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

通过阻断 CDK5 的双管驱动激酶功能来对抗乳腺癌脑转移

基本信息

批准号：
10380589
负责人：
Dihua Yu
金额：
$ 44.46万
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：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380589
关键词：
Affect Antineoplastic Agents Archives Biological Blood - brain barrier anatomy Brain Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line CDK2 gene Carotid Arteries Cell Proliferation Cells Clinical Clinical Trials Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinase Inhibitor Development Diagnosis Disease Early Intervention Early treatment Environment Event Excision Generations Geographic Distribution Glucose Goals Human Hypoxia Immune Immunocompetent Immunophenotyping Immunosuppression Immunotherapy In Vitro Intracarotid Lead Lesion Libraries MDA MB 231 MHC Class I Genes Malignant Neoplasms Mammary Neoplasms Metastatic malignant neoplasm to brain Modeling Mus Neoplasm Metastasis Nude Mice Operative Surgical Procedures Organ Patients Pharmacotherapy Phase II Clinical Trials Phosphotransferases Population Primary Neoplasm Proliferating Quality of life Recurrence Research SCID Mice Signal Transduction Site Specimen Stains Survival Rate Systemic disease T-Lymphocyte Testing Therapeutic Agents Time Translating Trastuzumab Woman angiogenesis anti-PD-1 base cancer cell cancer therapy cell killing clinical application clinically relevant drug development effective therapy efficacy testing improved in vivo inhibitor kinase inhibitor knock-down loss of function malignant breast neoplasm migration mortality mouse model neoplastic cell next generation sequencing novel novel therapeutics overexpression palliative patient derived xenograft model response roscovitine targeted treatment therapeutic target triple-negative invasive breast carcinoma tumor tumor progression vector control

项目摘要

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.

在每年被诊断出患有乳腺癌的160万妇女中，有10-16％的脑转移毁灭性<20％的一年生存。目前，对于患者乳腺癌脑转移。因此，迫切需要该人群需要有效的疗法。不幸的是，开发有效的脑转移疗法在很大程度上受到了深入的影响了解脑转移的生物学机制，这可以指导药物开发和临床试验。为了克服这一挑战，我们进行了一个体内的人类Kinome屏幕以发现促进小鼠乳腺癌脑转移的新型激酶。激酶处于癌症的中心节点细胞信号网络对于癌症进展和转移至关重要，可以用作可吸毒的治疗目标。其中，依赖细胞周期蛋白的激酶5（CDK5）是最高的“命中”，富集> 26倍。 CDK5，a 非典型的CDK可以增加细胞增殖，迁移和血管生成。 CDK5过表达（+++）与高年级乳腺癌显着相关，患者的生存率较低，但其功能在大脑中的功能转移被忽略了。这，我们进一步检查了脑转移中的CDK5功能，发现 CDK5 +++细胞a）会议增加了小鼠的脑转移和增加的生存率； b）可以适应，并且在模仿大脑环境的低葡萄糖和低氧培养条件下增殖； c）诱导通过下调MHC I类（MHC-I）通过下调的免疫抑制。相反，含老鼠的脑转移 CDK5敲低肿瘤细胞的生存时间延长。吸引人的是，CDK5很容易在临床上 - 适用的，血脑屏障的穿透抑制剂。在这里，我们假设CDK5激活促进乳腺癌脑转移是通过支持大脑中的癌细胞适应/出生以及通过免疫抑制； CDK5抑制剂可能被开发为乳腺癌大脑的新疗法转移。该提案的主要目标是1）确定大脑转移的促进功能赞助大脑转移模型和免疫功能的小鼠模型中的CDK5，并检查其患者标本中的临床相关性； 2）探索CDK5增强脑转移的新型机制检查CDK5 +++对癌细胞对乳腺癌细胞适应/产物的影响大脑和b）诱导免疫抑制； 3）评估靶向CDK5进行早期干预的潜力以及脑转移以延长小鼠存活的处理。这些研究的成功完成将对乳腺癌大脑转移和第一代有效的大脑有了新的了解靶向转移的疗法。最终，我们的发现将转化为临床试验，从而导致新的和更好地治疗患有脑转移的乳腺癌患者。