The pituitary TGFβ family, novel target for the treatment of pituitary tumors

M VICTORIA RECOUVREUX; ABELEDO-MACHADO, ALEJANDRA; FARAONI, ERIKA YANIL; DÍAZ -TORGA GRACIELA; CAMILLETTI, MARÍA ANDREA

Palm Beach

Congreso; FASEB TGFb; 2019

FASEB

Pituitary tumors are commonly benign adenomas, accounting for 10-15% of all intracranial neoplasms. Among functioning pituitary tumors, prolactinomas are the most frequently observed in the clinic (about 40%). Dopamine, acting through the dopamine type 2 receptor (Drd2), is the main inhibitor of lactotroph proliferation and prolactin secretion, therefore, these tumors are usually treated with dopaminergic agonists with a high efficiency. However, there is a subset of prolactinomas (15 and 20%) that do not respond to this treatment, named dopamine agonist resistant prolactinomas, which represent a major challenge for clinical management, because up to date, no alternative treatments have been found. Transforming growth factor β1 (TGFβ1) and activins are known inhibitors of lactotroph cell proliferation and prolactin secretion. In our lab we have studied the role of TGFβ1 and activins in normal and tumoral pituitaries, and we postulate that: due to the inhibitory action on lactotroph proliferation and PRL synthesis, the TGFβ-family members represent targets to develop alternative treatments for resistant prolactinomas. We demonstrated, in 3 different animal models of prolactinomas, the Drd2 knock-out mice, the estrogen-treated rat and the hCGβ overexpressing mice, that: 1-Pituitary TGFβ1 activity, several components of the TGFβ1 system (LTBPs, TβRII, local activators), as well as activin expression are reduced in prolactinomas vs normal pituitaries (Endocrinology 2011;152(7):2722-). 2-in vivo treatments that recover pituitary TGFβ1 activity reduce the hyperprolactinemia and counteract tumor growth (Endocrinology 2012;153(8):3861-71; J Endocrinol. 2016;228(3): R73-83; J Endocrinol. 2017;232(3):535-546).3-TGFβ1 activity and activin expression are higher in male pituitaries (sex differences: protective factors?), (Endocrinology 2013;154(11):4192-205; Front Neuroendocrinol. 2018;50:118-122).4-Ovariectomy in animal models of prolactinoma recovers pituitary TGFβ1 activity and activin expression preventing prolactinoma development. These findings open new possible therapies in treatment for prolactinomas, especially in those that are resistant to dopaminergic drugs.