Mechanisms of Tyrosine Kinase Inhibitor Resistance in GI Stromal Tumors

胃肠道间质瘤酪氨酸激酶抑制剂耐药机制

• 批准号: 8258641
• 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 2013-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258641
• 关键词: Accounting; Acute Myelocytic Leukemia; Adult; Adverse effects; Adverse reactions; Age; Alleles; American; Apoptosis; BAY 54-9085; Biochemical; Biological Assay; Biological Models; Budgets; Cancer Biology; Caring; Cell Line; Cell model; Cells; Chinese Hamster Ovary Cell; Clinical; Clinical Trials; Cloning; Colon Carcinoma; Combined Modality Therapy; Comorbidity; Cytoplasmic Tail; Cytotoxic agent; DNA; Dasatinib; Development; Diabetes Mellitus; Diagnosis; Drug resistance; Effectiveness; Ethylnitrosourea; Frequencies; Gastrointestinal Stromal Tumors; Genomics; Genotype; Health; Healthcare; High Pressure Liquid Chromatography; Hospitalization; Imatinib; In Vitro; Investigation; Laboratories; Life; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measurement; Modeling; Morbidity - disease rate; Mucositis; Mutagenesis; Mutation; Neutropenic Fever; Oncogenic; PDGFRA gene; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Pulmonary Heart Disease; Quality of life; Radiation; Receptor Protein-Tyrosine Kinases; Recurrence; Research; Resistance; Risk; Role; Seminoma; Signal Transduction; Signaling Molecule; Solid Neoplasm; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stromal Neoplasm; System; Techniques; Testing; Therapeutic Agents; Time; Toxic effect; Transfection; Treatment outcome; Tumor Biology; Tyrosine Kinase Inhibitor; Unresectable; Variant; Veterans; advanced disease; base; cancer care; cancer therapy; chemotherapy; clinically relevant; conventional therapy; cost; extracellular; improved; inhibitor/antagonist; insight; kinase inhibitor; malignant breast neoplasm; mastocytosis; medical complication; melanoma; mortality; mutant; novel; novel therapeutics; prevent; programs; research study; resistance mechanism; sarcoma; small molecule; soft tissue; treatment strategy; tumor; tumor progression

DESCRIPTION (provided by applicant): Gastrointestinal stromal tumors (GISTs), the most common type of adult soft tissue sarcoma, are diagnosed in approximately 5,000-10,000 Americans each year. Genomic activation of KIT or PDGFRA receptor tyrosine kinases plays a role in the development of ~85% of GISTs. Imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), has revolutionized the treatment of patients with advanced, unresectable GIST. Nevertheless, primary resistance to the drug is observed in some patients and secondary (acquired) resistance occurs with increasing frequency over time. The median time to tumor progression during front-line imatinib therapy is only 18-22 months. Notably, in the majority of treated GISTs, imatinib resistance results from selection of clones with drug-resistant kinase mutations. Hypothesis: the most efficient pathway for optimizing the treatment of patients with advanced GIST is to identify the relevant mechanisms of TKI-resistance and establish model systems that allow the testing of alternative or complementary agents, including combination therapy. Specific Aim 1. Using cell-based models, we will identify and validate treatment strategies to circumvent and/or prevent the emergence of secondary resistance to TKIs caused by the selection of tumor subclones with acquired KIT kinase mutations. This aim will utilize two different cellular models: 1) a transient transfection expression system to biochemically profile the activity of our panel of TKIs against previously identified imatinb-resistant mutant kinases; and 2) an ENU-mutagenesis/TKI drug selection system to identify novel KIT kinase mutations that confer TKI-resistance. Specific Aim 2. To determine the frequency and spectrum of secondary KIT (or PDGFRA) kinase mutations present in TKI-resistant clinical specimens. Clinical specimens will be obtained from patients treated with two or more successive TKIs (e.g imatinib followed by sunitinib). Novel kinase mutations that are identified will be cloned and biochemically characterized as described above. Potential impact on Veterans Health Care: Cancer is a major cause of morbidity and mortality in American veterans, especially in veterans over the age of 50. The development of new cancer therapeutic agents that target pathogenetic or significant aspects of tumor biology would greatly increase the quality and duration of life for veterans with cancer. PUBLIC HEALTH RELEVANCE: Relevance to Veterans Health Cancer is a major cause of morbidity and mortality in American veterans, especially in veterans over the age of 50. The care of veterans with cancer represents a significant portion of the overall Veterans Affairs Health Care budget. The development of new cancer therapeutic agents that target pathogenetic or significant aspects of tumor biology will greatly increase the quality of life of veterans with cancer. Such targeted agents have the potential to be much more effective than conventional treatments and with significantly less toxicity. Reducing toxicity of cancer treatments should reduce cancer care costs by decreasing hospitalizations for side effects of cancer treatment (such as neutropenic fever and/or mucositis). Decreasing treatment-related medical complications is of particular relevance to the treatment of veterans who often have significant co-morbidities such as cardiopulmonary disease and/or diabetes that increase the risk of adverse reactions to conventional cytotoxic agents. The model to be studied in the current application has direct relevance to patients with Gastrointestinal Stromal Tumors, but will likely provide major insights into cancer biology and the mechanisms of resistance to other small molecule kinase inhibitors. These insights will be directly applicable to improving the treatment of other malignancies that are dependent upon KIT and/or PDGFRA signaling (e.g. melanoma, acute myeloid leukemia, seminoma, and mastocytosis). However, the results for this project will also be valuable for the evolving development of molecularly targeted therapies for the more common solid tumors such as lung, colon, prostate, and breast cancer.

