Inhibition of brain metastasis by blocking MAPK12 driver kinase functions

在每年被诊断患有乳腺癌的160万女性中，约10-16%发生脑转移。 即使有最先进的临床护理，脑转移患者一年内也有毁灭性的<20%。 生存目前，对于转移至乳腺癌的难治性乳腺癌患者， 大脑因此，这一人群迫切需要新的有效疗法。不幸的是， 开发脑转移的有效疗法在很大程度上受到缺乏对以下方面的深入了解的阻碍： 脑转移瘤的基本机制，可指导药物开发和临床试验。到 为了克服挑战，我们对人类激酶组进行了前所未有的体内筛选， 促进小鼠乳腺癌脑转移的新型激酶，因为激酶位于中心节点 对癌症进展/转移至关重要的癌细胞信号传导网络， 目标的在我们确定的与侵袭性脑转移相关的最佳候选激酶中，有丝分裂原- 此前尚不清楚活化蛋白激酶12（MAPK 12，也称为p38γ）在大脑中发挥作用 转移，但在高度侵袭性的人乳腺癌中过表达，并且MAPK 12高表达的患者， 表达乳腺癌的患者以后脑转移的发生率更高。因此，我们进行了 使用MAPK 12过表达乳腺癌细胞的实验性脑转移测定，并验证了 MAPK 12确实促进动物脑转移。MAPK 12是MAPK家族的一员， 过表达增加癌细胞运动性和侵袭性。令人兴奋的是，我们发现MAPK 12位于 脑转移富集激酶的信号网络的“枢纽”，其增强脑转移细胞的 利用乳酸作为大脑生长的能量来源。此外，MAPK 12可与 在临床上用于其他疾病的可用抑制剂。在这里，我们假设激活/ MAPK 12的过表达协调乳腺癌细胞中的信号通路以促进脑转移， 并且通过使用临床上可应用的激酶抑制剂可以有效地抑制MAPK 12。的主要目标 本研究的目的是：1）确定MAPK 12在自发性脑转移和免疫调节中的功能作用， 合适的脑转移模型，并进一步验证其临床相关性; 2）研究新的 MAPK 12介导的乳腺癌脑转移的机制，通过关注MAPK 12如何激活 脑转移癌细胞有效地利用乳酸作为能量来源， 3）探索MAPK 12作为治疗和/或预防乳腺癌的治疗靶点的潜力 癌症脑转移这些研究的成功完成将使人们对 乳腺癌脑转移和第一代有效的脑转移靶向治疗。 最终，我们的发现将顺利转化为临床试验，从而产生新的更好的治疗方法。 乳腺癌脑转移患者在苦苦寻找希望。

Among 1.6 million women diagnosed with breast cancer every year, about 10-16% develop brain metastasis. Even with the most advanced clinical care, patients with brain metastasis have a devastating <20% one-year survival. At present, no effective drug treatment exists for patients with refractory breast cancer metastatic to the brain. Therefore, novel and 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 basic mechanisms of brain metastasis, which could guide drug development and clinical trials. To surmount the challenge, we have performed an unprecedented in vivo screen of the human kinome to uncover novel kinases that promote breast cancer brain metastasis in mice, because kinases are at the central nodes of cancer cell signaling networks critical for cancer progression/metastasis and are druggable as therapeutic targets. Among the top candidate kinases associated with aggressive brain metastasis we identified, Mitogen- Activated Protein Kinase 12 (MAPK12, also known as p38γ) was not previously known to play roles in brain metastasis but is overexpressed in highly aggressive human breast cancers, and patients with MAPK12 high- expressing breast cancers have higher incidences of brain metastasis later on. Therefore, we performed experimental brain metastasis assays using MAPK12-overexpressing breast cancer cells, and validated that MAPK12 indeed promotes brain metastasis in animals. MAPK12 is a member of the MAPK family and its overexpression increases cancer cell motility and invasion. Excitingly, we identified that MAPK12 is located at the "hub" of a signaling network of brain metastasis-enriched kinases that enhances brain metastatic cells’ utilization of lactate as an energy source for outgrowth in the brain. Furthermore, MAPK12 is targetable with available inhibitors that are used in the clinic for other diseases. Here, we hypothesize that activation/ overexpression of MAPK12 coordinates signaling pathways in breast cancer cells to promote brain metastasis, and MAPK12 may be effectively inhibited by using clinically applicable kinase inhibitors. The major goals of this proposal are 1) Determine the functional roles of MAPK12 in spontaneous brain metastasis and in immune competent brain metastasis models, and further validating their clinical relevance; 2) Investigate novel mechanisms of MAPK12-mediated breast cancer brain metastasis by focusing on how MAPK12-activated brain metastatic cancer cells efficiently use lactate as an energy source for adaptation and outgrowth in the brain; 3) Explore the potential of MAPK12 as a therapeutic target for the treatment and/or prevention of breast cancer brain metastasis. 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 smoothly translated to clinical trials, leading to new and better treatments for breast cancer brain metastasis patients in dire search of hope.