Molecular Mechanisms in Gastrointestinal Stromal Tumor

胃肠道间质瘤的分子机制

• 批准号: 7367879
• 负责人: Ronald P Dematteo
• 金额: $ 57.34万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367879
• 关键词: 17q; 20q; Achievement; Adjuvant; Adjuvant Therapy; American College of Surgeons; American College of Surgeons Oncology Group; Cancer Therapy Evaluation Program; Cancer and Leukemia Group B; Cell Proliferation; Characteristics; Chronic; Clinical; Cytogenetics; Data; Disease; Dose; Double-Blind Method; Drug resistance; Eastern Cooperative Oncology Group; Enrollment; Excision; Future; Gastrointestinal Stromal Tumors; Gene Expression; Genes; Intestines; Ligands; Logic; Malignant Neoplasms; Mesenchymal Cell Neoplasm; Mitotic Activity; Molecular; Multicenter Trials; Mutation; Myelogenous; Natural History; Neoplasms; Ontology; Operative Surgical Procedures; Outcome; Pathogenesis; Pathologic; Patients; Phase; Phenotype; Placebo Control; Placebos; Primary Neoplasm; Protein Tyrosine Kinase; Proto-Oncogenes; Randomized; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent disease; Recurrent tumor; Resistance; Role; ST 1571; STI571; Site; Southwest Oncology Group; Specimen; Standards of Weights and Measures; Testing; Therapeutic; Tissues; Tumor Biology; Upper arm; base; comparative genomic hybridization; day; gain of function mutation; inhibitor/antagonist; molecular oncology; prospective; protein activation; research study; response; size; small molecule; tumor; 17q; 20q; Achievement; Adjuvant; Adjuvant Therapy; American College of Surgeons; American College of Surgeons Oncology Group; Cancer Therapy Evaluation Program; Cancer and Leukemia Group B; Cell Proliferation; Characteristics; Chronic; Clinical; Cytogenetics; Data; Disease; Dose; Double-Blind Method; Drug resistance; Eastern Cooperative Oncology Group; Enrollment; Excision; Future; Gastrointestinal Stromal Tumors; Gene Expression; Genes; Intestines; Ligands; Logic; Malignant Neoplasms; Mesenchymal Cell Neoplasm; Mitotic Activity; Molecular; Multicenter Trials; Mutation; Myelogenous; Natural History; Neoplasms; Ontology; Operative Surgical Procedures; Outcome; Pathogenesis; Pathologic; Patients; Phase; Phenotype; Placebo Control; Placebos; Primary Neoplasm; Protein Tyrosine Kinase; Proto-Oncogenes; Randomized; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent disease; Recurrent tumor; Resistance; Role; ST 1571; STI571; Site; Southwest Oncology Group; Specimen; Standards of Weights and Measures; Testing; Therapeutic; Tissues; Tumor Biology; Upper arm; base; comparative genomic hybridization; day; gain of function mutation; inhibitor/antagonist; molecular oncology; prospective; protein activation; research study; response; size; small molecule; tumor

DESCRIPTION (provided by applicant): Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the intestinal tract. Until recently, surgery has been the only effective therapy for patients with GIST. Despite complete resection of their tumor, most patients develop, and eventually die from, recurrent disease. The majority of GISTs possess a gain of function mutation in the KIT proto-oncogene resulting in constitutive KIT protein activation and uncontrolled cell proliferation. STI571 is a small molecule that selectively inhibits KIT and a few other tyrosine kinases. It represents a landmark achievement in cancer therapeutics. STI571 validates the field of molecular oncology as it proves that a specific inhibitor can be used to target a molecular aberration responsible for the pathogenesis of neoplasia. STI571 is effective in about two-thirds of patients with metastatic GIST. Patients with primary GIST who undergo surgical resection may benefit from adjuvant STI571 and this is the subject of an ongoing CTEP sponsored Phase III randomized, double blind, placebo controlled, intergroup trial. We propose to study the tissue specimens collected from the patients enrolled in the multicenter trial. We hypothesize that the molecular characteristics of primary GIST predict the clinical outcome after adjuvant STI571 therapy. Furthermore, we postulate that subsequent molecular changes in recurrent GIST will reveal the mechanism of STI571 resistance in GIST. In Aim 1, we will correlate specific pathologic (tumor site and size) and cytogenetic (gains of 5p, 17q, or 20q or loss of 9p) phenotype of primary GIST to recurrence and survival. Aim 2 focuses on the relationship of KIT mutation status of primary GIST to recurrence and survival. In Aim 3, we will compare the pathologic and molecular features of primary GIST to recurrent GIST to begin to define the molecular mechanisms of STI571 resistance. The proposed experiments represent the first prospective clinical and pathologic study of primary GIST and will reveal the natural history of GIST (placebo arm) as well as the response to an adjuvant therapy (STI571 arm). The data will set the standard for future clinicopathologic studies in primary GIST and may provide approaches to treat patients with GIST who become resistant to STI571. The results will further define GIST biology and be applicable to other diseases treated with molecular agents.

描述（由申请人提供）：胃肠道肿瘤（GIST）是肠道最常见的间充质肿瘤。直到最近，手术一直是GIST患者的唯一有效疗法。尽管完全切除了肿瘤，但大多数患者仍会发育并最终死于复发性疾病。大多数GIST在试剂盒原型癌基因中具有功能突变的增益，从而导致组成型试剂盒蛋白激活和不受控制的细胞增殖。 STI571是一个小分子，可有选择地抑制试剂盒和其他一些酪氨酸激酶。它代表了癌症治疗中的具有里程碑意义的成就。 STI571验证了分子肿瘤学领域，因为它证明特定抑制剂可用于靶向负责肿瘤发病机理的分子像差。 STI571在大约三分之二的转移性观点患者中有效。接受手术切除的主要要点的患者可能会受益于STI571辅助性STI571，这是正在进行的CTEP赞助的III期随机，双盲，安慰剂控制，组间试验的主题。我们建议研究从多中心试验的患者中收集的组织标本。我们假设主要要点的分子特征预测了辅助性STI571治疗后的临床结果。此外，我们假设随后的复发性要点的分子变化将揭示出GIST中STI571抗性的机制。在AIM 1中，我们将将特定的病理学（肿瘤部位和大小）和细胞遗传学（5p，17q或20q的增长或9p的损失）与原发性观点的表型相关联，以复发和生存。 AIM 2专注于基本要点与复发和生存的套件突变状态的关系。在AIM 3中，我们将比较主要要点的病理和分子特征，以重复出现要点，以开始定义STI571抗性的分子机制。提出的实验代表了原发性观点的首次前瞻性临床和病理研究，并将揭示要点（安慰剂组）的自然历史以及对辅助治疗（STI571 ARM）的反应。该数据将为原发性要点的未来临床病理学研究奠定标准，并可能提供治疗对STI571具有抗性患者的方法。结果将进一步定义GIST生物学，并适用于用分子剂治疗的其他疾病。