描述（由申请人提供）： 胃肠道间质瘤（GIST）是最常见的成人软组织肉瘤类型，每年约有5，000 - 10，000名美国人被诊断出。KIT或PDGFRA受体酪氨酸激酶的基因组激活在约85%的GIST的发生中起作用。伊马替尼是一种KIT/PDGFRA酪氨酸激酶抑制剂（TKI），彻底改变了晚期不可切除GIST患者的治疗。然而，在一些患者中观察到对药物的原发性耐药性，并且随着时间的推移，继发性（获得性）耐药性的发生频率增加。一线伊马替尼治疗期间肿瘤进展的中位时间仅为18-22个月。值得注意的是，在大多数接受治疗的GIST中，伊马替尼耐药是由于选择了具有耐药激酶突变的克隆。假设：优化晚期GIST患者治疗的最有效途径是确定TKI耐药的相关机制，并建立允许测试替代或补充药物（包括联合治疗）的模型系统。具体目标1.使用基于细胞的模型，我们将确定和验证治疗策略，以规避和/或预防由于选择具有获得性KIT激酶突变的肿瘤亚克隆而引起的TKI继发性耐药的出现。这一目标将利用两种不同的细胞模型：1）瞬时转染表达系统，以生物化学分析我们的TKI组对先前鉴定的伊马替尼抗性突变激酶的活性; 2）ENU诱变/TKI药物选择系统，以鉴定赋予TKI抗性的新型KIT激酶突变。具体目标2。确定TKI耐药临床标本中继发性KIT（或PDGFRA）激酶突变的频率和谱。将从接受两种或更多种连续TKI治疗的患者（例如伊马替尼，随后舒尼替尼）中获得临床样本。如上所述，将对鉴定的新激酶突变进行克隆和生物化学表征。对退伍军人医疗保健的潜在影响：癌症是美国退伍军人发病和死亡的主要原因，特别是在50岁以上的退伍军人中。针对肿瘤生物学的致病或重要方面的新癌症治疗剂的开发将大大提高癌症退伍军人的生活质量和持续时间。 公共卫生关系： 癌症是美国退伍军人发病率和死亡率的主要原因，特别是在50岁以上的退伍军人中。癌症退伍军人的护理占退伍军人事务部整体医疗保健预算的很大一部分。靶向肿瘤生物学的致病或重要方面的新癌症治疗剂的开发将大大提高癌症退伍军人的生活质量。这种靶向药物有可能比常规治疗有效得多，并且毒性显著降低。降低癌症治疗的毒性应通过减少因癌症治疗的副作用（如贫血性发热和/或粘膜炎）而住院来降低癌症护理成本。减少治疗相关的医疗并发症与退伍军人的治疗特别相关，退伍军人通常患有显著的合并症，如心肺疾病和/或糖尿病，这些疾病会增加对传统细胞毒性药物的不良反应风险。本申请中待研究的模型与胃肠道间质瘤患者直接相关，但可能会为癌症生物学和对其他小分子激酶抑制剂的耐药性机制提供重要见解。这些见解将直接适用于改善依赖于KIT和/或PDGFRA信号传导的其他恶性肿瘤（例如黑素瘤、急性髓性白血病、乳腺癌和肥大细胞增多症）的治疗。然而，该项目的结果也将对更常见的实体瘤（如肺癌、结肠癌、前列腺癌和乳腺癌）的分子靶向治疗的不断发展具有价值。