for cancer progression

激酶作为癌症进展的治疗靶点

• 批准号: 8403646
• 负责人: SARA A COURTNEIDGE
• 金额: $ 38.03万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403646
• 关键词: 3-Dimensional; Actins; Adjuvant; Anchorage-Independent Growth; Behavior; Biological Assay; Blood Vessels; Cancer Cell Growth; Cancer cell line; Cell Cycle Progression; Cell Cycle Regulation; Cell Death Signaling Process; Cell Survival; Cells; Characteristics; Chemotherapy-Oncologic Procedure; Collagen; Disseminated Malignant Neoplasm; Endothelial Cells; Failure; Future; Growth; HK2 gene; Human; Intravenous; Libraries; Malignant Neoplasms; Mediating; Membrane; Molecular Profiling; Molecular Target; Morbidity - disease rate; Neoplasm Metastasis; PAK6 gene; Phagocytes; Phosphotransferases; Plastics; Play; Primary Neoplasm; Proteolysis; Public Health; Publications; Research; Resources; Role; Small Interfering RNA; Smooth Muscle Myocytes; Staging; Testing; Therapeutic; Tissues; Tumorigenicity; Validation; angiogenesis; base; cancer cell; cancer therapy; cell behavior; chemotherapeutic agent; follow-up; implantation; in vivo; inhibitor/antagonist; kinase inhibitor; member; mortality; new therapeutic target; novel; novel therapeutic intervention; oncology; overexpression; public health relevance; research clinical testing; research study; screening; small molecule; standard of care; subcutaneous; therapeutic target; tissue culture; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Cancer cells acquire characteristics that promote growth, survival and dissemination, including dysregulation of cell cycle control, failure to respond to cell death signals, elicitation of angiogenesis and invasiveness. The most invasive cancer cells have invadopodia: actin-rich membrane protrusions that control pericellular proteolysis. Invadopodia are related to podosomes, which are elaborated in migratory differentiated cells such as phagocytes, vascular smooth muscle and endothelial cells. Although invadopodia are not required for cancer cell growth on tissue culture plastic, they facilitate growth in 3-dimensional collagen matrices. Furthermore, loss of invadopodia correlates with decreased tumorigenicity and dissemination in vivo. We hypothesized that key regulators of invadopodia were yet to be discovered. We set out to isolate these regulators, which may represent novel therapeutic targets. Many important oncology targets are kinases. Indeed, several kinase inhibitors are approved chemotherapeutic agents, and many others are in clinical testing. Most were selected on the basis of inhibition of cell cycle progression, cell survival or angiogenesis. Few studies have focused on kinases that regulate invasive cell behavior. Furthermore, there are few publications on most members of the human kinome, suggesting that this is an untapped resource for target identification. We therefore focused our search on kinases. We established a high content screening assay to quantify invadopodia in high throughput. We screened for invadopodia inhibitors in an siRNA library specific for the kinome, and identified 14 strong hits. To date we have focused on three of these hits. In preliminary studies we found that each is involved in invadopodia formation, and overexpressed in human cancer cells. Other kinases are at an earlier stage of validation. Thus we have developed a prioritized list of kinases with invadopodia functions, which may play roles in human tumor growth and progression. Our high content screening assay has provided us with a rich pipeline of kinase regulators, and we hypothesize that some of these kinases are novel therapeutic targets. We propose to further evaluate the therapeutic potential of our top hits, as well as extend our validation efforts to other kinases in the pipeline. The overarching significance of this research is the extraordinary opportunity to develop new therapeutic approaches to the treatment of disseminated cancers. The near term impact lies in the ability of this research to identify new molecular targets with novel mechanisms of action.

描述(申请人提供)：癌细胞获得了促进生长、存活和扩散的特征，包括细胞周期控制的失调，对细胞死亡信号的不反应，诱导血管生成和侵袭。最具侵袭性的癌细胞有侵袭足：富含肌动蛋白的膜突起，控制细胞周围的蛋白分解。卷足虫与足体有关，足体在吞噬细胞、血管平滑肌和血管内皮细胞等迁移分化细胞中表达。虽然组织培养塑料上的癌细胞生长并不需要使用无脚架，但它们可以促进三维胶原基质的生长。此外，侵袭性的丧失与体内肿瘤的成瘤性和播散性的降低有关。我们假设，还没有发现内陷的关键调控因子。我们开始分离这些调节子，它们可能代表新的治疗靶点。许多重要的肿瘤学靶点都是激酶。事实上，有几种激酶抑制剂是被批准的化疗药物，还有许多其他药物正在进行临床测试。大多数是根据抑制细胞周期进程、细胞存活或血管生成来选择的。很少有研究关注调节侵袭细胞行为的激酶。此外，关于人类亲属组大多数成员的出版物很少，这表明这是一种尚未开发的目标识别资源。因此，我们把研究重点放在了蛋白激酶上。我们建立了一种高含量的筛选方法来高通量地定量检测内侧足纲。我们在针对动态组的siRNA文库中筛选出了不定形抑制物，并鉴定出14种强烈的匹配。到目前为止，我们已经专注于其中的三个热门话题。在初步研究中，我们发现每一种基因都参与了内向足类的形成，并在人类癌细胞中过表达。其他的激酶还处于早期验证阶段。因此，我们开发了一份具有不同功能的激酶的优先列表，它们可能在人类肿瘤的生长和进展中发挥作用。我们的高含量筛选试验为我们提供了丰富的激酶调节剂管道，我们假设其中一些是新的治疗靶点。我们建议进一步评估我们的热门药物的治疗潜力，并将我们的验证努力扩展到其他正在筹备中的激酶。这项研究最重要的意义是有机会开发新的治疗方法来治疗播散性癌症。近期的影响在于这项研究有能力用新的作用机制识别新的分子靶标。