Search

Contains fulltext : 172720.pdf (Publisher’s version ) (Open Access) Recently, activating mutations of the hypoxia-inducible factor 2alpha gene (HIF2A/EPAS1) have been recognized to predispose to multiple paragangliomas (PGLs) and duodenal somatostatinomas associated with polycythemia, and ocular abnormalities. Previously, mutations in the SDHA/B/C/D, SDHAF2, VHL, FH, PHD1, and PHD2 genes have been associated with HIF activation and the development of pseudohypoxic (cluster-1) PGLs. These tumors overlap in terms of tumor location, syndromic presentation, and noradrenergic phenotype to a certain extent. However, they also differ especially by clinical outcome and by presence of other tumors or abnormalities. In the present study, we aimed to establish additional molecular differences between HIF2A and non-HIF2A pseudohypoxic PGLs. RNA expression patterns of HIF2A PGLs (n=6) from 2 patients were compared with normal adrenal medullas (n=8) and other hereditary pseudohypoxic PGLs (VHL: n=13, SDHB: n=15, and SDHD: n=14). Unsupervised hierarchical clustering showed that HIF2A PGLs made up a separate cluster from other pseudohypoxic PGLs. Significance analysis of microarray yielded 875 differentially expressed genes between HIF2A and other pseudohypoxic PGLs after normalization to adrenal medulla (false discovery rate 0.01). Prediction analysis of microarray allowed correct classification of all HIF2A samples based on as little as three genes (TRHDE, LRRC63, IGSF10; error rate: 0.02). Genes with the highest expression difference between normal medulla and HIF2A PGLs were selected for confirmatory quantitative reverse transcriptase polymerase chain reaction. In conclusion, HIF2A PGLs show a characteristic expression signature that separates them from non-HIF2A pseudohypoxic PGLs. Unexpectedly, the most significantly differentially expressed genes have not been previously described as HIF target genes.

457 Background: Malignant pheochromocytoma/paraganglioma (P/PG) is a rare malignancy. Management of metastatic disease includes surgery, external radiation, 131I-MIBG and systemic chemotherapy. CVD (cyclophosphamide, vincristine and dacarbazine) is the only chemotherapy commonly used to treat metastatic disease. Putative anti-angiogenic agents such as the tyrosine kinase inhibitor (TKI) axitinib target a well-recognized pathway thought to be active in many tumors. Methods: Patients with histologically confirmed P/PG previously treated or naive to treatment received axitinib at initial dose of 5 mg BID. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival, response rate and safety. Results: Between January and September 2014 nine patients have been enrolled. The median age was 54.7 years, (range 42.5 – 70.5); median number of previous systemic treatments was one (range 0 – 3). Three of the nine patients achieved a partial response. An additional 5 patients have had tumor shrinkage insufficient to qualify as a partial response with only one patient response scored as progression. Tumor shrinkage has been observed in lymph node, soft tissue and lung metastases; and has been associated with reductions in circulating cathecholamines. Median time to progression has not been reached. A total of 50 cycles have been administered. Toxicity has led to a reduction of the dose of axitinib from a starting dose of 5 mg BID to 3 mg BID in six and 2 mg BID in two patients. The axitinib dose could be increased to 7 mg BID in only one patient Principal grade 3-4 toxicities included hypertension (6 patients), fatigue (4 patients), diarrhea (1 patient) and mucositis (1 patient). Conclusions: Preliminary data shows axitinib can result in tumor shrinkage in patients with a diagnosis of malignant P/PG. The high rate of dose reduction related to toxicity may reflect a different pharmacokinetic profile of the drug in these patients a possibility now under investigation. Clinical trial information: NCT01967576.