The Therapeutic Landscape of Salivary Gland Malignancies-Where Are We Now?

Abstract

Salivary gland malignancies (SGMs) account for less than 5% of new diagnoses in head and neck tumors. If feasible, surgery is the preferred treatment modality. Nevertheless, some malignancies have a tendency of recurrence, with possible distant metastasis. Alternative treatment strategies, such as primary radiation or chemotherapeutics, often present low response rates. As a result, there is an unmet need for novel therapeutic approaches. Nowadays, target-based therapies (e.g., small inhibitors and immunotherapy) are used by the medical oncologist for possible treatment of advanced SGMs. Based on recent published trials, some novel treatments may provide additional disease control for some patients. However, sample sizes are small, the general findings are unsatisfactory, and a lot of uncertainties remain to be elucidated. Nevertheless, research shows that patients do not benefit from blind administration of systemic treatments and therefore a more personalized approach is highly needed. The aim of this review paper is to summarize the most recent advances in the biological understanding and molecular pathways of salivary gland cancers, the association of these pathways with the current treatments used and their implications for more personalized targeted-based therapies.

Keywords: diagnostics; molecular pathways; personalized medicine; salivary gland malignancies; targeted therapy.

Figure 1

Overview of receptors and molecular pathways involved in SGMs. Illustration of the receptors and intracellular pathways that can initiate angiogenesis, proliferation, and survival in SGMs. Red spheres indicate targeted therapies which have been developed for numerous of these receptors and intracellular molecules: 1: abiraterone, bicalutamide, enzalutamide, leuprorelin; 2: apatinib, axitinib, dasatinib, dovotinib, imatinib, lenvatinib, sorafenib, sunitinib; 3: cetuximab, dacomitinib, gefitinib, lapatinib; 4: dovotinib, nintedanib, lenvatinib, regorafenib; 5: cabozantinib, dovotinib, sorafenib, sunitinib; 6: lapatinib, pertuzumab, trastazumab; 7: figitumumab, R1507; 8: everolimus; 9: bortezomib; 10: AL101, BMS-986115, brontictuzumab, CB-103, crenigacestat; 11: axitinib, dovotinib, imatinib, lenvatinib, nintedanib, regorafenib, sorafenib, sunitinib; 12: apatinib, axitinib, cabozantinib, dovotinib, lenvatinib, nintedanib, regorafenib, sorafenib, sunitinib; 13: apatinib, cabozantinib, dovotinib, lenvatinib, sorafenib, sunitinib; 14: nelfinavir; 15: VMD-928; and 16: APG-115. It is clear that SGMs have a multitude of pathways which can sustain carcinogenesis and therefore provide the carcinoma with an excellent tool for drug resistance to a specific targeted therapy. AR, androgen receptor; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; FLT3, fms-like tyrosine kinase 3; HER, human epidermal growth factor receptor; IGF1R, insulin-like growth factor 1 receptor; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; NOTCH, Neurogenic locus notch homolog protein; PDGFR, platelet-derived growth factor receptor; RET, rearranged during transfection; SGMs, salivary gland malignancies; Trk, tropomyosin receptor kinase; VEGFR, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.