Pituitary adenoma is one of the most common intracranial tumors, with the third highest incidence of intracranial tumors and a population incidence of about 20%. Although pituitary adenomas are mostly benign, about 45-55% of them are aggressive and often invade peritumoral structures such as the pterygoid bone, cavernous sinus or dura mater, causing clinical manifestations such as headache, visual impairment or even blindness and endocrine dysfunction, which seriously affects patients’ quality of life and even shortens their life span. Pituitary adenoma has a long course. When the tumor is small and has no symptoms of hormonal disorder, it can grow invisibly in the patient’s body for many years without being detected or diagnosed. However, once a patient develops hormonal disorders or tumor compression symptoms, surgery, radiation therapy and medication are required. Although surgery can completely resect most of the tumors, for some invasive pituitary adenomas, it is difficult to completely resect the tumors, whether through the oronasal pterygoid sinus surgery or through the inferior frontal or pterygoid point approach, and tumor recurrence occurs in about 20% of cases after surgery. The invasive growth habit of tumor tissue and insensitivity to radiation also limit the efficacy of radiotherapy for pituitary adenoma, and radiotherapy in the saddle area can easily cause damage to the normal pituitary gland, hypothalamus and optic nerve and other important structures, resulting in complications such as hypoplasia of pituitary gland and hypothalamus and impaired vision. In contrast, commonly used drugs such as bromocriptine and long-acting growth inhibitors are only effective in some pituitary adenomas. Therefore, in-depth study on the mechanism of pituitary adenoma and the search for molecular targets for tumor treatment has become one of the current research hotspots.
The monoclonal origin of pituitary adenomas suggests that the same general pattern of tumorigenesis exists in pituitary adenomas. The current hypothesis is that some transformational event causes the pituitary cells to mutate and acquire proliferative functions, and that secondary pituitary cell proliferation regulators such as hypothalamic hormones contribute to the clonal expansion of such cells. Thus, activation of oncogenes or inactivation of oncogenes is the underlying cause of pituitary adenoma development. It has been found that elevated expression of Ras gene, Gsα gene and PTTG gene or downregulated expression of oncogenes p21 or p16 are present in pituitary adenomas. Although the specific role played by these genes in the development of pituitary adenomas is not known.
However, these specific genes or proteins provide good molecular targets for the treatment of pituitary adenomas. The most studied ones are baramine type 2 receptor (D2-R) agonists, such as bromocriptine and capsaicin, which can effectively reduce peripheral blood PRL levels in patients with prolactin adenoma and reduce tumor size or even make the tumor disappear, and have become the preferred treatment modality for PRL adenoma in clinical practice. Other research on some molecular targets for drug therapy is also gaining momentum. Nucleolar receptors such as estrogen receptor, PPARγ and retinoic acid receptor are specifically highly expressed in pituitary adenomas, and a series of ligand-targeted drugs related to them are under investigation. Targeted therapies for pituitary adenoma transforming genes (PTTG) are also under active investigation. Doxazosin, an α-adrenergic receptor blocker originally used for the treatment of hypertension, specifically blocks nuclear factor kappa-B ((NFκB) and epidermal growth factor receptor-mediated signaling pathways, making it a potentially safe and effective novel agent for pituitary adenomas. Recently, it has been found that Folate Receptor α (FRα) is specifically highly expressed in non-functional pituitary adenomas and may become one of the new branching targets for the treatment of NFPA. The following is a review of the research progress of targeted therapy for pituitary adenoma.
PTTG, a proto-oncogene obtained from mouse pituitary adenoma cells using differential display PCR, controls the segregation of chromosomes in mitosis of tumor cells. In animal models of tumors, a range of growth factors have been found to increase the expression level of PTTG. It has been reported that PTTG expression levels are low in normal tissues, including the pituitary gland, and elevated in a range of tumors, including pituitary adenomas and lung cancer. A recent paper reported that PTTG expression was found to be elevated in more than 90% of pituitary adenomas using protein blotting and immunohistochemistry, and that there was a positive correlation between expression levels and cell proliferation markers such as Ki-67. in vivo studies in PTTG knockout or transgenic mice also found that PTTG correlated with the ability of cells to increase in value. For example, it has been reported that heterozygous Rb+/C mice are capable of spontaneous pituitary adenomas, but if they are crossed with mice without PTTG expression, their offspring PTTGC/C Rb+/C mice will have a slower rate of cell division and a longer time to develop pituitary adenomas. Similarly, PTTG transgenic mice will show proliferation of multiple pituitary cells, such as GH cells, LH cells, and TSH cells. In summary, although the mechanism is not yet clear, both in vivo and ex vivo experiments have confirmed that PTTG expression levels are related to the value-added status of pituitary adenoma cells, which provides a good target for early diagnosis and targeted treatment of pituitary adenoma in clinical practice.
Estrogen receptor: It was found that: in vivo injection of estrogen in mice can promote the proliferation of pituitary lactin cells. Also, it was found clinically: about 20% of lactotrophic macroadenomas appear to increase in size during pregnancy. Further studies also found that pituitary adenomas, especially lactin adenomas, specifically overexpress estrogen receptors. All of this evidence suggests that estrogen receptors could be one of the effective therapeutic targets for pituitary adenomas. It has been demonstrated that estrogen antagonists, such as raloxifene, tamoxifen and ICI182780, are effective in inhibiting estrogen-induced proliferation of prolactin cells. Although there are very few reports on estrogen antagonists for the treatment of pituitary adenomas, targeted therapy targeting estrogen receptors still holds some promise.
