Pheochromocytomas and Paragangliomas: From Genetic Diversity to Targeted Therapies

Ying Pang, Yang Liu, Karel Pacak, Chunzhang Yang, Ying Pang, Yang Liu, Karel Pacak, Chunzhang Yang

Abstract

Pheochromocytoma and paraganglioma (PCPGs) are rare neuroendocrine tumors that arise from the chromaffin tissue of adrenal medulla and sympathetic ganglia. Although metastatic PCPGs account for only 10% of clinical cases, morbidity and mortality are high because of the uncontrollable mass effect and catecholamine level generated by these tumors. Despite our expanding knowledge of PCPG genetics, the clinical options to effectively suppress PCPG progression remain limited. Several recent translational studies revealed that PCPGs with different molecular subtypes exhibit distinctive oncogenic pathways and spectrum of therapy resistance. This suggests that therapeutics can be adjusted based on the signature molecular and metabolic pathways of PCPGs. In this review, we summarized the latest findings on PCPG genetics, novel therapeutic targets, and perspectives for future personalized medicine.

Keywords: neuroendocrine tumor; paraganglioma; pheochromocytoma; targeted therapy; therapy resistance.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustrations of cancer-associated mutations in pheochromocytomas and paragangliomas (PCPGs). Cluster I PCPGs exhibit dysfunction in the Krebs cycle and hypoxia sensing pathways. Loss-of-function mutations in SDHx, FH, EGLN1 or VHL are commonly identified in this disease cluster. HIF2A mutations that activate hypoxia signaling are also found in Cluster I disease. Cluster II PCPGs exhibit abnormal kinase activity. This is caused by mutations of major regulators in the feedback loop, such as NF1, MAX and TMEM127. Gain-of-function mutations in RET prompt cellular proliferation and survival by initiating kinase pathways such as Ras/MEK and PI3K/Akt.

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