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

• 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
• 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

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，白血病是儿童中最常见的恶性肿瘤。每年，大约20%的儿童被诊断为急性白血病，被诊断为急性髓性白血病（AML）。虽然AML在儿童白血病中所占的比例小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（现在总生存率约为80%）相反，儿童AML的总生存率为50-60%，化疗是密集的，需要频繁住院治疗。复发性AML的生存率仅为20%至30%。这种次优预后表明需要更多的研究来改善儿童AML的预后。此外，目前的化疗药物产生显著的短期和长期毒性。因此，需要新的疗法来继续提高疗效并降低治疗相关的毒性。我的实验室研究Mer和Axl，在儿童急性髓细胞白血病中异常表达和激活的受体酪氨酸激酶蛋白。Mer和Axl具有与细胞周期、存活和增殖有关的多种功能。在目前的拨款提案中，我们将评估使用我实验室开发的新型生物抑制剂抑制儿童髓性白血病细胞中的Mer和/或Axl后的白血病细胞死亡。我们还将在细胞培养中为我们令人兴奋的初步结果提供额外的证据，即Mer抑制使白血病细胞对标准白血病化疗药物更敏感。此外，将在人白血病的小鼠动物模型中检测Mer和抑制的有效性。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。拟议的研究还可能为儿科肿瘤学家提供一种高效且毒性小得多的替代方案，以替代目前用于治疗儿童AML的化疗药物。 公共卫生关系：儿童白血病的癌症治疗已经取得了重大进展;然而，未来的改善可能依赖于发现新的药物来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。我的研究实验室已经发现了两种蛋白质的异常表达，这可能有助于儿童骨髓白血病的发展。我们建议测试我们已经开发的抑制剂，这些抑制剂可以杀死表达这些异常蛋白质的白血病细胞，从而为儿科白血病提供潜在的新疗法，这种疗法比目前使用的化疗药物毒性更小。