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.

Public Health Relevance

Aggressive prolactin secreting pituitary tumors are a continuing challenge for clinicians as current treatments are not effective and lead to complications which contribute to poor quality of life and even mortality. As ErbB receptors have been shown to play a role in these tumors, we propose to conduct a clinical trial treating patients with aggressive prolactinomas with ErbB targeted therapy. This work may potentially change the medical algorithm in treatment of patients with this difficult disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Malozowski, Saul N
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Cedars-Sinai Medical Center
Los Angeles
United States
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Ben-Shlomo, Anat; Cooper, Odelia (2017) Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: from bench to bedside. Curr Opin Endocrinol Diabetes Obes 24:301-305
Lee, Jane; Kulubya, Edwin; Pressman, Barry D et al. (2017) Sellar and clival plasmacytomas: case series of 5 patients with systematic review of 65 published cases. Pituitary 20:381-392