ErbB receptor tyrosine kinase inhibitor therapy for aggressive prolactinomas

ErbB 受体酪氨酸激酶抑制剂治疗侵袭性催乳素瘤

• 批准号: 8874043
• 负责人: Odelia Cooper
• 金额: $ 24.62万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-05 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874043
• 关键词: Affect; Algorithms; American; Animal Model; Animals; Area; Attenuated; Award; Behavior; Biological Markers; Biological Response Modifier Therapy; Blindness; Blood Vessels; Cell Line; Cell Proliferation; Cessation of life; Clinical; Clinical Sciences; Clinical Trials; Collaborations; Data; Dimerization; Disease; Dopamine Agonists; Endocrine; Ensure; Epidermal Growth Factor Receptor; ErbB4 gene; Excision; Exhibits; Foundations; Future; Gene Expression; General Hospitals; Grant; Hormones; Hospitals; Human; Hypopituitarism; Image; Immunohistochemistry; Implant; Injury; Intervention; Investigational Therapies; Knowledge; Laboratory Finding; Lead; Magnetic Resonance Imaging; Malignant neoplasm of thyroid; Massachusetts; Measurement; Measures; Medical; Medical center; Medicine; Molecular Target; Morbidity - disease rate; Nuclear; Oncologist; Operative Surgical Procedures; Patients; Phase; Phenotype; Pituitary Gland; Pituitary Gland Adenoma; Pituitary Neoplasms; Play; Prolactin; Prolactin Secreting Pituitary Gland Neoplasm; Prolactinoma; Protein Tyrosine Kinase; Quality of life; Radiation therapy; Recruitment Activity; Recurrent disease; Refractory; Regimen; Regulation; Resistance; Role; Sampling; Site; Specimen; Stroke; Testing; Therapeutic; Tissues; Translating; Translational Research; Tumor Cell Invasion; Tumor Cell Line; Tyrosine Kinase Inhibitor; Tyrosine Kinase Receptor Inhibition; United States National Institutes of Health; Visit; Work; adenoma; aggressive therapy; base; cancer therapy; chemotherapy; clinical efficacy; clinical practice; cost; design; improved; innovation; lactotroph; lapatinib; mortality; novel; protein expression; public health relevance; receptor; receptor expression; response; skills; targeted treatment; tool; tumor; tumor growth; tumor xenograft

 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.

 描述（由申请人提供）：我们提议响应号召，为垂体医学中的一种具有挑战性的疾病寻找新的疗法，即侵袭性催乳素瘤，这种疾病影响着十万美国人中的 13 人，目前除了标准手术、放射疗法和精选药物疗法之外，治疗选择有限，每种疗法都会导致显着的发病率和死亡率，而且每种疗法都不是最佳效果。为了弥补这一知识差距，我们寻求将实验室的研究结果转化为临床实践，并专注于针对垂体分子靶点（即 ErbB 受体）的疗法。我们已经证明，人类泌乳素瘤表达核 EGFR 和膜 ErbB2、ErbB3 和 ErbB4，并且表达与肿瘤侵袭相关。转染 EGFR 和 ErbB2 的垂体肿瘤细胞系对催乳素 (PRL) 基因表达和分泌以及细胞增殖产生下游影响。植入这些细胞系的动物模型出现了更大的肿瘤和泌乳素升高。使用 ErbB 酪氨酸激酶抑制剂 (TKI) 治疗可导致异种移植到这些动物体内的肿瘤消退，并减弱 PRL 分泌。人泌乳素瘤的原代培养证实了 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，这项新提案的目标是进行 IIa 期临床试验，作为对我们的转化假设的尖锐测试，即酪氨酸激酶抑制构成了针对这些迄今为止难治性侵袭性泌乳素分泌垂体腺瘤的高效靶向生物疗法。具体来说，我们的目标是测试：1）通过临床试验 TKI 治疗的功效； 2)达到TKI临床反应的肿瘤受体表达的阈值水平。与其他 2 个中心（约翰·霍普金斯医院和马萨诸塞州总医院）合作，19 名受试者将接受拉帕替尼治疗 6 个月，并结合他们目前的多巴胺激动剂治疗，每月测量 PRL 水平并每 3 个月进行 MRI 成像，以评估实现 PRL 降低 50% 的主要终点以及放射学稳定和/或降低以及 PRL 正常化的次要终点。将通过免疫组织化学比较从先前手术收集的这些受试者的垂体肿瘤样本中对拉帕替尼有反应的人和无反应者之间的平均ErbB受体蛋白表达。这项研究的结果将为 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。