Download presentation
Presentation is loading. Please wait.
1
Makoto Endo, Nokitaka Setsu, Kenichi Kohashi,
Annual Meeting of Connective Tissue Oncology Society Oct.15-18/2014, Berlin 1 Paper 066 Activation Status of AKT-mTOR and MAPK Pathways in Malignant Peripheral Nerve Sheath Tumors: Which Pathway Affects a Patient’s Survival? Makoto Endo, Nokitaka Setsu, Kenichi Kohashi, Hidetaka Yamamoto, Tomoya Matsunobu, Yoshihiro Matsumoto, Katsumi Harimaya, Yukihide Iwamoto, Yoshinao Oda Kyushu University Hi, I am Makoto Endo from Kyushu Univ., an orthopaedic oncologist in Japan. We, Japanese oncologist usually do surgery and chemotherapy both, as for me, I’m also doing pathologic research. I am interested in everything related to sarcoma. Someone calls me sarcoma addict. Anyway, my today’s presentation about Activation Status of AKT-mTOR and MAPK Pathways in Malignant Peripheral Nerve Sheath Tumors to clarify which pathway affects a patient’s survival.
2
No financial relationships to disclose
2 COI disclosure No financial relationships to disclose I have no financial relationships to disclose.
3
A half of MPNST arises from neurofibroma in patients with NF1.
3 A half of MPNST arises from neurofibroma in patients with NF1. You know, a half of MPNST arises from benign neurofibroma in patients with neurofibromatosis type 1. Neurofibromatosis type 1 is a genetic disorder making multiple neurofibromas all over the body. What happens in NF1 patient? Enzinger and Weiss: Soft Tissue Tumors 5th edition
4
？ ？ ？ 1% high-grade malignancy NF1 gene encoding neurofibromin
4 NF1 gene encoding neurofibromin suppressing MAPK activation MAPK hyperactivation sporadic case a half of MPNST multiple neurofibromas ？ high-grade malignancy 1% ？ This slide shows a molecular process occurs in NF1 patients. NF1 gene encodes neurofibromin protein suppressing MAPK activation, in NF1 patient, NF1 gene has dysfunction, leading to MAPK hyperactivation and multiple neurofibromas. Approximately 1% of neurofibromas shows malignant transformation and develops into MPNST. Also, there is sporadic MPNST occurs in non-NF1 patients. Detailed molecular mechanisms developing into MPNST and even more high-grade malignant transformation are still unclear. MPNST ？
5
mTOR AKT Growth factors （EGF, VEGF, IGF） RTK NF1 gene neurofibromin
5 RTK PI3K RAS GTP NF1 gene neurofibromin AKT AKT/mTOR pathway MAPK pathway mTOR RAF This slide shows MAPK signaling pathway. In NF1 patient, NF1 gene deficiency causes MAPK hyperactivation. So, we focused on AKT-mTOR pathway that has signaling crosstalk with MAPK pathway MEK p70S6K S6RP 4E-BP1 ERK protein synthesis cell proliferation
6
Purpose AKT-mTOR and MAPK pathways in MPNSTs To clarify
6 Purpose AKT-mTOR and MAPK pathways in MPNSTs To clarify the frequency of activation the clinicopathologic significance of activation the prognostic significance of activation The purpose of this study is to clarify the frequency, the clinicopathologic significance, and the prognostic significance of activation of AKT-mTOR and MAPK pathways in MPNSTs.
