Oral Presentation 5th International Symposium on Phaeochromocytoma and Paraganglioma 2017

Succinate mediated autocrine tumorigenic effects in succinate dehydrogenase deficient paragangliomas: Potential for new targeted treatment strategies (#28)

Dieter Matlac 1 , Guang-Bo Ge 2 , Luma Abunimer 3 , Peter Deen 4 , Henri J Timmers 5 , Hendrik Lehnert 1 , Zhengping Zhuang 6 , Karel Pacak 3 , Stephanie MJ Fliedner 1
  1. Neuroendocrine Oncology, Medical Department 1, University Medical Center Schleswig-Holstein, Lübeck, Germany
  2. Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
  3. Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
  4. Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
  5. Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, Netherlands
  6. Neurooncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Complete resection is not an option for many paragangliomas with loss-of-function mutations in succinate dehydrogenase (SDH) subunits A-D (SDHA-D, summarized as SDHx). Particularly SDHB mutations predispose to metastases, while for all SDHx mutations the prevalence of head and neck PGLs is high, often making complete resection impossible. Treatment options are thus extremely limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs are thus urgently needed.

Previously, we have shown that SDHx-deficient PGLs show elevated expression of succinate receptor 1 mRNA (SUCNR1). Furthermore, its ligand succinate has been shown to accumulate due to SDHx mutations. We hypothesized that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of SDHx mutation-derived PGLs.

We confirmed elevated SUCNR1 protein expression in SDHx PGL tissue compared to VHL PGLs and normal adrenal medulla. To functionally investigate the influence of SUCNR1 on the viability of PGL cells, we stably transfected rat pheochromocytoma cells (PC12) with human SUCNR1 and treated them with different concentrations of succinate as well as 3 potential SUCNR1 inhibitors. Succinate treatment significantly increased proliferation of SUCNR1-transfected PC12 cells compared to control cells. The tested candidate SUCNR1 inhibitors successfully reversed this effect. In agreement with a SUCNR1 mediated effect, succinate treatment induced ERK phosphorylation.

Our data indicate that succinate has a so far unrecognized oncometabolic function in activating SUCNR1 mediated growth advances in SDHx paragangliomas. SUCNR1 thus provides a promising new druggable target for inoperable and metastatic SDHx mutation-derived tumors.