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 vitrostudies 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.
Prolactinomas (PRLomas) are the most common secreting pituitary adenomas with an estimated prevalence of 35 to 60 cases per 100,000 individuals (1, 2). Most PRLomas are slow-growing benign tumors. They respond well to medical management with dopamine agonists (DAs) such as cabergoline or bromocriptine with symptom (galactorrhea, menstrual irregularity) control, normalization of prolactin (PRL) levels, and reduction in tumor volume in 80% of cases (1).
However, a minority of tumors are resistant to DA therapy, defined as the failure to achieve a normal serum PRL level and <50% tumor shrinkage with maximally tolerated doses of medication (3). These cases are then typically managed by surgical resection to reduce tumor mass and control PRL levels (4). However, given that these tumors often extensively invade the cavernous sinus and other adjacent sellar structures, normalization of PRL is achievable in only 8% to 50% of these patients (3, 4). Additionally, recurrence/regrowth rates are high, and although radiation therapy (single dose or fractionated) can be offered, only one third of patients achieve normalization of serum PRL (3), and the long-term side-effects include hypopituitarism and cognitive impairment. In the last 10 years, treatment with the oral chemotherapy alkylating agent temozolamide has emerged as an effective treatment of pituitary carcinoma. It is also increasingly used to treat aggressive locally invasive pituitary tumors, including DA-resistant PRLomas, and although ∼58% of aggressive PRLomas initially respond to temozolamide, the tumor response is not sustained in most cases (5, 6). Furthermore, the long-term consequences of temozolamide treatment and the risk of secondary malignancy in this group of patients remain unclear (5, 6).
Therefore, management of these refractory PRLomas poses a significant therapeutic challenge for clinicians, and other options are needed. Activation of the mammalian target of rapamycin (mTOR) pathway and in vitro antiproliferative responses to mTOR inhibitors have been previously reported in pituitary tumors (7). We describe a dramatic tumor response in association with a fall in serum PRL to everolimus in a 68-year-old patient, who was refractory to high-dose DA, prior multiple surgical resections, and maximal radiation therapy. His tumor remained stable and serum PRL levels have stayed below pretreatment levels across 12 months of everolimus therapy.
Materials and Methods
Cell culture
Murine pituitary tumor GH3 cells (American Type Culture Collection, Manassas, VA) were cultured using complete F-12K growth medium supplemented with 2.5% fetal bovine serum and 15% horse serum. On monolayer confluency, cells were dislodged using a soft rubber scraper, counted, and seeded for treatments as indicated.
Proliferation assay
Following cell treatment with cabergoline and/or mTOR inhibitors for 24 to 120 hours, cell viability was measured using a CellTiter-Glo® luminescent cell viability assay kit (Promega, Madison, WI). All experiments were performed in triplicate.
PRL ELISA
PRL concentration in GH3 cells following vehicle, cabergoline, and/or everolimus treatment was measured by an ELISA (Calbiotech, Spring Valley, CA).
Histopathologic analysis
Formalin-fixed, paraffin-embedded sections were stained with hematoxylin and eosin. Immunostaining for phosphorylated (p-)AKT, p-S6, and p-4EBP1 was performed on 5-μm tumor sections. Staining signals were scored using the histoscore (range, 0 to 300), representing the product of staining intensity (0, absent; 100, weak; 200, moderate; 300, strong) and percentage tumor cell staining (0 to 100). Tumors were classified using the World Health Organization classification (2004) by our neuropathologist (X.Z.).
Statistical analysis
All in vitro experiments were repeated at least three times. Results are expressed as mean ± SD. Differences were assessed by a Student t test. P values <0.05 were considered significant.
