Faculty Profiles - TOYOOKA Shinichi

Induction Chemoradiotherapy Followed by Surgical Resection for Clinical T3 or T4 Locally Advanced Non-Small Cell Lung Cancer Reviewed

Kazuhiko Shien, Shinichi Toyooka, Katsuyuki Kiura, Keitaro Matsuo, Junichi Soh, Masaomi Yamane, Takahiro Oto, Mitsuhiro Takemoto, Hiroshi Date, Shinichiro Miyoshi

ANNALS OF SURGICAL ONCOLOGY 19 ( 8 ) 2685 - 2692 2012.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

To examine the usefulness of trimodality therapy in patients with clinical T3 or T4 (cT3-4) locally advanced non-small cell lung cancer (LA-NSCLC).
Between 1997 and 2009, a total of 76 LA-NSCLC patients with cT3-4 underwent surgery. Among them, 36 patients underwent induction chemoradiotherapy with docetaxel and cisplatin plus concurrent radiation followed by surgery (IC group). The other 40 patients initially underwent surgery (IS group). The outcomes of the IC and IS groups were then investigated. To minimize possible biases caused by confounding treatment indications, we performed a retrospective cohort analysis by applying a propensity score (PS). Patients were divided into three groups according to PS tertiles, and comparisons between the IC and IS groups were made by PS tertile-stratified Cox proportional hazard models.
For the entire cohort, which had a median follow-up duration of 48 months, the 3- and 5-year overall survival rates were 83.8 and 78.9%, respectively, in the IC group, versus 66.8 and 56.5%, respectively, in the IS group (P = 0.0092). After adjustments for potentially confounding variables, the IC group continued to have a significantly longer overall survival than the IS group (P = 0.0045). In addition, when the analysis was limited to 52 patients with cT3-4N0 or N1 disease, the IC group had a significantly longer overall survival than the IS group after adjustments for confounding variables (P = 0.019).
Our study indicates that trimodality therapy is highly effective in patients with cT3-4 LA-NSCLC.

DOI： 10.1245/s10434-012-2302-x

肺切除後気胸の治療(Treatment for pneumothorax after pneumonectomy)

古川公之, 宗淳一, 山根正修, 豊岡伸一, 大藤剛宏, 三好新一郎

日本気胸・嚢胞性肺疾患学会雑誌 12 ( 1 ) 87 - 87 2012.8

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1 Reviewed

Kadoaki Ohashi, Lecia V. Sequist, Maria E. Arcila, Teresa Moran, Juliann Chmielecki, Ya-Lun Lin, Yumei Pan, Lu Wang, Elisa de Stanchina, Kazuhiko Shien, Keisuke Aoe, Shinichi Toyooka, Katsuyuki Kiura, Lynnette Fernandez-Cuesta, Panos Fidias, James Chih-Hsin Yang, Vincent A. Miller, Gregory J. Riely, Mark G. Kris, Jeffrey A. Engelman, Cindy L. Vnencak-Jones, Dora Dias-Santagata, Marc Ladanyi, William Pao

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 109 ( 31 ) E2127 - E2133 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/ BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

DOI： 10.1073/pnas.1203530109

Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy Reviewed

Kazuhiko Shien, Shinichi Toyooka, Kouichi Ichimura, Junichi Soh, Masashi Furukawa, Yuho Maki, Takayuki Muraoka, Norimitsu Tanaka, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Masaomi Yamane, Takahiro Oto, Katsuyuki Kiura, Shinichiro Miyoshi

LUNG CANCER 77 ( 1 ) 162 - 167 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

