ErbB receptor tyrosine kinase inhibitor therapy for aggressive prolactinomas

 描述(申请人提供)：我们建议响应号召，寻找新的治疗方法来治疗一种具有挑战性的疾病，即侵袭性催乳素瘤，这种疾病影响到10万名美国人中的13人，目前除标准手术、放射治疗和精选药物治疗外，治疗选择有限，每一种方法都会导致显著的发病率和死亡率，而且每一种方法都不是最佳有效的。为了改善这一知识差距，我们试图将实验室的发现转化为临床实践，并磨练针对垂体分子靶点的治疗方法，即ErbB受体。我们发现人催乳素瘤表达核的EGFR和膜的ErbB2、ErbB3和ErbB4，并且表达与肿瘤的侵袭性有关。转EGFR和ErbB2基因的垂体瘤细胞株对催乳素(PRL)基因的表达和分泌以及细胞的增殖均有下游作用。植入这些细胞系的动物模型出现了更大的肿瘤和PRL升高。使用ErbB酪氨酸激酶抑制剂(TKIs)治疗可导致移植到这些动物体内的肿瘤消退，并减弱PRL的分泌。原代培养的人催乳素瘤证实了ErbB受体的表达以及TKI对PRL分泌和细胞增殖的抑制作用。基于这些令人兴奋的初步数据，这项新建议的目标是进行IIa期临床试验，作为对我们的翻译假设的尖锐测试，即酪氨酸激酶抑制构成了对这些迄今难治的侵袭性催乳素分泌垂体腺瘤的高效靶向生物治疗。具体地说，我们的目标是通过临床试验测试TKI治疗的有效性；2)肿瘤受体表达的阈值水平，以实现TKI的临床反应。在约翰霍普金斯医院和马萨诸塞州综合医院的合作下，19名受试者将在目前的多巴胺激动剂治疗的同时，接受为期6个月的拉帕替尼治疗，每月测量PRL水平，每3个月进行核磁共振成像，以评估实现PRL下降50%的主要终点和放射学稳定和/或减少和PRL正常化的次要终点。通过免疫组织化学方法比较对拉帕替尼有反应和无反应的受试者脑垂体肿瘤标本中ErbB受体蛋白的平均表达。这项研究的结果将为更强的 为未来的R01拨款奠定基础，以进一步扩大对ErbB受体作用的了解，并改变治疗侵袭性垂体腺瘤的医学算法。

 DESCRIPTION (provided by applicant): We propose to answer the call to find new therapies for a challenging disease in pituitary medicine, that of aggressive prolactinomas which affects 13 out of 100,000 Americans and currently have limited therapeutic options beyond standard surgical, radiotherapy, and select medical therapies, each incurring significant morbidity and mortality, and each not optimally effective. To improve this gap in knowledge, we seek to translate findings from the laboratory into clinical practice and hone in on therapies directed at pituitary molecular targets, namely ErbB receptors. We have shown that human prolactinomas express nuclear EGFR and membranous ErbB2, ErbB3 and ErbB4, and expression correlates with tumor invasion. Pituitary tumor cell lines transfected with EGFR and ErbB2 translated to downstream effects on prolactin (PRL) gene expression and secretion,as well as cell proliferation. Animal models implanted with these cell lines developed larger tumors and PRL elevations. Treatment with ErbB tyrosine kinase inhibitors (TKIs) led to regression of tumors xenografted into these animals and attenuated PRL secretion. Primary culture of human prolactinomas confirmed expression of ErbB receptors and inhibitory effects of TKIs on PRL secretion and cell proliferation. Based on these exciting preliminary data, the objective of this new proposal is to conduct a Phase IIa clinical trial as a trenchant test of our translational hypothesis that tyrosine kinase inhibition constitutes highly effective targeted biologic therapy fr these hitherto refractory invasive prolactin-secreting pituitary adenomas. Specifically, our aims are to test the: 1) efficacy of TKI therapy with a clinical trial; 2) threshold level of tumor recetor expression to achieve TKI clinical response. In collaboration with 2 other sites, Johns Hopkins Hospital and Massachusetts General Hospital, 19 subjects will be treated with lapatinib for 6 months in combination with their current dopamine agonist therapy, with monthly measurements of PRL levels and MRI imaging every 3 months to evaluate the primary endpoints of achieving 50% reduction in PRL and secondary endpoints of radiologic stabilization and/or reduction and PRL normalization. Mean ErbB receptor protein expression will be compared between responders to lapatinib and non- responders by immunohistochemistry in pituitary tumor samples of these subjects collected from prior surgeries. Results of this study will lay a stronger foundation for a future R01 grant to further expand knowledge of the role of ErbB receptors and change the medical algorithm in treatment of aggressive pituitary adenomas.