7
Materials MPNST paraffin-embedded specimens 135cases (104patients)
7 Materials MPNST paraffin-embedded specimens 135cases (104patients) MPNST frozen specimens 5cases Diagnosed between 1964 and 2010 Primary 91, Recurrent 39, Metastatic 5 Neurofibromatosis type 1 (NF1) 37cases (41%) Sporadic 54cases (59%) Location: Extremity 39, Trunk 52 Depth: Superficial 21, Deep 70 Tumor size: <5cm 25, >=5cm 66 AJCC stage: I 28, II 41, III 17, IV 5 We used
8
Methods MPNST paraffin-embedded specimens MPNST frozen specimens
8 Methods MPNST paraffin-embedded specimens Immunohistochemistry(IHC) MPNST frozen specimens Western blotting(WB) Antibodies: p-AKT, p-mTOR, p-S6RP p-p70S6K, p-4E-BP1 p-MEK1/2, p-ERK1/2
9
Immunohistochemistry
9 Immunohistochemistry p-AKT p-mTOR p-S6RP p-p70S6K p-4E-BP1 p-MEK1/2 p-ERK1/2
10
10 p-AKT p-S6RP p-p70S6K p-4E-BP1 p-mTOR H&E MPNST NF *
11
11 Western blotting p-AKT AKT p-mTOR mTOR p-S6RP p-p70S6K p-MEK1/2
p-AKT IHC P P P P N 11 Western blotting ー Comparison of IHC and WB ー p-AKT AKT p-mTOR IHC N P N P N p-mTOR mTOR p-S6RP IHC P P P P N p-S6RP p-p70S6K IHC P P P P N p-p70S6K p-MEK1/2 IHC P P P P P p-MEK1/2 p-ERK1/2 IHC P P P P N p-ERK1/2 Actin T N T N T N T N T N Case Case Case Case Case 5
12
Frequency of activation of AKT-mTOR and MAPK pathways
12 Frequency of activation of AKT-mTOR and MAPK pathways Akt p-AKT (+): 53/91 (58.2%) p-mTOR (+): 43/91 (47.3%) p-p70S6K (+): 52/91 (57.1%) p-S6RP (+): 49/91 (53.8%) p-4E-BP1 (+): 57/91 (62.6%) * MEK1/2 mTOR * * ERK1/2 * p70S6K * * p-MEK1/2 (+): 85/91 (93.4%) p-ERK1/2 (+): 74/91 (81.3%) 4E-BP1 S6RP * associated significantly
13
Association between clinicopathologic factors and IHC results
13 Association between clinicopathologic factors and IHC results IHC p value Deep tumor location p-AKT 0.034 p-mTOR 0.0053 p-S6RP 0.0076 p-4E-BP1 0.035 p-ERK1/2 0.0024 High Ki67 labeling index 0.0026 Rhabdomyoblastic differentiation p-p70S6K 0.014 High mitotic counts 0.0069 0.0019 High histologic grade 0.011 NF1 none not significant
14
Prognostic analysis 14 p-AKT p-mTOR p-S6RP p-p70S6K p-4E-BP1 p-MEK1/2
p-ERK1/2
15
multivariate prognostic analysis
15 multivariate prognostic analysis hazard ratio 95% CI p value NF1 (present/absent) 1.73 0.10 adjuvant tx (given/not given) 2.84 tumor necrosis (absent/present) 1.62 0.24 Ki67 LI (0-29%/>30%) 2.35 0.023 epithelioid feature 0.37 AJCC stage (I/II+III+IV) 1.21 0.68 p-mTOR IHC (positive/negative) 2.61 0.0072
16
MPNST progression MPNST initiation 50-60% 80-90%
Summary 16 AKT/mTOR activation 50-60% PI3K RAS GTP neurofibromin AKT MAPK activation 80-90% RAF mTOR prognostic importance MEK p70S6K Neurofibroma formation & MPNST initiation S6RP MPNST progression 4E-BP1 ERK protein synthesis cell proliferation
17
AKT/mTOR/S6RP would be potential therapeutic target
17 Conclusion Activation of AKT/mTOR/S6RP was associated with poor prognosis in MPNSTs AKT/mTOR/S6RP would be potential therapeutic target in MPNSTs
18
Acknowledgement 18 Dr. Hiroshi Iwasaki, Fukuoka Univ.
Dr. Mikiko Aoki, Fukuoka Univ. Dr. Yoji Nagashima, Yokohama City Univ. Dr. Hiroshi Sonobe, Chugoku Chuo Hosp. Dr. Michiyuki Hakozaki, Fukushima Medical Univ. Dr. Yoh Dobashi, Saitama Medical Center, Jichi Medical Univ. Dr. Kenichi Nishiyama, National Kyushu Cancer Center Dr. Yusuke Takahashi, Kyushu Univ. Dr. Takeaki Ishii, Kyushu Univ. Ms. Naomi Tateishi, Kyushu Univ. Dr. Jun Kishimoto, Kyushu Univ. The Research Support Center of Kyushu Univ.
Similar presentations
