Biomedicines | Free Full-Text | From Genes to Therapy: Pituitary Adenomas in the Era of Precision Medicine

Pituitary adenomas are linked with several related disorders, including prolactinoma, acromegaly, Cushing’s disease, and non-functioning pituitary adenoma. Treatment often requires a combination of surgery, medical therapies (such as dopamine agonists or somatostatin receptor ligands), and radiotherapy, due to their significant impact on patient mortality, morbidity, and quality of life [82,83]. Transsphenoidal surgery is usually the first-line treatment for pituitary tumors, except for prolactinomas. However, the tumor’s local invasiveness may complicate surgical resection, occasionally necessitating initial medical therapy [84].

Prolactinomas, the most common type of secretory pituitary tumors, can cause symptoms from prolactin oversecretion, localized mass effects, or both [85]. Traditionally, dopamine agonists have been the primary treatment, with cabergoline effectively normalizing prolactin levels in most patients and inducing tumor shrinkage in many. The surgical resection of microprolactinomas and encapsulated macroprolactinomas can achieve remission rates similar to cabergoline treatment [86].

Acromegaly, a chronic disease caused mainly by growth hormone-secreting PitNETs, can lead to severe health issues and increased mortality if not properly managed. Transsphenoidal surgery is preferred for GH-secreting PitNETs, with medical therapy, especially long-acting somatostatin analogs, used when surgery is not possible or incomplete, achieving control in about half of the patients [87].

Cushing’s disease, caused by an ACTH-secreting pituitary tumor, is the most common form of Cushing’s syndrome and requires prompt diagnosis and treatment to improve outcomes [88]. Surgery is the initial therapy, but when it is not curative, medical therapy becomes a significant secondary option. New drugs and formulations are being investigated for their efficacy and safety in treating Cushing’s disease [89]. Recent medical advancements include using cabergoline or pasireotide to target dopamine and somatostatin receptors on corticotroph adenomas, effectively controlling cortisol production in some patients [90].

Non-functioning pituitary adenomas, benign tumors that do not cause hormonal hypersecretion, are primarily treated with surgery, but recurrence rates are high [91]. Post surgery, dopamine agonists have been explored to prevent recurrence, showing some initial promise but diminishing effectiveness over time. The role of medical therapy in preventing NFPA regrowth remains limited [92].

Surgical resection maintains its status as a core strategy in managing brain tumors (BM), with its effectiveness in BM surgery being well established. A critical aspect of surgical intervention is the method employed, wherein en bloc resection, the removal of the tumor in a single piece, has been shown to offer better local control compared to piecemeal tumor resection. This approach also involves the minimal removal of adjacent normal brain tissue [93]. En bloc resection is notable for its potential to decrease intraoperative tumor spread relative to piecemeal resection. Patel et al. observed that en bloc resection does not correlate with an increase in complications or adverse functional outcomes [94]. Additionally, studies by Suki et al. have supported the efficacy of en bloc resection in reducing intraoperative tumor dissemination [95,96]. However, en bloc resection may not always be viable, particularly in cases of larger or cystic tumors. During such surgeries, it is important to minimize the leakage of internal contents and the spread of tumor fragments. After resection, an exhaustive inspection of the cavity is crucial to confirm the complete removal of the tumor, especially following piecemeal resection.

Most pituitary adenomas can be effectively managed with current medical treatments, surgical interventions, and, in some cases, radiotherapy. However, gonadotroph adenomas are particularly challenging due to the lack of effective medical treatments. Additionally, the management of aggressive pituitary adenomas and pituitary carcinomas presents significant clinical challenges [97].

For prolactinomas, the use of dopamine agonists has been a primary treatment strategy since the 1970s. The initial use of bromocriptine later shifted to cabergoline, which has been effective in regulating prolactin levels in up to 85% of patients and reducing tumor size in about 80% of cases. The surgical removal of both microprolactinomas and larger macroprolactinomas, when performed by neurosurgeons specialized in pituitary disorders, has achieved remission rates comparable to those obtained with cabergoline therapy. For particularly aggressive prolactinomas and metastasized PitNETs, a comprehensive treatment approach is recommended. This includes higher doses of cabergoline, surgical intervention, radiation therapy (preferably stereotactic radiosurgery when possible), and temozolomide administration. While DAs remain effective for most prolactinoma cases, the success rates of transsphenoidal surgical methods have significantly improved recently, especially with the expertise of specialized surgeons [98].

