A clinical researcher, a basic researcher and a clinical practitioner discuss pituitary tumors and a new “revolution” occurring in their treatment.
In the last four decades, endocrinologists have witnessed a small revolution in the medical therapy of pituitary tumors. Starting with the fi rst reports on the effi cacy of bromocriptine in the treatment of prolactinomas, considerable scientifi c advances have dramatically enhanced our therapeutic options. Currently, expression profi ling of dopamine receptors in pituitary adenomas provides a clear rationale for the use of dopamine agonists as the fi rst-line therapy for prolactinomas as well as in a subset of patients with GH, ACTH, and non-secreting adenomas. Somatostatin receptor profi ling similarly provided the impetus to develop long-acting somatostatin analogues, which today are considered mainstays of acromegaly management. Despite this progress, many pituitary tumors remain poorly responsive to currently available drugs, highlighting the need for further studies to advance our understanding of the biological pathways underlying pituitary tumorigenesis. In this TriPoint article, three experts discuss the most recent advances and the ongoing challenges in the medical therapy of pituitary tumors: a clinical practitioner focuses on the importance of “bench to bedside and back” for the clinical management of pituitary tumors; a basic researcher describes novel intracellular signaling pathways in pituitary tumorigenesis and the potential for targeting these pathways in future therapeutic applications; and a clinical researcher provides additional examples of the translation of novel discoveries in basic science to clinical trials and patient care.
CLINCAL PRACTITIONER PERSPECTIVE — Mark E. Molitch, MD — Mark E. Molitch, MD
Bench to Bedside, and
Bedside to Bench
The medical therapy of pituitary tumors is the poster child for the concept of bench to bedside and back. Th e foundations for current treatments were laid in the 1950s by Sir Geoff rey Harris and others who demonstrated the control of pituitary function by the hypothalamus and subsequently in the 1960s, 1970s, and 1980s by the laboratories of Roger Guillemin, Andrew Schally, and Wylie Vale who identifi ed and characterized the hypothalamic releasing and inhibiting factors we now take for granted. With this newly acquired information regarding the regulation of pituitary hormone release, it was only a matter of time before this basic knowledge was applied to the treatment of pituitary diseases.
One of the first examples of the bench to bedside approach was the treatment of hyperprolactinemia. Following the discovery that dopamine was the prolactin (PRL) inhibitory factor, Peter Lutterbeck correctly reasoned that the dopaminergic properties of the ergot derivative bromocriptine might be effective in treating hyperprolactinemia. The success achieved in treating patients with prolactinomas initially with bromocriptine and later with cabergoline has been nothing short of astounding. But our now extensive experience with dopamine agonists has revealed several problems that need to be taken back to the bench, including: 1) uncommon patients who do not respond to dopamine agonists at all and 2) others who are resistant and require very high doses of dopamine agonists to normalize PRL levels. We do not fully understand the status of dopamine receptors in these patients, the relationship between their short and long isoforms, and receptor coupling to inhibitory transduction mechanisms. Do we need drugs working by different mechanisms of action for such patients?
There are other problems that require further research at the bench and in clinical studies. Cabergoline can cause cardiac valvular abnormalities when used in high doses for patients with Parkinson’s disease, but standard doses used for most patients with prolactinomas apparently do not. We need to identify the threshold dose responsible for cardiac valvular abnormalities so as to guide us in our management of those uncommon patients with dopamine agonist resistance who need high doses of cabergoline.
Treatment of acromegaly is another example of the bench-to-bedside approach. Hypothalamic extracts that could inhibit GH secretion were discovered in 1968. However, it was not until 1973 that somatostatin was characterized, 1978 that somatostatin receptors were discovered, 1984 that somatostatin analogues were shown to be benefi cial for the treatment of acromegaly, and many years later that the long-acting versions of the somatostatin analogues octreotide and lanreotide became standard parts of clinical practice. Although initial studies showed quite high rates of success, more recent studies suggest that fewer than 50% of patients normalize GH and IGF-1 levels when prescribed these drugs following noncurative surgery. Continued clinicto-bench interaction is needed here. Why is this success rate so low? Is this simply a somatostatin receptor issue? We have learned that many somatotroph tumors have dopamine receptors, and the use of dopamine agonists along with somatostatin analogues can be benefi cial in many patients. Do dopamine agonists work through a second inhibitory pathway, or is there some synergism between activation of these pathways? Further help may arise from the bench as new somatostatin analogues, such as pasireotide and possibly oral somatostatin analogues, reach the clinic.
