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Project

Aggressive salivary gland neoplasms: institutional-international collaborative evaluation of advances in clinical management and translational research into tumor biology

This Phd is focuses on evaluating and improving the treatment options for aggressive salivary gland neoplasms. Within this domain we have two aims. (1) Setting up a (prospective) database for salivary gland tumors with retrospective completion of available data. This will give the data for several institutional and international collaborative studies. Eg: a. Parapharyngeal space tumors b. Recurrent pleiomorphic adenoma c. Parotid Carcinoma (2) Translational research into tumor biology as a possible therapeutic target. Salivary Gland Cancer (SGC) is a heterogeneous family of cancers depending on the cell of origin, with a range of histologies, clinical presentations, biological behavior and prognosis following treatment. Adenoid Cystic Carcinoma (AdCC) is a slow growing SGC which is notorious for locoregional recurrence (40% at 5 years) and distant metastasis (up to 60% of patients).[1] For recurrent/metastasized (R/M) AdCC, the majority consists of slowly progressive disease that is insensitive to cytotoxic chemotherapy, and no alternative treatments (targeted therapy, immunotherapy, …) exist.[2] Salivary Duct Carcinoma (SDC), on the other hand, is one of the most aggressive and fast growing SGC. Median overall survival is 3-4 years, local recurrence occurs in up to 48% of patients and distant metastasis in up to 62%.[3] For distant disease, HER-2 expressing SDC can be treated with Trastuzumab (HER-2 inhibitor), and androgen receptor (AR)-expressing SDC can be treated effectively with AR inhibitors[4], but eventually will escape from this treatment. There thus exists an urgent need to develop new treatment strategies for this patient group. SGC in general and SDC in particular are tumors that have several analogies to cancer from the breast and the prostate gland, which are also exocrine glands.[5] In these latter cancer types, studies have consistently identified altered lipid metabolism as a hallmark of disease. Studies from the team of Johan Swinnen have revealed a strong link between altered lipid metabolism and the AR in carcinomas of the prostate gland and have identified several alterations in lipid metabolism pathways.[6–9] Intriguingly, a recent study in SDC has also indicated the role of droplets and fatty acid synthesis in the AR signaling pathway in SDC.[10] Therefore the lipid metabolism is an important therapeutic target in carcinomas of the prostate gland. In view of this striking similarity, we want to map alterations in lipid metabolism in SGC and aim to explore whether this novel approach of interfering with the lipid metabolism holds promise, and if successful, could constitute a possible breakthrough in a disease where we have been unable to make progress for a long time. Referenties: [1] Coca-Pelaz A, Rodrigo JP, Bradley PJ, Vander Poorten V, Triantafyllou A, Hunt JL, et al. Adenoid cystic carcinoma of the head and neck - An update. Oral Oncol 2015;51. https://doi.org/10.1016/j.oraloncology.2015.04.005. [2] Lorini L, Ardighieri L, Bozzola A, Romani C, Bignotti E, Buglione M, et al. Prognosis and management of recurrent and/or metastatic head and neck adenoid cystic carcinoma. Oral Oncol 2021;115:105213. https://doi.org/10.1016/j.oraloncology.2021.105213. [3] D’Heygere E, Meulemans J, Vander Poorten V. Salivary duct carcinoma. Curr Opin Otolaryngol Head Neck Surg 2018;26:142–51. https://doi.org/10.1097/MOO.0000000000000436. [4] Locati LD, Perrone F, Cortelazzi B, Lo Vullo S, Bossi P, Dagrada G, et al. Clinical activity of androgen deprivation therapy in patients with metastatic/relapsed androgen receptorpositive salivary gland cancers 2015. https://doi.org/10.1002/hed.23940. [5] Udager AM, Chiosea SI. Salivary Duct Carcinoma: An Update on Morphologic Mimics and Diagnostic Use of Androgen Receptor Immunohistochemistry. Head Neck Pathol 2017;11:288–94. https://doi.org/10.1007/s12105-017-0798-x. [6] Centenera MM, Scott JS, Machiels J, Nassar ZD, Miller DC, Zininos I, et al. ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer. Cancer Res 2021:canres.2511.2020. https://doi.org/10.1158/0008-5472.CAN-20-2511. [7] Nassar ZD, Mah CY, Dehairs J, Burvenich IJG, Irani S, Centenera MM, et al. Human decr1 is an androgen-repressed survival factor that regulates pufa oxidation to protect prostate tumor cells from ferroptosis. Elife 2020;9:1–34. https://doi.org/10.7554/eLife.54166.  [8] Itkonen HM, Brown M, Urbanucci A, Tredwell G, Lau CH, Barfeld S, et al. Lipid degradation promotes prostate cancer cell survival. Oncotarget 2017;8:38264–75. https://doi.org/10.18632/oncotarget.16123. [9] Tousignant KD, Rockstroh A, Poad BLJ, Talebi A, Young RSE, Taherian Fard A, et al. Therapyinduced lipid uptake and remodeling underpin ferroptosis hypersensitivity in prostate cancer. Cancer Metab 2020;8:11. https://doi.org/10.1186/s40170-020-00217-6. [10] Hirai H, Tada Y, Nakaguro M, Kawakita D, Sato Y, Shimura T, et al. The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma. Virchows Arch 2020;477:291–9. https://doi.org/10.1007/s00428-020-02777-w.

Date:11 Jan 2022 →  31 Dec 2023
Keywords:Salivary Gland Neoplasm
Disciplines:Otorhinolaryngology not elsewhere classified
Project type:PhD project