Results
Clinical findings
A 68-year-old man had undergone prior pituitary tumor resection and external beam radiation treatment 6 years previously for a PRL-secreting macroadenoma causing severe visual field deficit. Lost to follow-up, he re-presented to an outside institution with increased serum PRL of 7813 ng/mL [normal range (NR), 3 to 14.7 ng/mL] and central hypogonadism with 8:00 AM total testosterone of 136 ng/dL (NR, 250 to 1100 ng/dL). A brain MRI showed a large pituitary tumor filling the sphenoid sinus and extending along the pituitary stalk into the suprasellar and prepontine region with mass effect on the brain stem. Cabergoline was titrated to 0.75 mg twice weekly, he commenced androgen replacement, and his serum PRL fell to 19 ng/mL after 4 months. However, subsequently his PRL level gradually rose and a repeat MRI showed tumor growth and compression of the optic chiasm despite increasing cabergoline to 0.75 mg daily. Ultimately, he presented to our institution’s emergency department with light perception only. Serum PRL was 286 ng/mL, and he was panhypopituitary with central hypothyroidism with TSH of 0.9 μIU/L (NR, 0.2 to 4.7 μIU/mL) and free T4 of 0.4 ng/dL (NR, 0.8 to 1.6 ng/dL), central hypogonadism with FSH of <0.4 mIU/mL (NR, 1.6 to 9 mIU/mL) and LH of <0.1 mIU/mL (NR 2-12 mIU/mL), and central hypoadrenalism with 8:00 AM serum cortisol of 4 μg/L (NR, 8 to 25 μg/L). He denied galactorrhea or cold intolerance, and the physical examination was notable for bilateral blindness with unreactive pupils, as well as left sixth cranial nerve palsy. Brain MRI showed a large enhancing sellar mass invading both cavernous sinuses and displacing the optic chiasm (Fig. 1A). He commenced hydrocortisone (10 mg twice daily) and levothyroxine (100 μg daily) and underwent repeat transnasal transsphenoidal resection of his pituitary adenoma. Given its extent, total resection was not attainable (Fig. 1B). Histopathology demonstrated patchy immunoreactivity for PRL (Fig. 1F), frequent mitotic figures, an elevated Ki-67 labeling index of 30%, and increased p53 expression, in keeping with a partially dedifferentiated and atypical pituitary tumor. Unfortunately, his vision did not improve; immediate postoperative serum PRL was 225 ng/mL, but despite recommencing cabergoline (0.75 mg daily) his serum PRL level rose to 454 ng/mL during 5 months. Fluorodeoxyglucose–positron emission tomography/CT was negative for any site of disease outside the sella. Given that he had received maximal radiation previously, temozolamide therapy was considered but he declined chemotherapy.
Figure 1.
Pituitary MRI images (A) before, (B) 5 mo after the patient’s second surgery, and (C) 3, (D) 6, and (E) 12 mo following everolimus treatment demonstrating a marked and sustained reduction in tumor mass. (F) Hematoxylin and eosin (H&E, upper) and immunohistochemical PRL expression (PRL, lower). (G) Serum PRL levels, which rose after surgery, fell after 3 mo of everolimus therapy and then gradually increased during 12-mo duration.
Based on previous preclinical studies, he was empirically started on everolimus at 10 mg daily. After 3 months of everolimus treatment, he was readmitted with altered mental status due to hyperglycemia worsened by the mTOR inhibitor therapy, which was managed successfully with daily sitagliptin (100 mg) and insulin glargine (12 U). MRI at that time showed significant tumor shrinkage (Fig. 1D) with maximal tumor dimensions reduced to 38 × 43 × 32 mm (anteroposterior by transverse by craniocaudal) in comparison with 41 × 43 × 34 mm prior to everolimus treatment, and serum PRL had fallen to 253 ng/mL (NR, 3.8 to 18.9 ng/mL). He continued daily everolimus (10 mg) and cabergoline (1.5 mg) treatment, across which pituitary imaging remained stable for 12 months (Fig. 1E). However, serum PRL gradually increased to 261 ng/mL at 16 months postoperative (Fig. 1G). In addition to hyperglycemia, the patient experienced transient hypogeusia and mouth sores as side effects of everolimus, but otherwise the drug was quite well tolerated.
