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（由适用提供）：我们建议回答呼叫的呼吁，以寻找垂体医学中一种挑战疾病的新疗法，积极的催乳素瘤会影响100,000名美国人中的13个，目前在标准手术，放射疗法之外的治疗选择有限，并且每种药物疗法超出了精选的医疗疗法，每种治疗疗法，每种均为明显的疾病和死亡率，且无效。为了改善知识的差距，我们试图将实验室的发现转化为临床实践，并在针对垂体分子靶标（即ERBB受体）的疗法中转化为临床实践。我们已经表明，人催乳瘤表达核EGFR和膜的ERBB2，ERBB3和ERBB4，并且表达与肿瘤侵袭相关。用EGFR和ERBB2翻译的垂体肿瘤细胞系转化为对催乳素（PRL）基因表达和分泌以及细胞增殖的下游影响。植入这些细胞系的动物模型会出现较大的肿瘤和PRL升高。用ERBB酪氨酸激酶抑制剂（TKIS）治疗导致肿瘤在这些动物上的回归并减弱PRL分泌。人催乳素瘤的原发性培养证实了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，这项新提案的目的是进行IIA期临床试验，作为对我们的转化假设进行的一次测试，即酪氨酸激酶抑制构成了这些迄今为止这些迄今难以抗药性的侵袭性垂体垂体腺瘤的高效靶向生物治疗。具体而言，我们的目的是测试：1）通过临床试验的TKI治疗的有效性； 2）肿瘤接收器表达的阈值水平以实现TKI临床反应。约翰·霍普金斯医院和马萨诸塞州综合医院与其他两个网站合作，将有19名受试者与拉帕替尼进行6个月的治疗，并结合其当前的多巴胺激动剂治疗，每3个月对PRL水平和MRI成像的测量每3个月进行测量，以评估在prllodic and protal and radiologic and radi andirologic and radi and radiolic and radi and radi and radiodic and radiodic and radiology and radiogitiation and radiology and radiogition and radiogition septrical and intocipt上的范围和次数的较低范围的范围为50％。通过免疫组织化学在垂体肿瘤样本中，将比较响应者对拉帕替尼的反应者对拉帕替尼的反应者的平均ERBB受体蛋白表达。这项研究的结果将提高 未来R01赠款的基础，以进一步扩大对ERBB受体作用的了解，并改变医学算法在治疗侵袭性垂体腺瘤中的知识。