Regulation of oncogenic KIT by LMTK3

LMTK3 对致癌 KIT 的调节

• 批准号: 9260685
• 负责人: Michael C Heinrich
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260685
• 关键词: Acute Myelocytic Leukemia; Adult; Affect; Alleles; American; Antineoplastic Agents; Binding; Binding Proteins; Biological Assay; Biological Process; Budgets; Cancer Biology; Caring; Cell Line; Cell Survival; Cells; Clinical; Development; Disease; Drug resistance; Effectiveness; Gastrointestinal Stromal Tumors; Genetic Transcription; Growth; Healthcare; Human; Imatinib; In Vitro; Lemurs; Lesion; Libraries; Ligands; Luciferases; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Mast Cell Neoplasm; Mediating; Medical; Melanoma Cell; Messenger RNA; Methods; Morbidity - disease rate; Mutation; Nature; Neoplasms; Oncogenic; Pathogenicity; Patients; Phosphorylation Site; Phosphotransferases; Play; Protein Isoforms; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proteins; Quality of life; Radiation; Receptor Protein-Tyrosine Kinases; Regulation; Reporter; Resistance; Resistance development; Role; Seminoma; Series; Small Interfering RNA; Soft tissue sarcoma; Stem Cell Factor; Toxic effect; Transcriptional Regulation; Tumor Biology; Tyrosine Kinase Inhibitor; Veterans; agent orange; cancer cell; cancer therapy; chemotherapy; clinically relevant; conventional therapy; gain of function mutation; improved; in vivo; knock-down; mRNA Expression; mast cell; melanoma; model development; mortality; mutant; neoplastic cell; novel strategies; novel therapeutic intervention; promoter; protein complex; public health relevance; resistance mutation; response; scaffold; targeted agent; targeted cancer therapy; therapeutic target; transcription factor; tumor

 DESCRIPTION (provided by applicant): Gain-of-function mutations of KIT are found in a number of human malignancies, including gastrointestinal stromal tumors (GIST), mast cell neoplasms, melanoma, seminoma, and acute myeloid leukemia. GIST tumors are resistant to both radiation and chemotherapy. KIT mutations are the oncogenic driver in the case of most GISTs. Tyrosine kinase inhibitors (TKIs) such as imatinib have revolutionized the treatment of advanced GIST. In mast cell neoplasms (SM), the disease is caused by mast cells harboring activating KIT mutations. SM patients are candidates for chemotherapy, but these therapies are toxic and ineffective. Melanomas with activating KIT mutations are aggressive and do not respond to chemotherapy. In all three diseases, the effectiveness of KIT TKIs is limited by primary or secondary drug resistance. Our proposal seeks to improve therapy for KIT-mutant malignancies by identifying the role LMTK3 has in positively regulating the expression of oncogenic KIT protein. Plan: Our proposal has three specific aims. In SA1, we will determine the mechanisms by which LMTK3 regulates the transcription of oncogenic KIT isoforms. In SA2, we will determine the functional domains of LMTK3 required for regulated expression of oncogenic KIT. In SA3, we will identify proteins that interact with LMTK3 and determine their role in promoting KIT transcription. Methods: In SA1, we will use a KIT promoter-reporter construct to identify regions of the KIT promoter that are regulated by LMTK3 knockdown. In addition, we will identify candidate transcription factors that mediate indirect regulation of KIT transcription by LMTK3. In SA2, we will create a series of LMTK3 mutants with mutation of specific domains (e.g. LMTK3 kinase domain) and determine which domains are required for regulation of the KIT promoter. In addition, we will identify LMTK3 phosphorylation sites using mass spectrometry. In SA3 we will use mass spectrometry and protein pull down assays to identify proteins that interact with LMTK3 and potentially regulate KIT transcription. Clinical Relevance: The care of veterans with cancer represents a significant portion of the overall Veterans Affairs Health Care budget. New cancer treatment agents that target significant aspects of tumor biology will greatly increase the quality of life o veterans with cancer. Our study of the mechanisms by which LMTK3 regulates oncogenic KIT proteins has the potential to identify new treatments for KIT-mutant cancers. These new treatments are likely to be more effective than conventional treatments and be associated with significantly less treatment toxicity.

 描述（由申请人提供）： 在许多人类恶性肿瘤中发现了功能收益突变，包括胃肠道脊髓肿瘤（GIST），肥大细胞肿瘤，黑色素瘤，神经素和急性髓样白血病。要点肿瘤对放射线和化学疗法都有抗性。在大多数GIST的情况下，试剂盒突变是致癌驱动力。酪氨酸激酶抑制剂（TKIS）（例如伊马替尼）已彻底改变了晚期要点的治疗。在肥大细胞肿瘤（SM）中，该疾病是由具有激活试剂盒突变的肥大细胞引起的。 SM患者是化学疗法的候选者，但这些疗法有毒和无效。具有激活套件突变的黑色素瘤是侵略性的，对化学疗法无反应。在所有三种疾病中，试剂盒TKI的有效性受原发性或继发性耐药性的限制。我们的建议旨在通过确定LMTK3在积极调节致癌试剂蛋白的表达中的作用来改善对Kit-突变的治疗。计划：我们的建议具有三个具体目标。在SA1中，我们将确定LMTK3调节致癌试剂工具的转录的机制。在SA2中，我们将确定调节致癌试剂盒表达所需的LMTK3的功能域。在SA3中，我们将确定与LMTK3相互作用的蛋白质并确定其在促进试剂盒转录中的作用。方法：在SA1中，我们将使用Kit启动子重型构建体来识别由LMTK3敲低调节的Kit启动子的区域。此外，我们将确定LMTK3对套件转录的媒体间接调节的候选转录因子。在SA2中，我们将创建一系列具有特定域突变（例如LMTK3激酶结构域）的LMTK3突变体，并确定调节KIT启动子的调节所需的域。此外，我们将使用质谱法确定LMTK3磷酸化位点。在SA3中，我们将使用质谱和蛋白质下拉测定法来鉴定与LMTK3相互作用并可能调节试剂盒转录的蛋白质。临床相关性：癌症退伍军人的护理代表了退伍军人事务总体医疗保健预算的很大一部分。针对肿瘤生物学重要方面的新癌症治疗剂将大大提高癌症的退伍军人的生活质量。我们对LMTK3调节致癌试剂素蛋白的机制的研究有可能鉴定针对工具包癌的新治疗方法。这些新疗法可能比常规治疗更有效，并且与治疗毒性明显相关。