The expression of several cancer stem cell (CSC)-related markers has been confirmed in non-small cell lung cancer (NSCLC). The aim of this study was to clarify the clinical role of CSC-related markers in patients with NSCLC undergoing induction chemoradiotherapy (CRT). Fifty patients with clinically diagnosed N2 or N3 NSCLC who underwent induction CRT with docetaxel and cisplatin concurrently with thoracic radiation followed by surgery were examined in this study. The expressions of CSC related markers (CD133, ALDH1, ABCG2, and Bmi-1) were examined using immunohistochemical staining in surgically resected specimens. Among the 50 patients, 20 patients had no residual tumor cells in the resected specimen when examined pathologically; CSC-related marker expressions and their correlation to survival were evaluated in the other 30 patients. After a median follow-up period of 72 months, the 5-year overall survival rate of the patients with CD133-positive or ALDH1-positive specimens was significantly worse than that of the patients with both CD133-negative and ALDH1-negative expressions (449% vs. 90.0%, respectively; P=0.042). In a multivariate analysis. CD133 and ALDH1 negativity (P=0.047) and cN2-3 single station metastasis (P=0.03) were significant independent prognostic factors for prolonged survival. The expressions of CSC-related markers after CRT were significantly correlated with a poor prognosis in patients with NSCLC. The development of therapeutic strategies including adjuvant therapy that take CSC-related marker positivity into consideration is likely to be a key factor in further improvements of the prognosis of patients undergoing trimodality therapy. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2012.02.006

A Case of Delayed Massive Hemothorax Caused by the Rupture of a Pulmonary Artery Pseudoaneurysm after Radiofrequency Ablation of Lung Tumors Reviewed

Junichi Soh, Shinichi Toyooka, Hideo Gobara, Takao Hiraki, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Susumu Kanazawa, Shinichiro Miyoshi

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 ( 7 ) 646 - 649 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Radiofrequency ablation has been applied as a minimally invasive therapy for the local control of lung tumors, including primary and metastatic neoplasms. Hemorrhagic complications after radiofrequency ablation can usually be treated conservatively, but such complications can be massive and fatal in some cases. In this paper, we report the rare case of delayed massive hemothrax caused by the rupture of a pulmonary artery pseudoaneurysm after lung radiofrequency ablation that was treated using transcatheter coil embolization followed by a left lower lobectomy. A 75-year-old woman underwent radiofrequency ablation for the treatment of a metastatic lung tumor in the left lower lobe arising from a colorectal carcinoma located close to a branch of the pulmonary artery. Thirty-six hours later, hemothorax and hemorrhagic shock occurred as a result of a ruptured pulmonary artery pseudoaneurysm and radiofrequency ablation-induced damage to the interlobular pleura. After transcatheter coil embolization of the pulmonary artery pseudoaneurysm, she recovered from a state of shock and a left lower lobectomy was performed. Histological findings revealed the presence of residual tumor cells in the ablated lung tumor. The postoperative course was uneventful, and no evidence of recurrence of the primary disease was seen at 1 year after the surgery. Although hemothorax secondary to the rupture of a pulmonary artery pseudoaneurysm after lung radiofrequency ablation is a rare complication, it should be recognized as a serious potential complication of lung radiofrequency ablation for a tumor located close to the pulmonary artery branch.

