Metastatic Phaeochromocytoma: Spinning Towards More Promising Treatment Options

Abstract

Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare tumours arising from the chromaffin cells of the adrenal medulla (PCC) or the paraganglia located outside the adrenal gland (PGL). However, their incidence is likely to be underestimated; around 10% of all PCC/PGL are metastatic, with higher metastatic potential of PGLs compared to PCCs. If benign, surgery is the treatment of choice, but if metastatic, therapy is challenging. Here we review the currently existing therapy options for metastatic PCCs/PGLs including conventional chemotherapy (the original Averbuch scheme, but updated), radiopharmaceutical treatments (¹³¹I-MIBG, ⁹⁰Y- and ¹⁷⁷Lu-DOTATATE) and novel targeted therapies (anti-angiogenic tyrosine kinase inhibitors and mTORC1 inhibitors), emphasising future therapeutic approaches (HIF-2α and PARP inhibitors, temozolomide alone, metronomic temozolomide, somatostatin analogues) based on the oncogenic signalling pathways related to three different clusters comprising more than 20 well-characterised PCC/PGL susceptibility genes. We suggest that targeted combination therapies including repurposed agents may offer more effective future options worthy of exploration.

Fig. 1

(modified from [17] and [103]) Overview: Cluster-1, −2 and −3 with molecular-targeted therapeutic options: Cluster-1: The pseudohypoxic signalling cluster includes mutations in genes encoding for hypoxia-inducible factor 2 alpha (HIF2A), Krebs-Cycle enzymes such as succinate dehydrogenase subunits (SDHx [SDHA, SDHB, SDHC, SDHD]), succinate dehydrogenase complex assembly factor 2 (SDHAF2), fumarate hydratase (FH), malate dehydrogenase 2 (MDH2), and isocitrate dehydrogenase (IDH), moreover, von Hippel–Lindau tumour suppressor (VHL) and egl-9 prolyl hydroxylase 1 and 2 (EGLN1/2). SDH(A[AF2]/B/C/D), FH, MDH2 and IDH mutations impair the Krebs cycle and lead to an increase in succinate, fumarate, or 2-hydroxyglutarate. The accumulation of oncometobolites promote DNA hypermethylation and inactivate tumour suppressor genes, including egl-9 prolyl hydroxylase 1/2 (EGLN1/2). The impaired activity of EGLN1/2 leads less ubiquitination/degradation of HIF-α. The HIF-α degradation is VHL-dependent; Therefore, these mutations promote HIF-α stabilisation independent of hypoxia resulting in increased angiogenesis (VEGF/PDGF transcription amongst others), dysregulation of metabolism, migration, invasion and finally metastases. HIF-α is the common final point, the “Achilles’ heel”, of cluster-1 mutations, interconnecting cluster-1 with cluster-2 mutations. Cluster-2: The kinase signalling cluster comprises mutations in the RET proto-oncogene, NF1 tumour suppressor, H-RAS and K-RAS proto-oncogenes, TMEM127 and MAX. Receptor tyrosine kinases (amongst others RET, VEGFR, c-met) activate PI3K. PI3K activates AKT, which inhibits TSC1/2 leading to disinhibition/activation of mTORC1; mTORC1 phosphorylates and activates various proteins including p70S6K, by which p70S6 is phosphorylated. Activated p70S6 promotes cell growth, proliferation, cell survival, and leads amongst others to protein synthesis of HIF-1α, which favours angiogenesis (VEGF/PDGF transcription amongst others), invasion and metastasis under hypoxic or pseudohypoxic conditions in the case of SDHx-mutations. The RAS/RAF/ERK-pathway is also activated by tyrosine kinases (amongst others RET) and activates mTORC1. NF1 mutations lead to disinhibiton/activation of RAS. TMEM127 mutations lead to disinhibition/activation of mTORC1. The tumour suppressor MAX antagonises Myc-dependent cell survival, proliferation and angiogenesis: mutations lead to increased cell proliferation and angiogenesis. Cluster-3: The Wnt signalling cluster comprises somatic mutations in CSDE1 and the mastermind like transcriptional coactivator 3 (MAML3) fusion genes. MAML3 mutated PGLs/PCCs show hypomethylation and over-activation of Wnt signalling. CSDE1 mutations lead to over-activation of β-catenin, a taget of Wnt signalling. Over-activation of Wnt/β-catenin signalling favors tumour proliferation, invasion and metastases. ⦸Phaeochromocytoma promoting loss of function mutation of a tumour suppressor gene. Phaeochromocytoma promoting gain of function mutation of a proto-oncogene. ⬆Increase/up-regulation in the case of cluster-1 mutations of the Krebs cycle enzymes. ⟘Inhibition. ↘Activation.

Fig. 2

Current and potential future therapeutic options for PCC/PGL