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：
10025581
负责人：
Dihua Yu
金额：
$ 55.25万
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10025581
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.

每年诊断出患有乳腺癌的 160 万女性中，约 10-16% 会发生脑转移。即使采用最先进的临床护理，脑转移患者的一年死亡率仍低于 20% 目前，对于难治性乳腺癌转移患者尚无有效的药物治疗。因此，不幸的是，这一人群迫切需要新的、有效的治疗方法。由于缺乏对脑转移的深入了解，开发有效的脑转移疗法在很大程度上受到阻碍脑转移的基本机制，可以指导药物开发和临床试验。克服挑战，我们对人类激酶组进行了前所未有的体内筛选，以揭示促进小鼠乳腺癌脑转移的新型激酶，因为激酶位于中央节点癌细胞信号网络对于癌症进展/转移至关重要，并且可作为治疗药物在我们确定的与侵袭性脑转移相关的顶级候选激酶中，丝裂原- 此前并不知道激活蛋白激酶 12（MAPK12，也称为 p38γ）在大脑中发挥作用转移，但在高度侵袭性的人类乳腺癌和 MAPK12 高表达的患者中过度表达表达乳腺癌以后脑转移的发生率更高，因此我们进行了研究。使用 MAPK12 过度表达的乳腺癌细胞进行实验性脑转移测定，并验证了 MAPK12 确实促进动物的脑转移。MAPK12 是 MAPK 家族的成员。令人兴奋的是，我们发现 MAPK12 的过度表达会增加癌细胞的运动性和侵袭性。富含脑转移激酶的信号网络的“枢纽”，可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，MAPK12 是可靶向的。在这里，我们寻找可用于临床治疗其他疾病的抑制剂。 MAPK12 的过度表达协调乳腺癌细胞中的信号通路，促进脑转移，使用临床上适用的激酶抑制剂可以有效抑制MAPK12的主要目标。该提案是 1) 确定 MAPK12 在自发性脑转移和免疫中的功能作用有效的脑转移模型，并进一步验证其临床相关性2）研究新颖性； MAPK12介导的乳腺癌脑转移机制，重点关注MAPK12如何激活脑转移癌细胞有效地利用乳酸作为适应和生长的能量来源 3) 探索 MAPK12 作为治疗和/或预防乳腺疾病的治疗靶点的潜力这些研究的成功完成将带来对癌症脑转移的新认识。乳腺癌脑转移和第一代有效的脑转移靶向治疗。最终，我们的研究结果将顺利转化为临床试验，从而带来新的、更好的治疗方法乳腺癌脑转移患者在绝望中寻找希望。