Exploring the Role of Novel Medical Therapies for Aggressive Pituitary Tumors: A Review of the Literature—“Are We There Yet?”

Abstract

Aggressive pituitary tumors account for up to 10% of pituitary tumors and are characterized by resistance to medical treatment and multiple recurrences despite standard therapies, including surgery, radiotherapy, and chemotherapy. They are associated with increased morbidity and mortality, particularly pituitary carcinomas, which have mortality rates of up to 66% at 1 year after diagnosis. Novel targeted therapies under investigation include mammalian target of rapamycin (mTOR), tyrosine kinase, and vascular endothelial growth factor (VEGF) inhibitors. More recently, immune checkpoint inhibitors have been proposed as a potential treatment option for pituitary tumors. An increased understanding of the molecular pathogenesis of aggressive pituitary tumors is required to identify potential biomarkers and therapeutic targets. This review discusses novel approaches to the management of aggressive pituitary tumors and the role of molecular profiling.

The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas

“…PCs, defined by the presence of cerebrospinal or distant metastasis of a pituitary neuroendocrine tumor, are particularly rare and have mortality rates of up to 66% at 1 year after diagnosis. For many patients with refractory PAs and PCs, effective targeted therapy is still lacking (17). PCs have a very limited response to previous therapies, including somatostatin analogs, external beam radiotherapy, chemotherapies including TMZ, capecitabine, everolimus, sunitinib, and bevacizumab, and peptide receptor radionuclide therapy (55).…”

“…However, previous studies showed that only approximately 60% of pituitary tumors are responsive to TMZ treatment, and some of them are resistant to TMZ (13,14). Emerging targeted therapies, including those targeting vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor, the Raf/Mek/ErK pathway, the PI3K/Akt/mTOR pathway, the notch signaling pathway, the hedgehog signaling pathway, and CDK 4/6, have been studied preclinically and/or have been experimentally used for refractory PAs and PCs, but their efficacy is limited (15)(16)(17). Therefore, more effective and novel treatment approaches are needed.…”

Case Report: A Case of Pituitary Carcinoma Treated With Sequential Dual Immunotherapy and Vascular Endothelial Growth Factor Inhibition Therapy

“…The VEGF signaling pathway has been implicated in the tumorigenesis of many cancer types. It has a physiological and pathological role in angiogenesis and vascular permeability as well as modulating the immune microenvironment via several mechanisms which promote a pro-tumor immunosuppressive microenvironment (12,63,64). VEGF targeted therapies including antibody mediated inhibition of VEGF and VEGF receptor tyrosine kinase inhibitors are now used successfully in the treatment of many cancers (64).…”

“…Thirteen cases of APTs treated with VEGF inhibition therapy have been reported, with the majority responding to treatment (2,(7)(8)(9)(10)(11)(12). Published experience with ICI therapy in APTs is limited to two cases with markedly different outcomes (13,14).…”

Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting

“…Serioli et al present a complete and detailed review about invasiveness of pituitary adenoma [ 3 ], while Lamb et al review previous and current studies regarding therapies for aggressive pituitary tumors, discussing the appropriateness and effectiveness role of novel medical therapies [ 4 ]. In this frame, the original research by Vázquez-Borrego et al provides evidence that spliceosome machinery is dysregulated in a tumor subtype-dependent manner, being associated with aggressive features, suggesting the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in these tumors [ 5 ].…”