Anti-VEGF Therapy in Refractory Pituitary Adenomas and Pituitary Carcinomas: A Review

Abstract

Most pituitary tumors are considered benign adenomas, and only 0.1%–0.2% of them present metastasis and are defined as pituitary carcinomas (PCs). Refractory pituitary adenomas (PAs) lie between benign adenomas and true malignant PCs and are defined as aggressive-invasive PAs, characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments. Refractory PAs and PCs are notoriously difficult to manage because of limited therapeutic options. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis not only during development but also during pathological processes in pituitary tumors. Recently, increasing numbers of preclinical studies and clinical research have demonstrated that anti-VEGF therapy plays an important role in pituitary tumors. The purpose of this review is to report the role of VEGF in the development and pathology of pituitary tumors and the progress of anti-VEGF therapy in pituitary tumors, including refractory PAs and PCs. Previous preclinical studies indicated that cyclin-dependent kinase 5 (CDK5)-mediated VEGF expression might play a crucial role in the development of PAs. Vascular endothelial growth inhibitors have been reported as independent predictors of invasion in human PAs and have been indicated as markers for poor outcome. Furthermore, several studies have reported that angiogenesis decreases tumor sizes in experimental animal models of pituitary tumors. The expression of VEGF is relatively high in PAs; therefore, anti-VEGF therapy has been used in some refractory PAs and PCs. To date, anti-VEGF has been reported as monotherapy, in combination with temozolomide (TMZ), TMZ and radiotherapy, and with pasireotide, which might be a promising alternative therapy for refractory PAs and PCs resistant to conventional treatments. However, the role of anti-VEGF therapy in pituitary tumors is still controversial due to a lack of large-scale clinical trials. In summary, the results from preclinical studies and clinical trials indicated that anti-VEGF therapy monotherapy or in combination with other treatments may be a promising alternative therapy for refractory PAs and PCs resistant to conventional treatments. More preclinical studies and clinical trials are needed to further evaluate the exact efficacy of anti-VEGF in refractory PAs and PCs.

Transcriptome Analysis Reveals Distinct Patterns Between the Invasive and Noninvasive Pituitary Neuroendocrine Tumors

“…Angiogenesis, the formation of new blood vessels, is crucial for tumor development and metastasis [ 16 ]. Unlike most solid tumors, PitNETs are less vascularized compared to normal pituitary tissue.…”

“…Unlike most solid tumors, PitNETs are less vascularized compared to normal pituitary tissue. Even invasive, aggressive, or malignant PitNETs do not demonstrate a significant increase in vascularity, with the exception of some rare secondary deposits of metastatic PitNETs [ 16 ]. The genetic background of low vascular density in PitNETs is unclear.…”

VEGF-A in serum protects against memory impairment in APP/PS1 transgenic mice by blocking neutrophil infiltration

“…Therefore, these reports suggested that VEGF signaling is involved in the development of AD. Previous studies indicated that inhibition of Cdk5 activity in rat pituitary cells reduced VEGF-A expression [ 63 , 64 ], implying that an underlying link exist between VEGF-A and Cdk5 in the endothelium. Interestingly, in the present study, recombinant VEGF-A directly prevented Aβ-mediated Cdk5 inhibition and promoted endothelial cell proliferation in bEnd.3 cells, and prevented brain capillary loss in an AD mouse model.…”

From Genes to Therapy: Pituitary Adenomas in the Era of Precision Medicine

“…The rapid advancement in technology has spurred extensive research into a wide array of potential biomarkers, leading to significant developments in this field [62]. These biomarkers are varied, encompassing different biochemical forms such as nucleic acids, proteins, carbohydrates, lipids, small metabolic products, Recent studies, both preclinical and clinical, have underscored the importance of anti-VEGF therapy in treating pituitary tumors [61]. In murine models, anti-VEGF agents have demonstrated significant effectiveness when used as single agents.…”