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：
9904595
负责人：
Dihua Yu
金额：
$ 45.36万
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/9904595
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 Xenograft Model Xenograft procedure angiogenesis anti-PD-1 base cancer cell cancer therapy cell killing clinical application clinically relevant combat drug development effective therapy efficacy testing improved in vivo inhibitor/antagonist kinase inhibitor knock-down loss of function malignant breast neoplasm migration mortality mouse model neoplastic cell next generation sequencing novel novel therapeutics overexpression palliative 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.

每年被诊断患有乳腺癌的 160 万名女性中，10-16% 发生脑转移一年生存率低于 20% 的患者目前尚无有效的药物治疗方法。因此，该人群迫切需要有效的治疗方法。不幸的是，开发有效的脑转移疗法在很大程度上由于缺乏深入的研究而受到阻碍。了解脑转移的生物学机制，可以指导药物开发和为了克服这一挑战，我们进行了体内人类激酶组筛选以揭示这一点。促进小鼠乳腺癌脑转移的新型激酶位于癌症的中心节点。细胞信号网络对于癌症进展和转移至关重要，可作为药物治疗其中，细胞周期蛋白依赖性激酶 5 (CDK5) 是最“热门”的，CDK5 富集度超过 26 倍。非经典 CDK，可以增加细胞增殖、迁移和血管生成 (+++)。与高级别乳腺癌和患者较低的生存率显着相关，但其在大脑中的功能因此，我们进一步检查了脑转移中的CDK5功能，发现： CDK5+++ 细胞 a) 导致小鼠脑转移增加，存活率降低 b) 能够适应，并且在模拟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）来抑制小鼠脑转移瘤。 CDK5 敲低的肿瘤细胞具有更长的存活时间，令人感兴趣的是，CDK5 很容易成为临床靶标。在这里，我们发现 CDK5 激活可促进。乳腺癌脑转移通过促进癌细胞在大脑中的适应/生长以及通过免疫抑制；CDK5抑制剂可能被开发为乳腺癌脑部的新疗法该提案的主要目标是1）确定脑转移促进功能。 CDK5 在自发性脑转移模型和免疫活性小鼠模型中的作用，并检查其患者标本的临床相关性；2) 通过以下方式探索 CDK5 增强脑转移的新机制检查癌细胞中 CDK5+++ 对 a) 乳腺癌细胞适应/生长的影响 b) 诱导免疫抑制；3) 评估针对 CDK5 进行早期干预的潜力以及治疗脑转移以延长小鼠的生存期。带来对乳腺癌脑转移的新认识和第一代有效脑最终，我们的研究结果将转化为临床试验，从而产生新的治疗方法。为患有脑转移的乳腺癌患者提供更好的治疗。