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：
8267692
负责人：
DOUGLAS K GRAHAM
金额：
$ 29.73万
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/8267692
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岁儿童中与疾病相关的死亡的主要原因，白血病是儿童最常见的恶性肿瘤。每年，大约20％的被诊断患有急性白血病的儿童被诊断出患有急性骨髓性白血病（AML）。尽管AML比急性淋巴细胞白血病（ALL）占儿童白血病的比例较小，但AML的预后较低。与过去20至30年中所有治疗率的提高（现在的总生存率约为80％）相反，小儿AML的总生存期为50-60％，化学疗法是强化的，并且经常需要住院。复发的AML仅使用20％至30％的化学疗法携带存活率。这种次优的预后表明需要对小儿AML结果的改善进行更多的研究。此外，当前的化学治疗剂会产生明显的短期和长期毒性。因此，需要新的疗法来继续提高功效并降低治疗相关的毒性。我的实验室研究MER和AXL，受体酪氨酸激酶蛋白异常表达并在儿童急性髓样白血病中激活。 MER和AXL具有与细胞循环，存活和增殖有关的多个功能。在当前的赠款提案中，我们将使用我的实验室中开发的新生物学抑制剂在儿童期骨髓性白血病细胞中抑制MER和/或AXL后评估白血病细胞死亡。我们还将在细胞培养中提供更多的证据，以表明我们令人兴奋的初步结果，即Mer抑制作用使白血病细胞对标准白血病化学疗法药物更敏感。另外，将测试MER和抑制作用在人白血病的小鼠动物模型中的功效。这些实验将有助于建立相关的MER和AXL受体作为儿童AML治疗的新靶标。拟议的研究还将潜在地为小儿肿瘤学家提供高效且毒性较小的替代品，用于治疗儿童AML的当前化学疗法药物。公共卫生相关性：小儿白血病癌症治疗方面已取得了重大进展；但是，未来的改善可能会依靠发现新药物来改善结果并减少与当前使用的化学疗法药物相关的不良副作用。我的研究实验室已经确定了两种蛋白质的异常表达，这可能有助于小儿髓样白血病的发展。我们建议测试我们开发的抑制剂，以杀死表达这些异常蛋白质的白血病细胞，从而导致潜在的儿科白血病的新疗法，这与当前使用的化学疗法药物相比，毒性更少。