Looking Ahead — New Clinical
Trials and Areas to Explore
Although the bench-to-bedside medical therapies aff ecting tumors are most visible with PRL- and GHsecreting pituitary adenomas, we have learned that dopamine receptors and somatostatin receptors are often present on ACTH-producing tumors causing Cushing syndrome and on clinically non-functioning pituitary tumors, which are usually gonadotroph adenomas. Small studies have shown some success with the use of dopamine agonists in these two conditions; but, large, prospective, randomized, multicenter studies have yet to be performed using dopamine agonists for non-functioning adenomas and Cushing syndrome. On the other hand, a large, prospective, randomized study has recently shown that pasireotide, the newest somatostatin receptor analog, which has activity at somatostatin receptor 5, can lower ACTH and cortisol levels in many patients with Cushing disease, leading to its approval in many countries. One interesting area that also has clinical importance but has not been evaluated is the use of these drugs in patients with “silent” lactotroph, somatotroph, and corticotroph adenomas (i.e., tumors producing PRL, GH, or ACTH without clinical syndromes). Would the drugs that are eff ective in patients with the clinical syndrome be eff ective in preventing regrowth of their “silent” counterparts after surgery?
Clinicians and patients have benefited greatly from information generated in the laboratory and translated into pharmacologic agents with very high effi cacy/ adverse event ratios for pituitary tumors. Yet, some problem areas remain, and we trust that such continued collaboration will help solve them.
BASIC RESEARCHER PERSPECTIVE — Shlomo Melmed, MD — Shlomo Melmed, MD
Pituitary Adenoma Pathogenesis
Pituitary tumorigenesis is characterized by a dual disorder of excessive cell proliferation coupled with dysregulated hormone hypersecretion. Diff erentiated anterior pituitary cells produce ACTH, GH, TSH, PRL, FSH, or LH, which selectively regulate target gland hormone secretion to elicit peripheral tissue eff ects (Table 1). Each cell type also expresses tissue/cell-specifi c transcription factor(s) determining hormone gene expression. Each cell type may give rise to a diff erentiated adenoma characterized by a unique clinical syndrome. Early pituitary progenitor or fully diff erentiated hormone-expressing cells give rise to pituitary tumors that are monoclonal benign adenomas, which possess a proliferative advantage. For example, in a mouse model, a pituitary cell lineage expressing the Pax7 transcription factor gave rise to cell lineages downstream of nestinexpressing stem cells.
Adenomatous pituitary cell proliferation is sustained by genetic or epigenetic abnormalities, paracrine growth factor disruptions, and/or an altered intrapituitary microenvironment, leading to oncoprotein activation or tumor suppressor gene inactivation, and ultimately pituitary cell cycle dysregulation. Multiple factors impinge on the pituitary cell to elicit hyperplastic or neoplastic growth as well as respective hormone hypersecretion (Table 2). Although inactivated or overexpressed cell cycle regulators may initiate pituitary hyperplasia and tumorigenesis in murine models, classic oncogene mutations are rarely encountered in human pituitary tumors. Activating proliferative changes only very rarely facilitate malignant transformation, and pituitary adenomas are characterized by protective mechanisms buff ering against carcinoma development, including proliferative restraint at the microadenoma stage, and cell senescence occurring after macroadenoma development. Th ese mechanisms prevent transformation to carcinoma, thereby, enabling the overwhelmingly benign phenotype. As pituitary tumor cells exhibit premature cell proliferative arrest while maintaining hormone hypersecretion, targeting cell cycle disruptions is an attractive approach for novel therapeutic applications.
As an example of this approach, evidence is presented for targeting cell cycle disruptions employing ErbB receptors, including epidermal growth factor receptor (EGFR) and HER2, which regulate both pituitary hormone secretion and cell proliferation.
Developing novel targeted medical therapy for ACTHproducing pituitary adenomas is an important current challenge. Most ACTH-secreting adenomas express the EGFR. Proopiomelanocortin (POMC) gene expression and ACTH secretion are induced by EGF in an EGFR-dependent manner. In addition, p27Kip1, a cyclin-dependent kinase (CDK) inhibitor, is down-regulated in tumors expressing EGFR. Th erefore, the EGFR could be a novel target for Cushing disease therapy, targeting both hormone secretion and cell proliferation.
