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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：
10615611
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10615611
关键词：
Affect Antineoplastic Agents Archives Biological 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 EO771 Early Intervention Early treatment Environment Event Excision Generations Geographic Distribution Glucose Goals Human Hypoxia Immune Immunocompetent Immunophenotyping Immunosuppression Immunotherapy In Vitro Intracarotid Lesion Libraries MDA MB 231 MHC Class I Genes Malignant Neoplasms Malignant neoplasm of brain 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 Translating Trastuzumab Woman angiogenesis anti-PD-1 blood-brain barrier penetration 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.

在每年被诊断患有乳腺癌的160万女性中，10-16%的人会发生脑转移