Understanding the mechanisms of pituitary tumor growth continues to be challenging. In this proposal, we hypothesize that pituitary tumors progress from a non-invasive phenotype into a more aggressive one as a consequence of changes in the expression of erbB receptor tyrosine kinases. These changes lead to development of aggressive pituitary tumors. Our preliminary observations demonstrate differential expression of members of the erbB family in aggressive pituitary tumors in comparison to noninvasive tumors. We plan to conduct a prospective study examining changes in erbB expression from microadenomas to macroadenomas to increasingly invasive tumors using immunohistochemistry techniques, fluorescent in situ hybridization, and assays for serum EGFR and erbB2. Our laboratory will demonstrate that pituitary tumor invasiveness correlates with increasing levels of EGFR and erbB2 in animal models implanted with transfected pituitary cell lines. Next, we propose that lapatinib, a small molecule dual EGFR/erbB2 tyrosine kinase inhibitor, inhibits growth and invasion of pituitary tumor cells. We will prospectively collect human pituitary tumor surgical specimens, culture the tumor cells, and assess their response to the drug in vitro. We will use immunoprecipitation and immunoblotting to examine differential expression of erbB receptors, TUNEL assay to measure apoptosis, and prolactin measurements for prolactinomas. In addition, our laboratory will test lapatinib in animal models. Finally, we hypothesize that lapatinib will inhibit tumor growth and hormonal secretion in patients with pituitary tumors. In a proof of concept clinical trial, we plan to treat patients with recurrent nonfunctioning adenomas and prolactin-secreting adenomas resistant to standard medical therapy with lapatinib for six months prior to undergoing surgical resection and assess for stabilization of tumor size and pituitary tumor secretory profiles. The work proposed in this grant will shed insight into a new class of therapeutics in pituitary tumors that are resistant to standard therapies.

Public Health Relevance

NARRATIVE: We propose to investigate how pituitary tumors become more aggressive through the epidermal growth factor receptor pathways. We will test targeted therapy against this pathway to develop novel therapies in recurrent tumors.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
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Cedars-Sinai Medical Center
Los Angeles
United States
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Cooper, Odelia (2015) Silent corticotroph adenomas. Pituitary 18:225-31
Liu, Xiaohai; Kano, Maya; Araki, Takako et al. (2015) ErbB receptor-driven prolactinomas respond to targeted lapatinib treatment in female transgenic mice. Endocrinology 156:71-9
Cuevas-Ramos, Daniel; Carmichael, John D; Cooper, Odelia et al. (2015) A structural and functional acromegaly classification. J Clin Endocrinol Metab 100:122-31
Cooper, Odelia; Mamelak, Adam; Bannykh, Serguei et al. (2014) Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors. Endocrine 46:318-27
Ro, Cynthia; Cooper, Odelia (2013) Bisphosphonate drug holiday: choosing appropriate candidates. Curr Osteoporos Rep 11:45-51
Ghazi, Ali A; Amirbaigloo, Alireza; Dezfooli, Azizollah Abbasi et al. (2013) Ectopic acromegaly due to growth hormone releasing hormone. Endocrine 43:293-302
Cooper, Odelia; Melmed, Shlomo (2012) Subclinical hyperfunctioning pituitary adenomas: the silent tumors. Best Pract Res Clin Endocrinol Metab 26:447-60
Cooper, Odelia; Vlotides, George; Fukuoka, Hidenori et al. (2011) Expression and function of ErbB receptors and ligands in the pituitary. Endocr Relat Cancer 18:R197-211
Fukuoka, Hidenori; Cooper, Odelia; Mizutani, Jun et al. (2011) HER2/ErbB2 receptor signaling in rat and human prolactinoma cells: strategy for targeted prolactinoma therapy. Mol Endocrinol 25:92-103
Fukuoka, Hidenori; Cooper, Odelia; Ben-Shlomo, Anat et al. (2011) EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J Clin Invest 121:4712-21

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