Gefitinib, a tyrosine kinase inhibitor (TKI), targets the EGFR, blocking the intracellular ATP-binding site of the tyrosine kinase domain and suppressing Pomc promoter activity and ACTH secretion in an EGFRdependent manner. Th e suppression of POMC expression and ACTH secretion were also demonstrated in human pituitary corticotroph tumors and canine corticotroph adenoma cells. Gefi tinib also attenuates the corticotroph cell cycle, as evidenced by decreased BrdU incorporation, refl ecting drug eff ects on tumor cell proliferation. Finally, gefi tinib induces p27kip1, the CDK inhibitor, which is down-regulated in most ACTHsecreting tumors.
In mice inoculated with explanted ACTH-secreting tumors, only animals with EGFR expressing tumors exhibited the attenuating eff ects of gefi tinib on phenotypic features of hypercortisolism and the associated decreased serum corticosterone levels. Th erefore, gefi tinib action appears to be mediated by regulating EGFR signaling on corticotroph tumor cells. Th ese results support the clinical rationale for blocking EGFR signaling to attenuate corticotroph adenoma growth and ACTH secretion.
Roscovitine, a CDK inhibitor, suppresses experimental corticotroph tumor growth and POMC gene expression in zebrafi sh and in murine xenografts. Transgenic zebrafi sh with zPttg overexpression targeted to pituitary POMC lineages (corticotrophs and melanotrophs) develop phenotypes refl ective of Cushing disease, including neoplastic corticotrophs with partial glucocorticoid resistance, hypercortisolemia-mediated hyperglycemia, and fatty liver. PTTG is a pituitary transforming gene, and R-roscovitine suppressed PTTG-overexpressing corticotrophs. Th ese inhibitory actions were validated in murine corticotroph adenomas, supporting the use of selective CDK inhibitors as eff ective therapy for Cushing disease.
EGF, a pituitary cell growth factor, also directly induces prolactin synthesis. Th e EGFR family (ErbB receptors) and ligands are expressed in normal and tumorous lactotrophs, inducing PRL synthesis and secretion, and increases in prolactinoma size. Most prolactinomas exhibit variable ErbB expression, and selective ErbB receptor expression has been associated with tumor invasion and response to dopamine agonists. Th erefore, ErbB inhibitors have been used in cell and animal models of prolactinomas. In primary cells derived from human prolactinomas, lapatinib, a dual ErbB tyrosine kinase inhibitor, suppresses PRL mRNA expression and protein secretion. Gefi tinib decreases rat somato-lactotroph cell proliferation, PRL mRNA expression, and xenografted tumor PRL secretion in vivo. In stable cell transfectants of a constitutively active form of ErbB2 cDNA, lapatinib also suppresses EGF-induced ErB2 and MAPK phosphorylation, intracellular PRL levels and cell proliferation. Furthermore, in another animal model, estradiol-induced rat prolactinoma growth rate and prolactin production were inhibited by lapatinib.
As ErbB signaling is a determinant of prolactin synthesis, the association between ErbB receptors and clinical outcomes was examined. Immunofl uorescent staining of EGFR, ErbB2, ErbB3, and ErbB4 in human prolactinoma tissue arrays correlated with clinical features of tumors. When two patients with aggressive resistant prolactinomas received daily lapatinib for six months, tumor growth was restrained and prolactin levels attenuated, both associated with ErbB receptor expression.
In summary, the pituitary gland is sensitive to cellcycle disruptions mediated by dysregulated CDKs and by EGFRs (Table 3). Although CDK gene mutations have not been identifi ed in human pituitary tumors, overexpressed cyclins and dysregulated CDK inhibitors observed in pituitary adenomas underscore the relevance of CDK activation for potential therapeutic targeting. Th e EGFR regulators r-roscovitine and TKIs discussed may represent small therapeutic molecules for those targets.
CLINICAL RESEARCHER PERSPECTIVE — Aart Jan van der Lely, MD, PhD
Some Success Stories
One of the greatest achievements in the last decades has been the impressive increase in effi cacy of medical treatments for hormone-producing pituitary tumors. Th e success of medical treatment for functioning pituitary tumors has enabled clinical researchers to shift focus from suppressing elevated pathological hormone secretion into the normal range to addressing other important issues in patients, such as quality of life and tissue-specifi c control of disease activity. Two specifi c examples highlight the visible shift of focus, while also directing researchers to unmet needs requiring future developments.
