Dongyun Zhang1, Jennifer S Way1, Xinhai Zhang2, Mareninov Sergey2, Marvin Bergsneider3, Marilene B Wang4, William H Yong2, Anthony P Heaney1,3. 1. Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 2. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 3. Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 4. Department of Head and Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
Abstract
CONTEXT: Aggressive prolactin (PRL)-secreting pituitary adenomas that are resistant to conventional therapy with dopamine agonists, surgery, and radiation pose a therapeutic challenge. The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved to treat neuroendocrine tumors (NETs), and cotreatment with the somatostatin receptor ligand octreotide improved median progression-free survival in patients with metastatic pancreatic NETs. PATIENT, INTERVENTION, AND RESULTS: We describe off-label everolimus treatment of a prolactinoma (PRLoma) refractory to cabergoline, repeat surgical resection, and radiation therapy. Addition of everolimus to cabergoline led to decreased PRL levels and tumor regression after 5 months. Tumor size remained stable for 12 months, and although PRL levels rose, they remained below pretreatment levels. Immunohistochemical (IHC) evaluation of expression of key mTOR pathway drivers of cell proliferation revealed elevated phosphorylated (p-)AKT, p-4EBP1, and p-S6 in the index patient's tumor. IHC analysis of seven additional PRLomas demonstrated increased expression of nuclear p-AKT, cytoplasmic p-S6, and globally increased p-4EBP1 in the PRLomas compared with 11 autopsy-derived normal pituitary tissues. In in vitro studies in murine mammosomatotroph tumor GH3 cells, we observed that both the dopamine agonist cabergoline and the mTOR inhibitor everolimus inhibited GH3 cell proliferation and PRL secretion as single agents, and the synergistic effect was noted with combination treatment only on inhibition of PRL secretion but not proliferation. CONCLUSIONS: In summary, our findings demonstrate that the mTOR pathway is activated in PRLomas and that everolimus exhibits antiproliferative actions in vitro. We suggest that everolimus may be a novel therapeutic option for some aggressive PRL-secreting tumors unresponsive to conventional treatments.
CONTEXT: Aggressive prolactin (PRL)-secreting pituitary adenomas that are resistant to conventional therapy with dopamine agonists, surgery, and radiation pose a therapeutic challenge. The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved to treat neuroendocrine tumors (NETs), and cotreatment with the somatostatin receptor ligand octreotide improved median progression-free survival in patients with metastatic pancreatic NETs. PATIENT, INTERVENTION, AND RESULTS: We describe off-label everolimus treatment of a prolactinoma (PRLoma) refractory to cabergoline, repeat surgical resection, and radiation therapy. Addition of everolimus to cabergoline led to decreased PRL levels and tumor regression after 5 months. Tumor size remained stable for 12 months, and although PRL levels rose, they remained below pretreatment levels. Immunohistochemical (IHC) evaluation of expression of key mTOR pathway drivers of cell proliferation revealed elevated phosphorylated (p-)AKT, p-4EBP1, and p-S6 in the index patient's tumor. IHC analysis of seven additional PRLomas demonstrated increased expression of nuclear p-AKT, cytoplasmic p-S6, and globally increased p-4EBP1 in the PRLomas compared with 11 autopsy-derived normal pituitary tissues. In in vitro studies in murine mammosomatotroph tumor GH3 cells, we observed that both the dopamine agonist cabergoline and the mTOR inhibitor everolimus inhibited GH3 cell proliferation and PRL secretion as single agents, and the synergistic effect was noted with combination treatment only on inhibition of PRL secretion but not proliferation. CONCLUSIONS: In summary, our findings demonstrate that the mTOR pathway is activated in PRLomas and that everolimus exhibits antiproliferative actions in vitro. We suggest that everolimus may be a novel therapeutic option for some aggressive PRL-secreting tumors unresponsive to conventional treatments.
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