ErbB Family in Pituitary Tumors

垂体肿瘤中的 ErbB 家族

• 批准号: 7771064
• 负责人: Odelia Cooper
• 金额: $ 16.87万
• 依托单位: CEDARS-SINAI 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: 2009-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7771064
• 关键词: Animal Model; Apoptosis; Binding; Biological Assay; Breast Cancer Cell; Cancer cell line; Cell Line; Cells; Clinical Trials; Cultured Tumor Cells; Development; Disease Progression; EGF gene; ERBB2 gene; Epidermal Growth Factor Receptor; Excision; Extracellular Domain; Family; Fluorescent in Situ Hybridization; Gefitinib; Gene Amplification; Grant; Growth; Hormonal; Hormones; Human; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Implant; In Vitro; Laboratories; Lead; Measurement; Measures; Medical; Messenger RNA; Monoclonal Antibodies; Mus; Non-Small-Cell Lung Carcinoma; Nude Mice; Operative Surgical Procedures; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Pituitary Gland; Pituitary Hormones; Pituitary Neoplasms; Prolactin; Prolactinoma; Property; Prospective Studies; Protein Tyrosine Kinase; Rattus; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent tumor; Reporting; Resistance; Serum; Specimen; TdT-Mediated dUTP Nick End Labeling Assay; Techniques; Testing; Therapeutic; Tumor Volume; Tyrosine Kinase Inhibitor; Work; abstracting; adenoma; capecitabine; clinical effect; insight; kinase inhibitor; lapatinib; malignant breast neoplasm; member; neoplastic cell; novel; overexpression; protein expression; public health relevance; receptor; receptor expression; response; small molecule; tumor; tumor growth

DESCRIPTION (provided by applicant): Project Summary/Abstract: Understanding the mechanisms of pituitary tumor growth continues to be challenging. In this proposal, we hypothesize that pituitary tumors progress from a non-invasive phenotype into a more aggressive one as a consequence of changes in the expression of erbB receptor tyrosine kinases. These changes lead to development of aggressive pituitary tumors. Our preliminary observations demonstrate differential expression of members of the erbB family in aggressive pituitary tumors in comparison to noninvasive tumors. We plan to conduct a prospective study examining changes in erbB expression from microadenomas to macroadenomas to increasingly invasive tumors using immunohistochemistry techniques, fluorescent in situ hybridization, and assays for serum EGFR and erbB2. Our laboratory will demonstrate that pituitary tumor invasiveness correlates with increasing levels of EGFR and erbB2 in animal models implanted with transfected pituitary cell lines. Next, we propose that lapatinib, a small molecule dual EGFR/erbB2 tyrosine kinase inhibitor, inhibits growth and invasion of pituitary tumor cells. We will prospectively collect human pituitary tumor surgical specimens, culture the tumor cells, and assess their response to the drug in vitro. We will use immunoprecipitation and immunoblotting to examine differential expression of erbB receptors, TUNEL assay to measure apoptosis, and prolactin measurements for prolactinomas. In addition, our laboratory will test lapatinib in animal models. Finally, we hypothesize that lapatinib will inhibit tumor growth and hormonal secretion in patients with pituitary tumors. In a proof of concept clinical trial, we plan to treat patients with recurrent nonfunctioning adenomas and prolactin-secreting adenomas resistant to standard medical therapy with lapatinib for six months prior to undergoing surgical resection and assess for stabilization of tumor size and pituitary tumor secretory profiles. The work proposed in this grant will shed insight into a new class of therapeutics in pituitary tumors that are resistant to standard therapies. PUBLIC HEALTH RELEVANCE: NARRATIVE: We propose to investigate how pituitary tumors become more aggressive through the epidermal growth factor receptor pathways. We will test targeted therapy against this pathway to develop novel therapies in recurrent tumors.

描述（由申请人提供）： 项目摘要/摘要： 了解垂体肿瘤生长的机制仍然具有挑战性。在此提案中，我们假设垂体肿瘤从非侵入性表型发展为更具侵略性的肿瘤，这是由于ERBB受体酪氨酸激酶表达的变化而导致的。这些变化导致攻击性垂体肿瘤的发展。我们的初步观察结果表明，与非侵入性肿瘤相比，ERBB家族在攻击性垂体肿瘤中的成员表达差异。我们计划进行一项前瞻性研究，研究使用免疫组织化学技术，荧光原位杂交以及血清EGFR和ERBB2的测定法，从MICOXENOMAS到巨型瘤到越来越多的侵入性肿瘤的ERBB表达变化。我们的实验室将证明垂体肿瘤的侵入性与植入转染的垂体细胞系的动物模型中的EGFR和ERBB2水平的增加相关。接下来，我们建议Lapatinib是一种小分子双EGFR/ERBB2酪氨酸激酶抑制剂，抑制了垂体肿瘤细胞的生长和侵袭。我们将前瞻性地收集人垂体肿瘤的手术标本，培养肿瘤细胞，并在体外评估其对药物的反应。我们将使用免疫沉淀和免疫印迹来检查ERBB受体的差异表达，TUNEL分析以测量凋亡以及催乳素瘤的催乳素测量。此外，我们的实验室将在动物模型中测试拉帕替尼。最后，我们假设拉帕替尼将抑制垂体肿瘤患者的肿瘤生长和荷尔蒙分泌。在概念临床试验证明中，我们计划治疗复发性无功能的腺瘤和分泌催乳素分泌的患者，在进行手术切除和评估肿瘤大小和垂体肿瘤的分泌物的稳定性之前，将抗标准药物治疗的腺瘤对标准药物治疗有抵抗力。这笔赠款中提出的工作将洞悉垂体肿瘤中对标准疗法具有抗性的新型治疗剂。 公共卫生相关性： 叙述：我们建议研究垂体肿瘤如何通过表皮生长因子受体途径变得更具侵略性。我们将测试针对这种开发复发性肿瘤新疗法的靶向疗法。