ErbB Family in Pituitary Tumors

垂体肿瘤中的 ErbB 家族

• 批准号: 8325593
• 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/8325593
• 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; 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）：