Inhibition of brain metastasis by blocking MAPK12 driver kinase functions

通过阻断 MAPK12 驱动激酶功能抑制脑转移

基本信息

批准号：
10172862
负责人：
Dihua Yu
金额：
$ 43.26万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172862
关键词：
Address Affect Animals Area Biological Assay Brain Breast Cancer Cell Breast Cancer Patient Breast Cancer Prevention Breast Cancer Treatment Breast Cancer cell line Breast Cancer therapy Breast cancer metastasis Cancer Patient Carotid Arteries Cells Chemicals Citric Acid Cycle Clinic Clinical Clinical Trials Data Diagnosis Disease Disseminated Malignant Neoplasm Early Intervention Energy-Generating Resources FDA approved Family Future Generations Glucose Goals Growth Human Immunocompetent Incidence Libraries MAP Kinase Gene MAPK12 gene MDA MB 231 Malignant Neoplasms Mediating Metabolism Metastatic breast cancer Metastatic malignant neoplasm to brain Metastatic to Mitochondria Modeling Mus Neoplasm Metastasis Nude Mice Pathway interactions Patients Pharmacotherapy Phosphotransferases Play Population Prevention Primary Neoplasm Quality of life Recurrence Refractory Research Role Signal Pathway Signal Transduction Systemic disease Testing Therapeutic Agents Tissues Translating Trastuzumab Woman anticancer research brain metabolism cancer cell cell motility clinical application clinical care clinically relevant drug development effective therapy efficacy testing improved in vivo inhibitor/antagonist insight kinase inhibitor loss of function malignant breast neoplasm member mortality next generation sequencing novel novel therapeutics overexpression palliative targeted treatment therapeutic target tumor progression vector control

项目摘要

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.

在每年被诊断出患有乳腺癌的160万妇女中，大约10-16％的脑转移。即使拥有最先进的临床护理，脑转移患者的毁灭性<20％一年生存。目前，难治性乳腺癌转移性患者尚无有效的药物治疗大脑。因此，迫切需要对该人群进行新颖有效的疗法。很遗憾，缺乏对脑转移的有效疗法，这在很大程度上受到了对脑转移的基本机制，可以指导药物开发和临床试验。到克服挑战，我们进行了一个前所未有的人类Kinome的体内屏幕促进小鼠乳腺癌脑转移的新型激酶，因为激酶在中心节点癌细胞信号网络对癌症进展/转移至关重要，可作为治疗可吸毒目标。在与侵袭性脑转移相关的顶级候选激酶中，我们确定了有丝分裂原的激活的蛋白激酶12（MAPK12，也称为p38γ）以前尚不知道在脑中起作用转移，但在高度侵略性的人乳腺癌中过表达，MAPK12高 - 表达乳腺癌的脑转移较高的乳腺癌发作。因此，我们执行了使用MAPK12过表达乳腺癌细胞的实验性脑转移测定，并验证了 MAPK12确实促进了动物的脑转移。 MAPK12是MAPK家族及其的成员过表达增加了癌细胞的运动和侵袭。令人兴奋的是，我们确定MAPK12位于脑转移富含激酶的信号网络的“枢纽”，可增强脑转移细胞” 利用鞋底作为大脑生长的能源。此外，MAPK12是针对的可用于其他疾病的诊所中使用的可用抑制剂。在这里，我们假设激活/ MAPK12的过表达使乳腺癌细胞中的信号通路促进脑转移，通过使用临床适用的激酶抑制剂可以有效抑制MAPK12。主要目标该提议是1）确定MAPK12在赞助大脑转移和免疫中的功能作用有能力的脑转移模型，并进一步验证其临床相关性； 2）研究小说 MAPK12介导的乳腺癌脑转移的机制通过关注MAPK12激活的方式脑转移性癌细胞有效地使用缝隙作为适应和生长的能源脑; 3）探索MAPK12作为治疗和/或预防乳房的治疗靶标的潜力癌症脑转移。这些研究的成功完成将带来对乳腺癌脑转移和有效的脑转移靶向疗法的第一代。最终，我们的发现将顺利地转化为临床试验，从而为您提供新的更好的治疗方法乳腺癌脑转移患者在恐惧中寻找希望。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tumor microenvironment as a therapeutic target in cancer.

DOI：
10.1016/j.pharmthera.2020.107753
发表时间：
2021-05
期刊：
Pharmacology & therapeutics
影响因子：
13.5
作者：
Xiao Y;Yu D
通讯作者：
Yu D

Targeting Aberrant p70S6K Activation for Estrogen Receptor-Negative Breast Cancer Prevention.

针对雌激素受体阴性乳腺癌预防的异常 p70S6K 激活。

DOI：
10.1158/1940-6207.capr-17-0106
发表时间：
2017
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
0
作者：
Wang,Xiao;Yao,Jun;Wang,Jinyang;Zhang,Qingling;Brady,SamuelW;Arun,Banu;Seewaldt,VictoriaL;Yu,Dihua
通讯作者：
Yu,Dihua

Oncogenic Kinase-Induced PKM2 Tyrosine 105 Phosphorylation Converts Nononcogenic PKM2 to a Tumor Promoter and Induces Cancer Stem-like Cells.

DOI：
10.1158/0008-5472.can-17-2726
发表时间：
2018-05-01
期刊：
Cancer research
影响因子：
11.2
作者：
Zhou Z;Li M;Zhang L;Zhao H;Şahin Ö;Chen J;Zhao JJ;Songyang Z;Yu D
通讯作者：
Yu D

Blocking immunosuppressive neutrophils deters pY696-EZH2-driven brain metastases.

DOI：
10.1126/scitranslmed.aaz5387
发表时间：
2020-05-27
期刊：
Science translational medicine
影响因子：
17.1
作者：
Zhang L;Yao J;Wei Y;Zhou Z;Li P;Qu J;Badu-Nkansah A;Yuan X;Huang YW;Fukumura K;Mao X;Chang WC;Saunus J;Lakhani S;Huse JT;Hung MC;Yu D
通讯作者：
Yu D

The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1.

DOI：
10.1016/j.ccell.2021.11.002
发表时间：
2022-01-10
期刊：
Cancer cell
影响因子：
50.3
作者：
Li H;Xiao Y;Li Q;Yao J;Yuan X;Zhang Y;Yin X;Saito Y;Fan H;Li P;Kuo WL;Halpin A;Gibbons DL;Yagita H;Zhao Z;Pang D;Ren G;Yee C;Lee JJ;Yu D
通讯作者：
Yu D