Progress in drug treatment of refractory prolactinoma

Prolactinoma is the most common functional pituitary adenoma, accounting for 47%-66% of functional pituitary adenomas. It often causes amenorrhea, lactation, decreased libido and sexual dysfunction due to excessive secretion of prolactin (PRL). Tumor enlargement may also lead to headache, decreased vision, visual field defect and other cranial nerve dysfunction. This kind of refractory prolactinoma poses a great challenge to neurosurgeons. To explore an effective treatment method is an urgent problem.

At present, temozolomide (TMZ) is the most commonly used chemotherapeutic agent for refractory prolactinoma, and is commonly used as an oral alkylating agent for glioma. In recent years, TMZ has been used in the treatment of refractory pituitary adenomas and achieved good results. The guidelines of the European Endocrine Society (2018 Edition) recommend TMZ as the first-line chemotherapy for invasive pituitary adenomas and pituitary cancer.

2.1 Somatostatin analogue，SSA

 Somatostatin analogue (SSA) is a drug for the treatment of growth hormone adenoma. Immunohistochemistry showed that SSTR1, SSTR2 and sstr5 of somatostatin receptor (SSTR) were mostly expressed in prolactinoma cells. SSA combined with SSTR on prolactinoma cell membrane to inhibit PRL secretion. Sosa eroza and other research results showed that 5 patients with drug-resistant prolactin macroadenoma were treated with octreotide combined with carbergolin. Among them, 1 patients PRL level decreased by 97%, tumor volume decreased by 93%, 1 patients PRL level decreased by 81%, and tumor volume decreased by 93.6%.

2.2 estrogen receptor modulators (ERM)

Estrogen can promote prolactinoma cell proliferation, synthesis and secretion of PRL, and estrogen receptor is also involved in this process. Blocking estrogen receptor can inhibit PRL secretion and control prolactinoma cell proliferation. It has been reported that 14 patients with drug-resistant prolactinoma were treated with raloxifene, the PRL level of 10 patients decreased by about 25.9%, and the PRL level of 2 patients decreased to normal.

2.3 Prolactin receptor antagonists，PRLRA

Prolactin receptor antagonists (prlra) competitively inhibit the binding of endogenous PRL and PRLR, so as to inhibit the adverse effects caused by excessive PRL in blood, rather than inhibit its production. Prlra may be an ideal entry point for the treatment of PRL induced by refractory prolactinoma, but there is no clinical trial, and the effect of prlra on prolactinoma cell proliferation is not clear.

3.1 mammalian target of rapamycin (mTOR) inhibitor

PI3K / Akt / mTOR signal transduction pathway is widely existing in mammalian cells, which can regulate the survival, proliferation, differentiation and apoptosis of tumor cells. MTOR is a pivotal protein regulating PI3K / Akt signal transduction and downstream pathway. Inhibition of mTOR can inhibit tumor cell proliferation.

3.2 epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI)

EGFR is one of the members of receptor tyrosine kinase family. It is a transmembrane receptor with TK activity. By phosphorylating intracellular tyrosine residues, EGFR plays a role in cell proliferation. By inhibiting TK activity, EGFR can control tumor growth. Studies have shown that EGFR is highly expressed in prolactinoma cells, and the expression of ERBB3 subtype is positively correlated with the invasiveness of prolactinoma. After 6 months of treatment, the PRL level of one patient decreased by 78%, and the tumor volume of the other patient decreased by 42%, and the tumor volume remained stable.

3.3 Vascular endothelial growth factor，VEGF  

Anti vascular endothelial growth factor (VEGF) can promote angiogenesis. By inhibiting VEGF, it can inhibit tumor angiogenesis and degenerate the formed blood vessels. Bevacizumab and other drugs have been used in breast cancer, colorectal cancer, renal cancer and other tumors, which confirmed the effectiveness of anti VEGF therapy for tumors. But for pituitary tumor, the view of anti VEGF treatment is inconsistent with the research results. It is found that the angiogenesis of prolactinoma is not related to VEGF.

3.4 Nerve growth factor，NGF

Nerve growth factor (NGF) can promote the survival, development, differentiation and maturation of nerve cells, maintain normal nerve function and accelerate the repair of injured nerve.

3.5 Transforming growth factor β1，TGFβ1

 Transforming growth factor β 1 (TGF β 1) is an important growth factor involved in cell growth, development and degradation. The expression of TGF β 1 in prolactinoma is regulated by dopamine and estrogen. Estrogen inhibits its expression, while dopamine up regulates its expression. TGF β 1 cooperates with dopamine to antagonize estrogen and inhibit PRL secretion.

4.1 Peptide receptor radio-nuclide therapy，PRRT 

Peptide receptor radio nuclide therapy (PRRT) refers to SSTR mediated radionuclide therapy, which uses radionuclide labeled SSA to direct radionuclide to tumors with high expression of SSTR. SSA and radionuclide play dual therapeutic roles in tumor primary site, such as chemotherapy and internal irradiation.

4.2 Immunotherapy

With the development of oncology and immunology, immune checkpoint has attracted more and more attention. It is a signal pathway molecule in the immune system that participates in the negative regulation of immune response. It protects normal tissues from damage caused by excessive immune response. Tumor cells use immune checkpoint to escape the attack of the immune system and continue to proliferate Death-1 (PD-1) and its ligand (programmed death ligand 1, PD-L1) are widely studied immune checkpoint. Blocking PD-1 can inhibit the proliferation of tumor cells.

4.3 Metformin

Metformin (MET) is a widely used antidiabetic drug for type 2 diabetes mellitus. Related studies have shown that it can inhibit the proliferation of prolactinoma MMQ cells and promote apoptosis.

4.4 Chloroquine

Quinine is a common drug for malaria. Recent studies have found that chloroquine can increase the sensitivity of tumor to chemotherapeutic drugs and induce apoptosis of tumor cells. Clinical trials of chloroquine combined with chemoradiotherapy have confirmed its effectiveness in the treatment of tumors.

Although refractory prolactinoma is rare, its treatment is extremely difficult. Therefore, to explore an effective treatment method is an urgent problem to be solved. Although TMZ, SSA, SSTR, ERM, met and various targeted therapies have been developed, most of them are still in the exploratory stage, and the efficacy and safety need to be further confirmed. In the future, the molecular mechanism of refractory prolactinoma will be further clarified, and more effective treatment methods will benefit patients with refractory prolactinoma.

 

Cindy