| 1. |
Makoto Endo, Hidetaka Yamamoto, Nokitaka Setsu, Kenichi Kohashi, Yusuke Takahashi, Takeaki Ishii, Kei-ichiro Iida, Yoshihiro Matsumoto, Michiyuki Hakozaki, Mikiko Aoki, Hiroshi Iwasaki, Yoh Dobashi, Kenichi Nishiyama, Yukihide Iwamoto, Yoshinao Oda, Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors, Clinical Cancer Research, 10.1158/1078-0432.CCR-12-1067, 19, 2, 450-461, 2013.01, PURPOSE:
Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target.
EXPERIMENTAL DESIGN:
Immunohistochemistry was conducted to evaluate the activation profiles of AKT/mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines.
RESULTS:
Phosphorylated-AKT (p-AKT), p-mTOR, p-S6RP, p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 expressions were positive in 58.2%, 47.3%, 53.8%, 57.1%, 62.6%, 93.4%, and 81.3% of primary MPNSTs, respectively. Positivity for each factor showed no difference between NF1-related and sporadic MPNSTs. Univariate prognostic analysis revealed that p-AKT, p-mTOR, and p-S6RP expressions were associated with poor prognosis. Furthermore, activation of each p-mTOR and p-S6RP was an independent poor prognostic factor by multivariate analysis. mTOR inhibition by Everolimus showed antitumor activity on MPNST cell lines in vitro.
CONCLUSION:
mTOR inhibition is a potential treatment option for both NF1-related and sporadic MPNSTs.. |
| 2. |
Makoto Endo, Chikashi Kobayashi, Nokitaka Setsu, Yusuke Takahashi, Kenichi Kohashi, Hidetaka Yamamoto, Sadafumi Tamiya, Shuichi Matsuda, Yukihide Iwamoto, Masazumi Tsuneyoshi, Yoshinao Oda, Prognostic Significance of p14(ARF), p15(INK4b), and p16(INK4a) Inactivation in Malignant Peripheral Nerve Sheath Tumors, Clinical Cancer Research, 10.1158/1078-0432.CCR-10-2393, 17, 11, 3771-3782, 2011.06, PURPOSE:
p14(ARF), p15(INK4b), and p16(INK4a) are tumor suppressor genes that are located closely at 9p21 and are often coinactivated by genetic or epigenetic alterations. Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma with poor prognosis. However, the prognostic implications of inactivation of p14(ARF), p15(INK4b), and p16(INK4a) in MPNSTs have not been adequately investigated. Here we carried out a genetic, epigenetic, and expression analysis of p14(ARF), p15(INK4b), and p16(INK4a), and clarified the prognostic significance of their inactivation in MPNSTs.
EXPERIMENTAL DESIGN:
p14(ARF), p15(INK4b), and p16(INK4a) protein expressions were assessed by immunohistochemistry in 129 formalin-fixed samples of MPNST including 85 primary tumors. Thirty-nine samples, for which frozen material was available, were also investigated by Western blotting and quantitative reverse transcription PCR (RT-PCR) to detect p14(ARF), p15(INK4b), and p16(INK4a) protein and mRNA expression, and by multiplex real-time PCR, PCR single strand conformation polymorphism and methylation-specific PCR to detect p14(ARF), p15(INK4b), and p16(INK4a) gene alterations.
RESULTS:
Immunohistochemically decreased expressions of p14(ARF), p15(INK4b), and p16(INK4a) were observed in 48%, 54%, and 49% of primary MPNSTs, respectively, and were significantly correlated with their concordant mRNA levels. As for gene alterations, homozygous deletion of CDKN2A was detected in one third of the cases. Inactivation of p14(ARF) and p16(INK4a) was associated with poor prognosis by both univariate and multivariate analyses. Furthermore, cases with inactivation of all p14(ARF), p15(INK4b), and p16(INK4a) genes showed the worst prognosis in a combined prognostic assessment.
CONCLUSION:
A comprehensive analysis of p14(ARF), p15(INK4b), and p16(INK4a) inactivation status provides useful prognostic information in MPNSTs.. |