A Real Breakthrough in
Th e fi rst example is Cushing disease in which ACTH production by the pituitary tumor is the driving force behind the disease. Transsphenoidal removal of the tumor remains the cornerstone of proper disease management because the tumors are often relatively small and eff ective medical therapy is still in its infancy. However, current medical options are promising. Pasireotide, a somatostatin analog that lowers ACTH secretion, drops cortisol levels to the normal range. Although pasireotide monotherapy appears to be eff ective in only a minority of Cushing patients, this compound shows better effi cacy when combined with cabergoline and/or ketoconazole.
Other lights at the end of the tunnel come from studies that investigated the therapeutic eff ects of glucocorticoid and ACTH receptor antagonists. Mifepristone, a glucocorticoid receptor antagonist, remains an option for treatment of Cushing syndrome. Th e problem with this type of therapy in everyday clinical use is that overtreatment with glucocorticoid receptor antagonists is diffi cult to assess. Cortisol levels themselves no longer give information about cortisol actions when the glucocorticoid receptors are blocked. ACTH receptor antagonists would alleviate the problem by blocking ACTH action and cortisol levels. Introducing ACTH receptor antagonists into clinical trials would make an incredible breakthrough in treatment trials.
Acromegaly is Now “Easy” to Treat
Th e second example of eff ective medical therapy for pituitary disease is, of course, the treatment of acromegaly. Nowadays, one can say that virtually all acromegaly patients can be controlled with medical therapy when serum IGF-I levels are used as a parameter of disease activity. After “only” 30 years in the evolution of medical treatment modalities, acromegaly patients are no longer untreatable. With the caveat that the high cost of intensive medical treatment [e.g., high dose somatostatin analogs (LA-SAs) or the growth hormone receptor antagonist pegvisomant] limits availability, virtually all patients can now be controlled. Th e next task for the medical community will be to understand and address tissue-specifi c aspects of the disease to optimize the necessary tailored approach to the individual patient.
But Do We Really Understand
Disease Activity in Acromegaly?
Th ese recent medical developments allowed clinical investigators to focus on quality of life (QoL) as a function of therapeutic modality. Diff erences in QoL are observed between patients with IGF-I levels normalized by surgery versus those with IGF-I levels normalized by the use of LA-SAs. Interestingly, QoL in the LA-SAs treated group was lower and correlated with growth hormone (GH) levels. In fact, GH levels in medically treated patients were almost twice as high as in the surgically treated subjects. Th is and other observations following GH receptor antagonists (pegvisomant) have shown that tissue-specifi c actions of LA-SAs diff er from blocking GH or eliminating GH at the same tissues. Th ese tissue-specifi c eff ects of low GH levels or GH blockade versus somatostatin suppression may explain the diff erence in QoL. LA-SAs decrease pathological GH levels, which will decrease IGF-I generation by the liver. Equally important, LA-SAs inhibit portal insulin secretion, both of which result in a relative GH-resistant state of the liver.
While only liver IGF-I production is controlled via direct and GH-dependent eff ects of LA-SAs, GH levels are still elevated. What remains is that the rest of the body still might have the disease in the sense that the slightly elevated GH levels do act on all tissues, except the liver, as this organ is made selectively GH resistant by the presence of LA-SAs. Th is discrepancy between GH and IGF-I levels in which GH levels are relatively high while IGF-I concentrations are normalized during LA-SA treatment might give the treating physician the wrong impression that the disease activity is controlled by LA-SAs. Th is concept of “extra-hepatic” acromegaly is the perfect example of the need to develop treatment goals that focus on tissue-specifi c activities of the disease that are modality and patient specifi c.
As an example, Neggers and co-workers studied 20 acromegaly subjects in which the disease was so-called controlled by LA-SAs (i.e., their IGF-I levels were normalized). Improvement in QoL was observed without signifi cant change in IGF-I after the addition of 40 mg pegvisomant weekly to their monthly LA-SA therapy. Th ese data question the current recommendations regarding assessment of disease activity in acromegaly during LA-SA therapy. Moreover, the fi ndings question the validity of the current approach of medical treatment in which pegvisomant is used only when LA-SA therapy has failed to normalize IGF-I.
— This article was reviewed by Cesar Boguszewski, MD, PhD,
and the Endocrine Society’s Research Aff airs Core Committee
Co-Chairs Daniel J. Bernard, PhD, and Corrine Welt, MD.