Phospho-mTOR is not upregulated in metastatic SDHB paragangliomas

Hans K. Ghayee, Alessio Giubellino, Arielle Click, Payal Kapur, Alana Christie, Xian Jin Xie, Victoria Martucci, Jerry W. Shay, Rhonda F. Souza, Karel Pacak

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Pheochromocytomas (PCCs)/paragangliomas (PGLs) are neuroendocrine tumours that may cause arrhythmia and death if untreated. Treatment for patients with metastatic tumours is lacking. As new PCC/PGL susceptibility genes are discovered that are associated with the mTOR pathway, treatment targets focusing on this pathway are being intensively explored. Design: Twenty-one human PCC/PGLs were analysed from two tertiary care centres. Immunohistochemistry (IHC) analysis was performed for phospho-mTOR (pmTOR), phospho-S6K (pS6K), phosphoinositide 3-kinase (PI3K), phospho-4EBP1 (p4EBP1), HIF1α and MIB-1 in 6 metastatic SDHB PCC/PGLs, 15 nonmetastatic PCC/PGLs, (including 1 TMEM127 PCC and 1 nonmetastatic SDHB PGL) and 6 normal adrenal medullas. The product of the intensity of stain and percentage of cells stained was calculated as an H score. Results: Using a two-sample t-test and paired t-test, pmTOR and pS6K had significantly higher H scores in nonmetastatic PCC/PGLs than in metastatic SDHB PCC/PGLs. HIF1α had significantly higher H scores in metastatic SDHB PCC/PGLs compared with nonmetastatic PCC/PGLs and normal adrenal medulla. No difference in H scores was seen with p4EBP1, PI3K and MIB-1 when comparing metastatic SDHB PCC/PGLs and nonmetastatic PCC/PGLs. Significantly higher difference in pS6K was seen in normal adrenal medullas compared to nonmetastatic PCC/PGLs and metastatic SDHB PCC/PGLs. Conclusion: The present results suggest that the use of mTOR inhibitors alone for metastatic SDHB PCC/PGLs may not achieve good therapeutic efficacy in patients.

Original languageEnglish (US)
Pages (from-to)970-977
Number of pages8
JournalEuropean Journal of Clinical Investigation
Volume43
Issue number9
DOIs
StatePublished - Sep 2013

Fingerprint

Paraganglioma
Pheochromocytoma
Phosphatidylinositols
Tumors
Phosphotransferases
Coloring Agents
Genes
Adrenal Medulla
1-Phosphatidylinositol 4-Kinase
Neuroendocrine Tumors
Immunohistochemistry
Tertiary Care Centers

Keywords

  • Paraganglioma
  • PmTOR
  • SDHB

ASJC Scopus subject areas

  • Medicine(all)
  • Clinical Biochemistry
  • Biochemistry

Cite this

Phospho-mTOR is not upregulated in metastatic SDHB paragangliomas. / Ghayee, Hans K.; Giubellino, Alessio; Click, Arielle; Kapur, Payal; Christie, Alana; Xie, Xian Jin; Martucci, Victoria; Shay, Jerry W.; Souza, Rhonda F.; Pacak, Karel.

In: European Journal of Clinical Investigation, Vol. 43, No. 9, 09.2013, p. 970-977.

Research output: Contribution to journalArticle

Ghayee, Hans K. ; Giubellino, Alessio ; Click, Arielle ; Kapur, Payal ; Christie, Alana ; Xie, Xian Jin ; Martucci, Victoria ; Shay, Jerry W. ; Souza, Rhonda F. ; Pacak, Karel. / Phospho-mTOR is not upregulated in metastatic SDHB paragangliomas. In: European Journal of Clinical Investigation. 2013 ; Vol. 43, No. 9. pp. 970-977.
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AU - Ghayee, Hans K.

AU - Giubellino, Alessio

AU - Click, Arielle

AU - Kapur, Payal

AU - Christie, Alana

AU - Xie, Xian Jin

AU - Martucci, Victoria

AU - Shay, Jerry W.

AU - Souza, Rhonda F.

AU - Pacak, Karel

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AB - Background: Pheochromocytomas (PCCs)/paragangliomas (PGLs) are neuroendocrine tumours that may cause arrhythmia and death if untreated. Treatment for patients with metastatic tumours is lacking. As new PCC/PGL susceptibility genes are discovered that are associated with the mTOR pathway, treatment targets focusing on this pathway are being intensively explored. Design: Twenty-one human PCC/PGLs were analysed from two tertiary care centres. Immunohistochemistry (IHC) analysis was performed for phospho-mTOR (pmTOR), phospho-S6K (pS6K), phosphoinositide 3-kinase (PI3K), phospho-4EBP1 (p4EBP1), HIF1α and MIB-1 in 6 metastatic SDHB PCC/PGLs, 15 nonmetastatic PCC/PGLs, (including 1 TMEM127 PCC and 1 nonmetastatic SDHB PGL) and 6 normal adrenal medullas. The product of the intensity of stain and percentage of cells stained was calculated as an H score. Results: Using a two-sample t-test and paired t-test, pmTOR and pS6K had significantly higher H scores in nonmetastatic PCC/PGLs than in metastatic SDHB PCC/PGLs. HIF1α had significantly higher H scores in metastatic SDHB PCC/PGLs compared with nonmetastatic PCC/PGLs and normal adrenal medulla. No difference in H scores was seen with p4EBP1, PI3K and MIB-1 when comparing metastatic SDHB PCC/PGLs and nonmetastatic PCC/PGLs. Significantly higher difference in pS6K was seen in normal adrenal medullas compared to nonmetastatic PCC/PGLs and metastatic SDHB PCC/PGLs. Conclusion: The present results suggest that the use of mTOR inhibitors alone for metastatic SDHB PCC/PGLs may not achieve good therapeutic efficacy in patients.

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