Kinases as therapeutic targets for cancer progression

描述（由申请人提供）：癌细胞获得促进生长、存活和传播的特性，包括细胞周期控制失调、对细胞死亡信号反应失败、引发血管生成和侵袭性。最具侵袭性的癌细胞具有浸润性：富含肌动蛋白的膜突起，控制细胞周蛋白水解。凹足与足小体有关，足小体在吞噬细胞、血管平滑肌和内皮细胞等迁移分化细胞中发育成熟。虽然癌细胞在组织培养塑料上生长不需要侵过体，但它们促进了三维胶原基质的生长。此外，内过足缺失与体内致瘤性和播散性降低有关。我们假设入侵性发育的关键调节因子尚未被发现。我们开始分离这些可能代表新的治疗靶点的调节因子。许多重要的肿瘤靶点都是激酶。事实上，一些激酶抑制剂已被批准为化疗药物，还有许多其他药物正在临床试验中。大多数选择是基于抑制细胞周期进程，细胞存活或血管生成。很少有研究关注调节侵袭性细胞行为的激酶。此外，关于人类基因组大多数成员的出版物很少，这表明这是一个尚未开发的目标识别资源。因此，我们将研究重点放在激酶上。我们建立了一种高含量的筛选方法，以高通量定量侵殖虫。我们在kinome特异性的siRNA文库中筛选了侵过性抑制剂，并确定了14个强命中。到目前为止，我们已经专注于其中的三个热门产品。在初步研究中，我们发现这两种基因都参与了侵过足的形成，并在人类癌细胞中过度表达。其他激酶正处于验证的早期阶段。因此，我们已经开发了一个具有侵袭性功能的激酶的优先列表，这些激酶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因子管道，我们假设其中一些激酶是新的治疗靶点。我们建议进一步评估我们的热门药物的治疗潜力，并将我们的验证工作扩展到其他正在开发的激酶。这项研究的总体意义在于为开发治疗播散性癌症的新治疗方法提供了难得的机会。近期的影响在于这项研究能够识别出具有新的作用机制的新分子靶点。

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.