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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

基本信息

批准号：
9063059
负责人：
Odelia Cooper
金额：
$ 18.26万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-05 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063059
关键词：
Affect Algorithms American Animal Model Animals Area Attenuated Award Behavior 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 Health 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 Tumor Markers 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 erbB-2 Receptor improved innovation lactotroph lapatinib mortality novel novel therapeutics protein expression receptor receptor expression response skills targeted treatment tool tumor tumor growth tumor xenograft

项目摘要

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）：我们建议响应为垂体医学中的一种具有挑战性的疾病寻找新疗法的呼吁，即侵袭性泌乳素瘤，其影响10万美国人中的13人，目前除了标准手术，放射治疗和选择药物治疗外，治疗选择有限，每种治疗都会引起显著的发病率和死亡率，并且每种治疗都不是最佳有效的。为了改善这一知识差距，我们寻求将实验室的发现转化为临床实践，并针对垂体分子靶点（即ErbB受体）进行治疗。我们已经发现，人泌乳素瘤表达细胞核EGFR和膜ErbB 2，ErbB 3和ErbB 4，表达与肿瘤侵袭相关。EGFR和ErbB 2转染的P450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效应。植入这些细胞系的动物模型产生更大的肿瘤和PRL升高。用ErbB酪氨酸激酶抑制剂（TKI）治疗导致异种移植到这些动物中的肿瘤消退并减弱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，这项新提议的目的是进行一项IIa期临床试验，作为对我们翻译假设的有力检验，即酪氨酸激酶抑制是迄今为止难治的侵袭性泌乳素分泌型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）临床试验中TKI治疗的疗效; 2）达到TKI临床缓解的肿瘤复发表达阈值水平。与其他2家研究中心（约翰霍普金斯医院和马萨诸塞州综合医院）合作，19例受试者将接受拉帕替尼治疗6个月，联合其当前的多巴胺受体激动剂治疗，每月测量一次PRL水平，每3个月进行一次MRI成像，以评价实现PRL降低50%的主要终点和放射学稳定和/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拉帕替尼应答者和非应答者在这些受试者既往手术中采集的垂体瘤样本中的平均ErbB受体蛋白表达。这项研究的结果将奠定一个更强有力的为未来的R 01基金奠定了基础，以进一步扩大ErbB受体作用的知识，并改变侵袭性垂体腺瘤治疗的医学算法。