In cases where hypercortisolism persists or recurs after transsphenoidal surgery, or when surgery is not an option or is declined by the patient, medical therapy becomes crucial. This treatment primarily focuses on three areas: inhibiting the production of ACTH by corticotroph tumors, suppressing steroidogenesis in the adrenal glands, and blocking the action of glucocorticoid receptors. Pituitary-directed medications include pasireotide and cabergoline. Pasireotide has demonstrated effectiveness in reducing cortisol levels in patients with Cushing’s disease, indicating its utility in treating corticotropin-secreting pituitary adenomas [99,100]. Cabergoline, when used as a sole treatment, can be effective over the long term for select Cushing’s disease patients, although it requires ongoing monitoring for dose adjustments [101]. Steroidogenesis inhibitors currently used include ketoconazole, metyrapone, mitotane, and etomidate. The management of Cushing’s syndrome, particularly Cushing’s disease, remains complex, with adrenal steroidogenesis inhibitors playing a key role in controlling hypercortisolism at various stages, both before and after surgery.

In the case of growth hormone pituitary adenoma (GHPA), new pharmacological approaches have been employed. The role of p300, a histone acetyltransferase (HAT) coactivator implicated in PA tumorigenesis and progression, and its catalytic inhibitors in GHPA is an active area of research. Recent findings indicate that using the selective inhibitor A-485 to target HAT p300 may be a promising treatment strategy for GHPA [102].

For thyrotropin-secreting pituitary neuroendocrine tumors, employing high-sensitivity TSH detection methods is crucial for early diagnosis and effective treatment. Advances in MRI techniques have enhanced the non-invasive detection of smaller PitNETs. Treatment options for TSH PitNETs include surgery, pharmacological treatments, and radiotherapy [103].

Innovative targeted therapies for pituitary tumor treatment are focusing on inhibitors of the mammalian target of rapamycin (mTOR), tyrosine kinase, and vascular endothelial growth factor. Advances in the molecular characterization of endocrine tumors through genomic, epigenomic, and transcriptomic analyses have provided a more in-depth understanding of their pathogenesis and molecular pathology. This has led to an increased application of molecular targeted therapies (MTTs) in patient care [104]. The mTOR protein kinase is vital for regulating various cellular processes, including metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, thus maintaining cellular homeostasis. Recent studies have shown that the constitutive activation of the mTOR pathway, due to genetic changes like mutations, amplifications, or deletions in mTOR itself, its complexes (mTORC1 and mTORC2), or its upstream targets, plays a role in aging, neurological disorders, and various human cancers. Progress in targeting mTOR signaling could significantly improve anti-cancer treatments and benefit patients in clinical settings [105].

Immune checkpoint treatment represents a very promising therapeutic avenue for neoplasms [106,107,108]. This therapeutic avenue is also a very hopeful option for pituitary adenomas. There is a well-established correlation between mismatch repair deficiency (MMRd) and the heightened responsiveness to anti-PD-1 therapies in various malignancies. This association can be effectively identified through the immunohistochemical analysis of markers such as MLH1, MSH2, MHS6, and PMS2. An instance of accelerated disease progression was reported in the literature following the administration of pembrolizumab in a patient diagnosed with an MMRd pituitary ACTH-secreting adenoma, showcasing the limited efficacy observed with pembrolizumab in the treatment of an ACTH-secreting pituitary adenoma characterized by mismatch repair deficiency, potentially attributable to elevated cortisol levels in the patient [50]. Furthermore, the expression of PD-L1 is prevalent in functional pituitary adenomas, concomitant with an association with aggressive clinical manifestations in these adenomas [109]. The therapeutic blockade of the CTLA-4 and PD-1 pathways plays a pivotal role in modulating immune response against tumors. This blockade enables the activation of T cell stimulatory signaling pathways, subsequently augmenting antitumor T cell cytotoxicity, promoting the production of proinflammatory cytokines, stimulating T cell proliferation, and facilitating tumor cell destruction. The concurrent inhibition of the CTLA-4 and PD-1/PD-L1 pathways, owing to their distinct and nonredundant coinhibitory functions, has been observed to yield superior clinical remission rates [110,111,112,113]. However, this combination therapy is associated with an increased incidence of immune-related toxicities. While typically well tolerated, the combined therapeutic approach elevates the likelihood of encountering high-grade immune-related adverse events (irAEs). Within the clinical treatment paradigm, irAEs precipitated by ICIs exhibit a toxicity profile that is often more pronounced than that of conventional chemotherapy, encompassing a range of organ systems. Pertaining to the gastrointestinal system, afflictions such as colitis, hepatitis, cholangitis, and gastritis frequently manifest as common irAEs. Conversely, in the hematologic domain, these adverse events are typically characterized by autoimmune hemolytic anemia, immune thrombocytopenia, and aplastic anemia [114,115].

The epigenetic novel markers as well as targeted proteins in current emerging therapies mentioned throughout our study are comprehensively summarized for a broader view of those therapeutic possibilities (Table 2).