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M. Noguchi



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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.08 - A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high grade pulmonary neuroendocrine carcinona (Large cell neuroendocrine carcinoma and small cell lung cancer) (ID 1562)

      10:30 - 12:00  |  Author(s): M. Noguchi

      • Abstract
      • Presentation
      • Slides

      Background
      Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high grade neuroendocrine carcinoma (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients.

      Methods
      Patients with completely resected stage I- IIIA HGNEC received 4 cycles of irinotecan (60 mg/m[2], day 1, 8, 15) plus cisplatin (60 mg/m[2], day 1). This regimen was repeated every 4 weeks. Other eligibility criteria included ECOG PS 0–1, age 20, and <75 years old, adequate organ function, and no prior chemotherapy or radiotherapy. Patients with UGT1A1 polymorphisms (homozygous for *6 or *28, or simultaneously heterozygous *6 and *28), associated with irinotecan-related severe toxicity, were excluded. The primary endpoint was the rate of completion of chemotherapy (defined as underwent 3 or 4 cycles), and secondary endpoints were 3-year relapse free survival (RFS), rate of 3-year survival and toxicities.

      Results
      Forty patients were enrolled between September 2007 and April 2010. Patients’ characteristics were as follows: median age (range) 65 (45-73) years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90% C.I.; 71-90%). The rate of overall survival at 3 years was estimated at 81%, and of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86% and 74% among 23 LCNEC patients, and 74%, 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutrophils, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and 4 patients (10%) had grade 3 nausea. No treatment related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC at pathological central review among 7 pathologists. There were two specimens that showed the difference in between institutional diagnosis and central pathological diagnosis.

      Conclusion
      The combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.In Japan, a randomized phase III trial is ongoing to evaluate adjuvant chemotherapy of irinotecan and cisplatin, compared with etoposide and cisplatin, for completely resected HGNEC.

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    P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.02-002 - Stratifin expressed in early invasive lung adenocarcinoma functionally enhances tumor progression and down-regulates SCF<sup>Fbw7 </sup>ubiquitin ligase activity (ID 659)

      09:30 - 16:30  |  Author(s): M. Noguchi

      • Abstract

      Background
      Adenocarcinoma in situ (AIS) of the lung shows a very favorable prognosis, with a 5-year survival rate of 100%. However, early but invasive adenocarcinoma (eIA) sometimes has a fatal outcome. In order to elucidate the key molecule that affects the malignant progression of adenocarcinoma at an early stage, we previously compared the expression profiles of AIS with those of eIA, and found that stratifin (SFN, 14-3-3 sigma) is one of the differentially expressed genes related to tumor progression (Aya Shiba-Ishii, IJC. 2011). Immunohistochemistry (IHC) with anti-SFN antibody revealed that more than 95% of eIAs were SFN-positive, in comparison with only 13% of AISs. We also found that promoter demethylation triggered aberrant SFN overexpression in eIAs (Aya Shiba-Ishii, AJP. 2012). Here, we performed functional analysis of SFN and identification of SFN binding protein (SBP) to clarify how SFN affects the progression of lung adenocarcinoma.

      Methods
      For in vitro functional analysis, we performed RNA interference and expression vector transfection analyses and subsequent cell proliferation assays or cell cycle phase assay using a lung adenocarcinoma cell line (A549). An in vivo animal study was also performed using siSFN-transfected A549. Additionally, in order to identify SBP, SFN vector-transfected A549 was subjected to pull-down assay and subsequent LC-MS analysis. Interaction of SFN and SBP was examined using co-IP and western western blotting.

      Results
      Suppression of SFN expression by siSFN significantly reduced cell proliferation activity and the S-phase subpopulation. Transfection of the SFN expression vector led to a significant increase in cell proliferation. A549 treated with siSFN showed reduced tumor development relative to the controls. Pull-down assay and LC-MS analysis revealed that SKP1 is one of the SBPs. SKP1 is a component of the SKP1-Cullin1-F-box containing complex (SCF complex). We found that Fbw7, one of the substrate recognition subunits of SCF complex, also binds to the SFN-SKP1 complex, resulting in up-regulation of cyclin E1 phosphorylation by SFN.

      Conclusion
      Although SFN was originally identified as a negative regulator of the cell cycle, especially in response to p53-sensitive DNA damage, subsequent reports indicated that it is a positive mediator of cell proliferation. In breast cancer, SFN induces G1/S progression by increasing the expression of cyclin D1. Here, we demonstrated that SFN enhanced the proliferative capacity of lung adenocarcinoma cells both in vitro and in vivo. We also revealed that SFN down-regulated expression of the SCF[Fbw7] complex. As cyclin E1 is a common target of SCF[Fbw7] ubiquitination, we predict that SCF[Fbw7] down-regulation by SFN might induce stabilization of cyclin E1. Since we also found that the S-phase subpopulation was decreased after siSFN treatment, SFN might induce G1/S progression through an increase of cyclin E1 phosphorylation in lung adenocarcinoma. In conclusion, SFN facilitates cell proliferation and malignant progression of lung adenocarcinoma, and its mechanism of action is thought to be associated with inhibition of SCF[Fbw7] ubiquitination and degradation.