Retinoic acid receptors and PPARγ: It has been found that the nuclear receptor PPARγ can form homodimeric complexes with and retinoic acid receptors α, β, and γ, or combine with retinoic acid receptor X to form heterodimers. Their role is to release co-repressors while recruiting transcription-associated co-activators to regulate gene expression associated with transcription, apoptosis and value-added. The natural receptors for retinoic acid receptors and PPARγ include retinoids, eicosanoids and fatty acids. Various synthetic vitamin A derivatives and thiazolidinediones (TZD), which also act as ligands for retinoic acid receptors and PPARγ, are also available. One study found that therapeutic doses of retinoic acid and synthetic PPARγ ligands inhibited the proliferation of cultured tumor cells in vitro. Clinical trials in patients with leukemia, skin and cervical squamous epithelial cell carcinoma have also shown some efficacy. And a recent paper reported good efficacy of retinoic acid in a canine model of Cushing’s disease. However, therapeutic doses of retinoic acid often lead to severe hepatotoxicity, mucositis and conjunctivitis, limiting its potential use. Meanwhile, elevated PPARγ expression, slowed proliferation and accelerated apoptosis have been reported in TZD-treated in vitro cultured pituitary adenoma cells. Moreover, one study reported that in vivo injection of rosiglitazone in a mouse ruffled tumor model inhibited pituitary adenoma growth while decreasing pituitary hormone levels.
Quinazoline-based alpha-adrenoceptor blockers: doxazosin, an alpha-adrenoceptor blocker originally used for the treatment of hypertension and obstructive nephropathy. And its antitumor effects have been recently discovered in prostate cancer. Doxazosin caused accelerated apoptosis and decreased PSA levels in peripheral blood of prostate cancer cells. In vitro culture experiments on murine pituitary adenoma cell lines AtT20 and αT3-1 confirmed that 10-30 μM doxazosin inhibited cell proliferation and promoted apoptosis, while tumor growth inhibition was also found in a murine tumor model. Further studies confirmed that doxazosin inhibited NFκB-mediated expression of a series of genes by decreasing the phosphorylation level of κB inhibitor kinase. In breast cancer cells, doxazosin exhibited similar tyrosine kinase activity, reduced phosphorylated epidermal growth factor receptor levels, and inhibited protein kinase-mediated signal transduction pathways.
Folate receptor α et al. first used cDNA microarrays in 2001 to compare genome-wide expression differences between non-functioning pituitary adenomas, PRL, GH and ACTH adenomas and normal pituitary tissue, and first found that FR α was specifically highly expressed in non-functioning pituitary adenomas (NFPA), while it was not or very lowly expressed in other subtypes of adenomas and normal pituitary. To further confirm the specificity of FR α expression in NFPA, Oyesiku et al. performed immunohistochemistry, Western Blotting, RT-PCR, and [3H]folate quantification on 39 additional pituitary adenoma specimens and obtained the same conclusion. The most recent study by this scholar found that overexpression of FR α in the murine NFPA cell line αT3-1 promoted tumor cell proliferation through activation of the NOTCH cell signaling pathway. Therefore, this specificity of FR α expression provides a good molecular target for targeted diagnosis and treatment of NFPA and ovarian cancer and other tumors. Currently, FR α-targeted contrast agents and drugs for malignant tumors such as ovarian cancer and non-small cell lung cancer are continuously being developed. There are two main strategies to use folate receptors to mediate drug-targeted transport: one is to use antibodies to folate receptors coupled with drugs to bind to folate receptors; the other is to use folate coupled with drugs to bind to folate receptors. However, due to the application limitations of the folate receptor monoclonal antibody itself and the advantages of folate-coupled targeted drugs, such as high affinity, low immunogenicity, easy modification, high chemical stability and biologically stable components, physiological compatibility with organic solvents and low cost, folate-coupled targeted drugs are increasingly used. Currently, two drugs have entered clinical trials for folate receptor-mediated targeted contrast agents: 111In-DTPA-folate (FolateScan?) and 99mTc-EC20-folate, while two targeted therapeutics have also entered phase II clinical trials: EC17 and EC145. EC17 is a fluorescein semi-antigen coupled with folate EC145 is a chelator of folic acid with desacetylvinblastine hydrazide. Unlike the therapeutic mechanism of EC17, EC145 enters cells and kills tumor cells by releasing desacetylvinblastine hydrazide. These drugs have been used to treat ovarian, breast, kidney, and non-small cell lung cancers with favorable results in preliminary clinical trials; therefore, these folate-receptor-targeted drugs may provide new diagnostic and therapeutic targets for non-functioning pituitary adenomas.
Conclusion: In-depth studies on the pathogenesis of pituitary adenoma can not only further reveal the mechanism of tumorigenesis, but also help to identify new molecular targets for tumor diagnosis and treatment. Targeted drug therapy targets for other malignant tumors, such as ovarian cancer, can also be applied to the treatment of pituitary adenoma.