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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.