Evaluation of mTOR activation in PRLoma tumor tissues
Given the tumor response we had observed in this patient, we compared immunohistochemical (IHC) mTOR pathway protein expression (p-AKT, p-S6, and p-4EBP1) in his tumor, 7 other PRLomas (3 of which had exhibited D2 agonist resistance), and 11 autopsy-derived normal pituitary tissues. As depicted in Fig. 2A, low-level p-AKT was noted to be evenly distributed in the cytosol in normal pituitary tissues (panel 2), whereas elevated p-AKT expression was seen in both the cytosol and nucleus of the patient’s tumor (panel 6). IHC analysis of the mTOR pathway in an additional seven PRLomas is summarized in Fig. 2B. Both cytoplasmic and nuclear p-AKT expression were higher in PRLomas compared with autopsy-derived normal pituitary tissues (cytoplasmic p-AKT: PRLoma, 267 ± 28 vs normal pituitary tissues, 205 ± 24, P > 0.05; nuclear p-AKT: p-PRLoma, 357 ± 65 vs normal pituitary tissues, 189 ± 34, P < 0.01; Fig. 2C, left panel) although differential cytoplasmic p-AKT IHC expression did not attain statistical significance. Quantitation of IHC expression (see details in Materials and Methods) of the immediate downstream effector of the mTOR pathway, p-4EBP1 (Fig. 2C, middle panel), demonstrated that whereas phosphorylated cytoplasmic and nuclear 4EBP1 (Thr37/46) was barely detectable in normal pituitary tissues, cytoplasmic and nuclear p-4EBP1 was abundant in both the mTOR-responsive PRLoma tissue and the seven additional PRLomas (cytoplasmic: PRLoma, 201 ± 46 vs normal pituitary tissues, 10 ± 1, P < 0.01; nuclear: PRLoma, 308 ± 67 vs normal pituitary tissues, 10 ± 1, P < 0.05; Fig. 2C). Additionally, cytoplasmic expression of p-S6 was higher in PRLoma tissues compared with normal pituitary tissues (PRLoma, 249 ± 24 vs normal pituitary tissues, 174 ± 21, P < 0.05; Fig. 2C, right panel). These findings demonstrate that the mTOR pathway is activated in a significant number of PRLomas.
Figure 2.
Evaluation of mTOR pathway activation in PRLomas (n = 8) and normal pituitary autopsy-derived tissues (n = 11). (A) Hematoxylin and eosin (H&E) (panels 1 and 5), p-AKT (panels 2 and 6), p-4EBP1 (panels 3 and 7), and p-S6 (panels 4 and 8) expression in representative autopsy-derived pituitary tissues (upper panels) and the index refractory PRLoma (lower panels). (B and C) Immunohistochemical quantitation of p-AKT, p-4EBP1, and p-S6 in 7 additional PRLoma tissues and 11 normal pituitary tissues. Staining signals were scored according to intensity (0, absent; 100, weak; 200, moderate; 300, strong) and percentage tumor cell staining (0 to 100) to give a combined histoscore. *P < 0.05, **P < 0.01. Shadowed bars indicate the normal pituitary tissues. Tiled bars indicate PRLomas. C, cytoplasmic; N, nuclear.
Effects of single agents and combination of cabergoline and everolimus in murine mammosomatotroph proliferation and PRL secretion in vitro
Given our findings in the index patient and our observed mTOR pathway activation in PRLomas, we sought to determine whether the tumor-stabilizing actions we had observed were due to actions of everolimus alone and/or its combination with cabergoline. We first determined the antiproliferative effects of single agent cabergoline and everolimus in murine PRL-secreting tumor GH3 cells. As shown in Fig. 3A, cabergoline treatment (10 to 160 μM for 24 to 120 hours) inhibited GH3 cell in vitro proliferation in a dose- and time-dependent manner with an EC50 of 87 μM and 120 μM at 48-hour and 72-hour treatment (Fig. 3A). Everolimus alone (25 to 400 nM for 24 to 120 hours) inhibited cell proliferation in a time-dependent manner by 10% to 50%, but no significant dose-dependent effect was seen (Fig. 3B).
Figure 3.
Effects of cabergoline and mTOR inhibitors on in vitro GH3 cell proliferation and PRL secretion. (A–D) Antiproliferative effects of single agent cabergoline (10 to 160 μM for 24 to 120 h) (A) or everolimus (25 to 400 nM for 24 to 120 h) (B), and combination of cabergoline (10, 40, and 80 μM) with everolimus (100 nM for 48 h) (C) or with rapamycin (10 nM for 48 h) (D) on GH3 cell proliferation were evaluated using CellTiter-Glo® luminescent cell viability assay. (E–G) Effects of cabergoline (10 to 160 μM for 24 to 72 h) (E) or everolimus (25 to 400 nM for 24 to 72 h) (F) alone or combination treatment (cabergoline 40 and 80 μM/everolimus 100 nM for 72 h) (G) on GH3 cell PRL secretion were measured by ELISA assay. *P < 0.05, **P < 0.01. Eve, everolimus; Rap, rapamycin.
