Combating Breast Cancer Brain Metastasis by Blocking the Two-Pronged Driver Kinase Function of CDK5

在每年被诊断患有乳腺癌的160万女性中，10-16%发生脑转移 一年存活率低于20%的人目前，没有有效的药物治疗存在的患者， 乳腺癌脑转移因此，这一人群迫切需要有效的治疗方法。 不幸的是，开发脑转移的有效疗法在很大程度上受到缺乏深入研究的阻碍。 了解脑转移的生物学机制，这可以指导药物开发， 临床试验为了克服这一挑战，我们进行了体内人类激酶组筛选， 促进小鼠乳腺癌脑转移的新型激酶。激酶位于癌症的中心节点 细胞信号传导网络对癌症进展和转移至关重要，并可作为药物治疗 目标的其中，细胞周期蛋白依赖性激酶5（CDK 5）是最高“命中”，具有>26倍富集。CDK5，a 非典型CDK可增加细胞增殖、迁移和血管生成。CDK 5过表达（+） 与高级别乳腺癌和患者生存率降低显著相关，但其在脑中的功能 转移被忽视。因此，我们进一步检查了CDK 5在脑转移中的功能，发现 CDK 5+细胞a）在小鼠中赋予增加的脑转移和降低的存活; B）可以适应，并且 在模拟脑中环境的低葡萄糖和缺氧培养条件下增殖; c）诱导 通过下调MHC I类（MHC-I）来抑制免疫抑制。相反，小鼠脑转移瘤 CDK 5敲除的肿瘤细胞具有延长的存活。有吸引力的是，CDK 5很容易与临床靶向- 适用的血脑屏障穿透抑制剂。在这里，我们假设CDK 5激活促进了 乳腺癌脑转移通过促进脑中的癌细胞适应/生长以及 免疫抑制; CDK 5抑制剂可能被开发为乳腺癌脑的新疗法 转移本提案的主要目标是：1）确定脑转移促进功能， CDK 5在自发性脑转移模型和免疫活性小鼠模型中的作用，并检查其在脑转移模型中的作用。 患者标本中的临床相关性; 2）通过以下方法探索CDK 5增强脑转移的新机制： 检查癌细胞中CDK 5+对以下两者的影响： 脑和B）诱导免疫抑制; 3）评估靶向CDK 5用于早期干预的潜力 和治疗脑转移以延长小鼠存活。这些研究的成功完成将 带来对乳腺癌脑转移的新认识和第一代有效脑 转移靶向治疗。最终，我们的研究结果将转化为临床试验，从而产生新的， 更好地治疗患有脑转移的乳腺癌患者。

Among the 1.6 million women diagnosed with breast cancer every year, 10-16% develop brain metastases who have a devastating <20% one-year survival. At present, no effective drug treatment exists for patients with breast cancer brain metastasis. Therefore, effective therapies are urgently needed for this population. Unfortunately, developing effective therapies for brain metastasis is largely hampered by a lack of in-depth understanding of the biological mechanisms of brain metastasis, which could guide drug development and clinical trials. To surmount this challenge, we have performed an in vivo human kinome screen to uncover novel kinases that promote breast cancer brain metastasis in mice. Kinases are at the central nodes of cancer cell signaling networks critical for cancer progression and metastasis, and can serve as druggable therapeutic targets. Among them, cyclin-dependent kinase 5 (CDK5) was a top “hit”, with >26-fold enrichment. CDK5, a non-canonical CDK, can increase cell proliferation, migration, and angiogenesis. CDK5 overexpression (+++) significantly correlated with high grade breast cancer and lower survival in patients, but its function in brain metastasis was overlooked. Thus, we further examined CDK5 function in brain metastasis and found that CDK5+++ cells a) confer increased brain metastasis and decreased survival in mice; b) can adapt to, and proliferate in, low glucose and hypoxic culture condition that mimics the environment in the brain; c) induce immunosuppression by down-regulating MHC class I (MHC-I). Conversely, mice-bearing brain metastases of CDK5 knockdown tumor cells had prolonged survivals. Attractively, CDK5 is readily targetable with clinically- applicable, blood-brain-barrier penetrating inhibitors. Here, we hypothesize that CDK5 activation promotes breast cancer brain metastasis by both facilitating cancer cell adaptation/outgrowth in the brain and by immunosuppression; CDK5 inhibitors may be developed as new therapeutics for breast cancer brain metastasis. The major goals of this proposal are 1) Determine the brain metastasis-promoting functions of CDK5 in spontaneous brain metastasis models and in immune competent mouse models, and examine its clinical relevance in patient specimens; 2) Explore novel mechanisms of CDK5-enhanced brain metastasis by examining the impact of CDK5+++ in cancer cells on both a) breast cancer cell adaptation/outgrowth in the brain and b) inducing immune suppression; 3) Evaluate the potential of targeting CDK5 for early intervention and treatment of brain metastasis to prolong mouse survival. The successful completion of these studies will bring about new understanding of breast cancer brain metastasis and the first generation of effective brain metastasis-targeted therapies. Ultimately, our findings will be translated to clinical trials, leading to new and better treatments for breast cancer patients having brain metastasis.