ErbB Family in Pituitary Tumors

描述(由申请人提供)： 项目摘要/摘要： 了解脑下垂体瘤生长的机制仍然是一个挑战。在这项建议中，我们假设由于erbB受体酪氨酸激酶表达的变化，垂体肿瘤从非侵袭性表型演变为更具侵袭性的表型。这些变化会导致侵袭性垂体瘤的发展。我们的初步观察显示，与非侵袭性肿瘤相比，erb B家族成员在侵袭性垂体肿瘤中的表达有所不同。我们计划进行一项前瞻性研究，利用免疫组织化学技术、荧光原位杂交和血清EGFR和erbB2检测，检测从微腺瘤到大腺瘤再到侵袭性越来越强的肿瘤中erB表达的变化。我们的实验室将证明，在植入转基因垂体细胞系的动物模型中，垂体肿瘤的侵袭性与EGFR和erbB2水平的增加有关。接下来，我们提出了一种小分子双重EGFR/erbB2酪氨酸激酶抑制剂拉帕替尼，它可以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，并在体外评估它们对药物的反应。我们将使用免疫沉淀和免疫印迹来检测erb B受体的差异表达，TUNEL法来检测细胞凋亡，催乳素在催乳素瘤中的检测。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，我们计划对复发性无功能腺瘤和分泌催乳素的腺瘤患者进行为期六个月的治疗，这些患者在接受手术切除之前使用拉帕替尼进行标准药物治疗，并评估肿瘤大小和垂体瘤分泌情况的稳定性。这项拨款中提出的工作将深入了解对标准疗法具有抵抗力的一类新的脑下垂体瘤疗法。 公共卫生相关性： 叙述：我们建议研究如何通过表皮生长因子受体途径使垂体肿瘤变得更具侵袭性。我们将针对这一途径测试靶向治疗，以开发复发肿瘤的新疗法。

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.