ErbB Family in Pituitary Tumors

描述（由申请人提供）： 项目概要/摘要： 了解垂体瘤生长的机制仍然具有挑战性。在这个建议中，我们假设，垂体瘤的进展，从一个非侵袭性的表型成为一个更具侵略性的erbB受体酪氨酸激酶的表达变化的结果。这些变化导致侵袭性垂体瘤的发展。我们的初步观察表明，erbB家族成员的差异表达的侵袭性垂体瘤相比，非侵袭性肿瘤。我们计划进行一项前瞻性研究，采用免疫组化技术、荧光原位杂交和血清EGFR和erbB 2检测，研究从微腺瘤到大腺瘤再到侵袭性越来越强的肿瘤erbB表达的变化。我们的实验室将证明垂体肿瘤侵袭性与植入转染垂体细胞系的动物模型中EGFR和erbB 2水平的增加相关。接下来，我们提出拉帕替尼，一种小分子EGFR/erbB 2酪氨酸激酶双重抑制剂，抑制垂体瘤细胞的生长和侵袭。我们将前瞻性地收集人垂体瘤手术标本，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法来检测erbB受体的差异表达，TUNEL法来测量细胞凋亡，并对泌乳素瘤进行泌乳素测量。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瘤患者的肿瘤生长和激素分泌。在一项概念验证临床试验中，我们计划在接受手术切除前使用拉帕替尼治疗对标准药物治疗耐药的复发性无功能腺瘤和泌乳素分泌腺瘤患者6个月，并评估肿瘤大小和垂体瘤分泌特征的稳定性。这项研究将深入了解对标准疗法有抵抗力的垂体瘤的一类新疗法。 公共卫生相关性： 叙述：我们打算研究垂体瘤如何通过表皮生长因子受体途径变得更具侵袭性。我们将测试针对该途径的靶向治疗，以开发复发性肿瘤的新疗法。

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.