Research Areas
The pituitary is a small endocrine gland that controls vital homeostatic functions. It is called the “master gland” because it directs other organs and endocrine glands, such as the thyroid, the adrenals and the liver to suppress or induce hormone production. Under control of growth factors and transcription factors, pituitary progenitor cells differentiate into five types of hormone-secreting cells: lactotrophs (prolactin secreting), somatotrophs (growth-hormone (GH) secreting), gonadotrophs (follicle-stimulating hormone and luteinizing-hormone secreting), thyrotrophs (thyroid-stimulating hormone secreting) and corticotrophs (adrenocorticotrophic-hormone (ACTH) secreting).
Drivers of Somatotroph Adenoma Progression
Anat Ben-Shlomo, MD, studies genomic changes that underlie development and progression of pituitary tumors, particularly GH-secreting somatotroph adenomas that lead to acromegaly. Using whole-exome sequencing and KEGG pathway analysis, she has shown somatic copy number alterations (SCNAs), rather than genetic mutations, are hallmarks of these tumors, and that activating the cAMP signaling pathway increases DNA damage (Ben-Shlomo et al., J Clin Invest. 2020). These findings help explain different phenotypes and treatment responses in patients with acromegaly and provide a basis for further studies linking SCNAs, cAMP signaling and DNA damage in the development of somatotroph adenomas.
Figure 2. Comet assay and tail appearance (magnification ×20) in representative mice treated with PBS as control (left) or the long-acting GHRH analogue CJC-1295 (right).
Figure 3. Comet assay Olive tail moment for the mice presented in Figure 2. The number of cells analyzed by a blinded observer is indicated. Results are presented as mean ± SEM. ###p ≤ 0.001 for each CJC-1295–treated mouse versus each PBS-treated mouse by one-way ANOVA.
Cuiqi Zhou, PhD, studies molecular drivers of pituitary adenomas utilizing cellular and animal models. She has investigated regulatory mechanisms and functions of pituitary tumor-transforming gene (PTTG), mediated by cell cycle regulators Rb/E2F1 and STAT3 as well as hormone regulation; extending our knowledge of tumor cell cycle control and other anti-tumor therapeutic approaches (Zhou et al., J Clin Invest. 2015).
Growth Hormone and Epithelial Cell Proliferation
Vera Chesnokova, PhD, studies the role of GH in the neoplastic transformation of epithelial cells. Recognizing that GH excess in acromegaly is associated with high rates of colon tumors, while genetic mutations leading to GH deficiency protect against cancer development, she has used colon tissues as a model to study mechanisms underlying effects of GH on the tumor microenvironment and on the DNA damage response. (Chesnokova et al., Proc Natl Acad Sci USA. 2016). These studies suggest that therapeutic approaches to block local GH signaling may disrupt epithelial proliferation and slow or prevent preneoplastic epithelial changes.
Figure 1. Two-month-old normal and GH-deficient Prop1-/- mice (left). Crossbreeding of APCmin+/- mice genetically predisposed to intestinal tumors with GH-deficient Prop1-/- mice resulted in a marked decrease in the number of mice bearing colon tumors (right).
Figure 2. Athymic nude mice were injected with HCT116 lenti-mGH (GH) or HCT116 lenti-vector (vector) cells. Four weeks later, when mice develop ~0.53 cm xenograft tumors, they received intrasplenic injections of 500,000 HCT116 cells and were sacrificed four weeks later. Left, percent of mice that developed distant metastasis. Right, number of metastases per mouse adjusted to the circulating GH levels. ##p < 0.05 by one-way ANCOVA, F = 4.66, degrees of freedom = 1.16.
Novel Therapeutics for Aggressive Pituitary Adenomas
The Melmed Lab partners with the Pituitary Center to conduct laboratory, translational and clinical studies of novel therapeutics for aggressive pituitary adenomas. Following on studies of the epidermal growth factor receptor (EGFR) pathway in pituitary tumor growth, a phase II multicenter clinical trial demonstrated that the EGFR tyrosine kinase inhibitor lapatinib can reduce prolactin levels and tumor size in select patients with aggressive prolactinoma (Cooper et al., J Clin Endocrinol Metab. 2020). The CDK inhibitor seliciclib (R-roscovitine) was shown first in zebrafish, then in mouse and human pituitary cells, to suppress POMC gene expression and inhibit ACTH production, thereby reducing levels of circulating cortisol (Liu et al., J Clin Endocrinol Metab. 2015). An ongoing phase II multicenter clinical trial supported by the FDA Office of Orphan Products Development is evaluating the ability of seliciclib to normalize cortisol levels in patients with Cushing disease.
Contact the Melmed Lab
8700 Beverly Blvd.
Davis Building, Room 3024
Los Angeles, CA 90048