Combination treatment with cabergoline (10, 40 and 80 μM) and everolimus (100 nM) for 48 hours did not demonstrate any synergistic and/or additive effect [cabergoline 10 μM/everolimus 100 nM, 0.6 ± 0.01; cabergoline 40 μM/everolimus 100 nM, 0.6 ± 0.003; cabergoline 80 μM/everolimus 100 nM, 0.4 ± 0.01 vs everolimus treatment alone (everolimus 100 nM, 0.7 ± 0.03, P > 0.05; Fig. 3C)]. Similarly, no synergistic or additive antiproliferative effect of cabergoline in combination with rapamycin (10 nM for 48 hours) was observed (cell viability fold difference: cabergoline 10 μM, 0.9 ± 0.02; rapamycin 10 nM, 0.7 ± 0.02; cabergoline 10 μM/rapamycin 10 nM, 0.6 ± 0.02, P > 0.05; Fig. 3D). As expected, cabergoline treatment (10 to 160 μM for 24 to 72 hours) led to reduced PRL secretion in a dose-dependent manner (Fig. 3E). Everolimus treatment (100 nM for 48 and 72 hours) inhibited PRL secretion ∼30% [PRL secretion (ng/mL), 48-hour vehicle: 755 ± 47; everolimus 100 nM, 496 ± 17, P > 0.057; 72-hour vehicle: 812 ± 14; everolimus 100 nM, 518 ± 61, P > 0.05; Fig. 3F] but this did not attain statistical significance. However, synergistic inhibition of PRL secretion using combined cabergoline (40 μM) and everolimus treatment (100 nM) for 72 hours was observed [PRL secretion (ng/mL), 72-hour vehicle: 713 ± 82; cabergoline 40 μM, 535 ± 7; everolimus 100 nM, 547 ± 8; cabergoline 40 μM/everolimus 100 nM, 408 ± 1, P < 0.05; Fig. 3G).
Discussion
PRLomas are frequently encountered functional pituitary adenomas. In the vast majority of PRLomas (∼80%), PRL level and tumor size are effectively controlled by the DAs cabergoline or bromocriptine (8). The remaining 10% to 20% of PRLomas exhibit either biochemical and/or radiological partial or complete resistance to DAs at initial treatment, or they may exhibit an initial response but later develop resistance even with escalating DA doses (9). In these situations, surgical debulking or radiation therapy may be offered in addition to medical treatment to achieve hormonal and tumor growth control (10). However, a small subset of PRLomas progresses through these multimodal treatment steps and recurs shortly after treatment, invading surrounding sellar structures, including the optic chiasm, carotid artery, sphenoid, and cavernous sinus (11). Management of these refractory PRLomas poses a significant therapeutic challenge for clinicians.
Many growth factor–regulated kinase pathways have been demonstrated to be overactivated in pituitary tumors, including the phosphoinositide 3-kinase/AKT/mTOR pathways (7). The mTOR pathway is involved in metabolism, apoptosis, and proliferation (12). mTOR forms two distinct functional complexes, namely mTORC1, comprising mTOR, regulatory-associated protein of mTOR, PRAS40, and mLST8, and mTORC2, made up of mTOR, RICTOR, mSin1, PROTOR, and mLST8. In a study of 53 pituitary adenomas, mTOR pathway activation was noted in GH-secreting pituitary adenomas (10 out of 14, 71%) compared with ACTH-secreting tumors (2 out of 6, 33%), nonfunctioning pituitary adenomas (11 out of 33, 33%), and cadaveric controls (1 out of 5, 20%) (13). AKT expression and phosphorylation have also been reported to be elevated in pituitary adenomas (n = 65) compared with autopsy-derived normal pituitary tissues (n = 5) (14). A further study of 95 pituitary adenomas demonstrated that expression of regulatory-associated protein of mTOR is reversely correlated with pituitary tumor cavernous sinus invasion (15).
