Novel Biologically Targeted Therapy Against the Mer and Axl Receptor Tyrosine Kin

针对 Mer 和 Axl 受体酪氨酸激酶的新型生物靶向疗法

基本信息

批准号：
8118019
负责人：
DOUGLAS K GRAHAM
金额：
$ 28.45万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8118019
关键词：
14 year old Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Adverse effects Affect Animal Model Apoptotic Applications Grants Biological Assay Biologically Based Therapy Cell Culture Techniques Cell Cycle Cell Death Cell Line Cell Survival Cell division Cells Cessation of life Child Childhood Childhood Acute Myeloid Leukemia Childhood Leukemia Dependence Development Diagnosis Disease ERBB2 gene FLT3 gene Future Hospitalization Human In Vitro Inferior Malignant Neoplasms Modeling Monoclonal Antibodies Mus Myeloid Leukemia NOD/SCID mouse New Agents Outcome Pathway interactions Patients Pediatric Oncologist Pharmaceutical Preparations Protein Tyrosine Kinase Proteins Proto-Oncogenes Receptor Protein-Tyrosine Kinases Relapse Relative (related person)Research Role Sampling Signal Pathway Signal Transduction Survival Rate Testing Time Toxic effect Transgenic Mice Transplantation Validation Xenograft Model Xenograft procedure axl receptor tyrosine kinase cancer therapy cell growth chemotherapeutic agent chemotherapy efficacy testing improved inhibitor/antagonist killings leukemia leukemia/lymphoma leukemogenesis lymphoblast myeloblast novel outcome forecast prevent public health relevance receptor research study response small hairpin RNA tyrosine receptor

项目摘要

DESCRIPTION (provided by applicant): Cancer is the leading cause of disease-related deaths among children 1 to 14 years of age, and leukemia is the most common malignancy in children. Every year, approximately 20% of children diagnosed with acute leukemia are diagnosed with acute myelogenous leukemia (AML). Though AML constitutes a smaller percentage of childhood leukemia than acute lymphoblastic leukemia (ALL), AML carries an inferior prognosis. In contrast to the improvements in ALL cure rates over the past 20-30 years (now ~80% overall survival), the overall survival for pediatric AML is 50-60% and the chemotherapy is intensive with frequent required hospitalization. Relapsed AML carries survival rate with chemotherapy alone of 20% to 30%. This suboptimal prognosis demonstrates the need for more research into improvement in the outcome of pediatric AML. Furthermore, current chemotherapeutics produce significant short-term and long-term toxicities. Thus, new therapies are needed to continue to improve efficacy and decrease treatment related toxicity. My lab studies Mer and Axl, receptor tyrosine kinase proteins abnormally expressed and activated in childhood acute myeloid leukemia. Mer and Axl have multiple functions pertaining to cell cycling, survival, and proliferation. In the current grant proposal, we will evaluate leukemia cell death after inhibition of Mer and/or Axl in childhood myeloid leukemia cells using novel biologic inhibitors developed in my lab. We will also provide additional evidence in cell culture for our exciting preliminary results that Mer inhibition makes leukemia cells more sensitive to standard leukemia chemotherapy drugs. Additionally, Mer and inhibition will be tested for efficacy in mouse animal models of human leukemia. These experiments will help establish the related Mer and Axl receptors as novel targets for childhood AML therapy. The proposed studies will also potentially provide pediatric oncologists with a highly effective and much less toxic alternative to the currently used chemotherapy drugs in the treatment of childhood AML. PUBLIC HEALTH RELEVANCE: Significant advances have been made in cancer therapy for pediatric leukemia; however, future improvements will likely rely on the discovery of new agents to improve outcome and decrease the adverse side effects associated with the currently used chemotherapy drugs. My research lab has identified abnormal expression of two proteins that may contribute to the development of pediatric myeloid leukemia. We propose to test inhibitors we have developed which kill leukemia cells expressing these abnormal proteins, leading to potential new therapies for pediatric leukemia which would cause less toxicity than the currently used chemotherapy drugs.

描述（由申请人提供）：癌症是 1 至 14 岁儿童疾病相关死亡的主要原因，而白血病是儿童最常见的恶性肿瘤。每年，大约 20% 被诊断患有急性白血病的儿童被诊断为急性髓性白血病 (AML)。尽管 AML 在儿童白血病中所占比例低于急性淋巴细胞白血病 (ALL)，但 AML 的预后较差。与过去 20-30 年 ALL 治愈率的提高（目前总生存率约为 80%）相比，儿科 AML 的总生存率为 50-60%，且化疗强度大且需要频繁住院治疗。单纯化疗复发的 AML 生存率为 20% 至 30%。这种次优的预后表明需要进行更多研究来改善儿科 AML 的预后。此外，目前的化疗药物会产生显着的短期和长期毒性。因此，需要新的疗法来继续提高疗效并减少治疗相关的毒性。我的实验室研究 Mer 和 Axl，这两种受体酪氨酸激酶蛋白在儿童急性髓性白血病中异常表达和激活。 Mer 和 Axl 具有与细胞周期、存活和增殖相关的多种功能。在当前的资助提案中，我们将使用我实验室开发的新型生物抑制剂来评估儿童髓系白血病细胞中 Mer 和/或 Axl 抑制后的白血病细胞死亡情况。我们还将在细胞培养中提供更多证据，证明我们令人兴奋的初步结果，即 Mer 抑制使白血病细胞对标准白血病化疗药物更加敏感。此外，Mer 和抑制作用将在人类白血病的小鼠动物模型中进行功效测试。这些实验将有助于建立相关的 Mer 和 Axl 受体作为儿童 AML 治疗的新靶点。拟议的研究还有可能为儿科肿瘤学家提供一种高效且毒性低得多的替代方案，替代目前用于治疗儿童 AML 的化疗药物。公共卫生相关性：儿童白血病的癌症治疗已取得重大进展；然而，未来的改进可能依赖于新药的发现，以改善结果并减少与目前使用的化疗药物相关的不良副作用。我的研究实验室发现了两种蛋白质的异常表达，这可能有助于儿童骨髓性白血病的发展。我们建议测试我们开发的抑制剂，这些抑制剂可以杀死表达这些异常蛋白的白血病细胞，从而为儿童白血病提供潜在的新疗法，其毒性比目前使用的化疗药物要小。