The current study demonstrates elevated nuclear p-AKT, cytoplasmic p-S6, and globally increased p-4EBP1 in a series of eight PRLomas, of which the index patient and three others exhibited DA resistance. This indicates that the mTOR pathway is generally activated in a significant proportion of PRLomas. AKT mediates growth factor–, hormone-, and cytokine-stimulated mTORC1 survival signal activation via phosphorylation of TSC1 to TSC2, releasing the negative control of the RHEB GTPase and potently activates the protein kinase activity of mTORC1 (16). In particular, nuclear AKT substrates have roles in cell cycle progression (FOXO, p21, p27, and Myt1) (17), mRNA exportation (ALY) (18), and DNA repair (DNA-PK) (19), and our findings of high nuclear p-AKT expression in PRLomas indicate its potential role in aberrant cell cycle progression.
Rapamycin (sirolimus) and everolimus (afinitor, RAD001) are mTOR inhibitors that form a complex with FK binding protein 12 to interrupt mTOR kinase activation (20). Both drugs exhibit immunosuppressive activity and antiproliferative actions in various neoplasms.
Everolimus is approved to treat neuroendocrine tumors (NETs) (21, 22), and combination somatostatin receptor ligand (octreotide) and everolimus improved median progression-free survival in patients with metastatic pancreatic NETs (23). In pituitary tumors in vitro everolimus treatment has been shown to potently inhibit pituitary tumor cell proliferation, reduce cell viability, and promote apoptosis (24, 25). Other studies have reported increased sensitivity of mammosomatotroph GH3 cells to ionizing radiation following rapamycin and everolimus treatment (26). Additionally, synergistic antiproliferative effects of rapamycin in combination with octreotide were reported in murine corticotroph tumor AtT20 cells and primary cultures of human nonfunctioning pituitary tumors (27). However, despite those many preclinical studies, use of everolimus has not previously been reported in human PRL-secreting adenomas. A single patient with an ACTH-secreting pituitary carcinoma that was resistant to temozolamide exhibited no response to everolimus, although it was noted that mTOR signaling was less activated in the treated case than in other corticotroph tumors tested (28). In our patient, everolimus exhibited a more dramatic effect on tumor shrinkage than on PRL secretion. In contrast, in cultured GH3 cells in vitro, we observed some additive effect of combination cabergoline and everolimus to inhibit PRL secretion, but not on cell viability. This apparent discrepancy may in part be explained by the dedifferentiated nature of this PRL-secreting tumor whereby tumor cells not actively secreting PRL may still have exhibited an antiproliferative response. Indeed, the observed high nuclear-activated AKT in this refractory tumor may have made it particularly susceptible to the antiproliferative effects of everolimus. As supported by prior in vitro studies (24, 25), everolimus may also have induced a proapoptotic response in our patient’s tumor. We have not been able to evaluate this latter possibility, as he did not undergo tumor biopsy after everolimus therapy. Finally, the actions of everolimus to regulate mTOR downstream 4E-BP1 and S6 to inhibit protein translation machinery may have been more pronounced in the comparatively well-differentiated GH3 cells and resulted in the more striking reduction in PRL secretion as we observed. Everolimus is administered as a daily oral pill and can cause side effects such as stomatitis, rash, fatigue, diarrhea, infections, anemia, and hyperglycemia. Rarer side effects include pneumonitis, which resolves on cessation of drug therapy (29).
In summary, we describe a patient with a nonmetastatic aggressive PRLoma, refractory to multimodal conventional therapy, where addition of the mTOR inhibitor everolimus to cabergoline caused significant tumor regression and decreased serum PRL levels after 4 months. Tumor size then remained stable on imaging for 12 months, although serum PRL levels rose but remained below pretreatment levels. In in vitro studies in murine somatolactotroph tumor GH3 cells, we observed an additive effect with combination treatment of cabergoline and everolimus for inhibition of PRL secretion but not cell proliferation.
At present there is a clear unmet need for these rare but challenging PRLomas that fail standard of care. Randomized prospective multicenter studies of kinase inhibitors, such as everolimus, that have demonstrated efficacy in other NET subtypes may be helpful to identify novel treatments for aggressive pituitary adenomas.
Abbreviations:
- DAdopamine agonist
- IHCimmunohistochemical
- mTORmammalian target of rapamycin
- NETneuroendocrine tumor
- p-phosphorylated
- PRLprolactin
- PRLomaprolactinoma
Acknowledgments
Disclosure Summary: The authors have nothing to disclose.
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