DOI： 10.1093/jjco/hys068

[Primary mediastinal lymphoma; a clinicopathologic case series]. Reviewed

Sugimoto S, Soh J, Maki Y, Kurosaki T, Yamane M, Toyooka S, Oto T, Miyoshi S

Kyobu geka. The Japanese journal of thoracic surgery 65 ( 7 ) 527 - 531 2012.7

縦隔悪性リンパ腫の臨床病理学的検討

杉本誠一郎, 宗淳一, 牧佑歩, 黒崎毅史, 山根正修, 豊岡伸一, 大藤剛宏, 三好新一郎

胸部外科 65 ( 7 ) 527 - 531 2012.7

Language：Japanese Publisher：(株)南江堂

縦隔悪性リンパ腫8例を対象に、診断、治療、臨床病理学的因子を検討した。その結果、発見動機は検診5例、有症状3例であった。白血球数高値は2例、CRP高値は4例、可溶性インターロイキン2受容体高値5例、LDH高値3例であった。最大腫瘍径中央値は8.5(1.5〜4)cmで、7例が7cm以上の巨大な腫瘍であった。PET-CTを5例に施行し、いずれも中等度以上のFDG集積を認め、うち2例は非常に高度の集積であった。診断方法はCTガイド下針生検5例、胸腔鏡補助下生検および切除術1例、小開胸生検1例、胸腺摘出術1例であった。組織型は結節硬化型Hodgkinリンパ腫3例、びまん性大細胞型B細胞性リンパ腫3例、前駆Tリンパ芽球性リンパ腫/白血病1例、胸腺MALTリンパ腫1例であった。治療は手術2例、化学療法もしくは化学療法+放射線療法6例であった。生存期間中央値は34.5(10〜71)ヵ月で、全例が生存中である。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00349&link_issn=&doc_id=20120621060002&doc_link_id=40019360672&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F40019360672&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer Reviewed

Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

Lung Cancer 108 254 - 255 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Ireland Ltd

The publisher regrets errors were introduced in Fig. 3 A of the article described above. The images for both p-Scramble and p-miR-34b/c in SBC5 were incorrect. An amended version of Fig. 3 is shown below. Note that the analyses for both migration and invasion assays were appropriate and thus it is not necessary to correct the bar graphs in Fig. 3 as well as the legends for Fig. 3. The authors also consider that there is no need to correct any other parts of this article. The publisher would like to apologise for any inconvenience caused.

DOI： 10.1016/j.lungcan.2016.04.016

Scopus

Phrenic Nerve Injury after Radiofrequency Ablation of Lung Tumors: Retrospective Evaluation of the Incidence and Risk Factors Reviewed

Yusuke Matsui, Takao Hiraki, Hideo Gobara, Mayu Uka, Yoshihisa Masaoka, Akihiro Tada, Shinichi Toyooka, Toshiharu Mitsuhashi, Hidefumi Mimura, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 23 ( 6 ) 780 - 785 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Purpose: To retrospectively investigate the incidence of and risk factors for phrenic nerve injury after radiofrequency (RF) ablation of lung tumors.
Materials and Methods: The study included 814 RF ablation procedures of lung tumors. To evaluate the development of phrenic nerve injury, chest radiographs obtained before and after the procedure were examined. Phrenic nerve injury was assumed to have developed if the diaphragmatic level was elevated after the procedure. To identify risk factors for phrenic nerve injury, multiple variables were compared between cases of phrenic nerve injury and randomly selected controls by using univariate analyses. Multivariate analysis was then performed to identify independent risk factors.
Results: Evaluation of phrenic nerve injury from chest radiographs was possible after 786 procedures. Evidence of phrenic nerve injury developed after 10 cases (1.3%). Univariate analysis revealed that larger tumor size >= 20 mm; P = .014), proximity of the phrenic nerve to the tumor (< 10 mm; P < .001), the use of larger electrodes (array diameter or noninsulated tip length >= 3 cm; P = .001), and higher maximum power applied during ablation (>= 100 W; P < .001) were significantly associated with the development of phrenic nerve injury. Multivariate analysis demonstrated that the proximity of the phrenic nerve to the tumor (< 10 mm; P < .001) was a significant independent risk factor.
Conclusions: The incidence of phrenic nerve injury after RF ablation was 1.3%. The proximity of the phrenic nerve to the tumor was an independent risk factor for phrenic nerve injury.

DOI： 10.1016/j.jvir.2012.02.014

【抗がん剤治療の最前線:分子標的薬剤の使用による進歩(前篇)】新たな標的となる遺伝子とその変異、新薬 HSP90阻害薬の幕開け非小細胞肺がんを中心に

上野剛, 豊岡伸一, 宗淳一, 猶本良夫, 三好新一郎

最新医学 67 ( 6月増刊 ) 1534 - 1542 2012.6

Language：Japanese Publisher：(株)最新医学社

熱ショックタンパク(HSP)90阻害薬は,発がん性タンパクの発現を抑制し,強い抗腫瘍効果を示す薬剤である.現在,我々が用いたAUY-922を始め,非常にHSP90に親和性の高い新規薬剤の開発がなされている.これらは,より低濃度で抗腫瘍効果を発揮し,初期の阻害薬で起った重度の副作用の発生を抑えた.また,肺がんでは,ALK遺伝子変異肺がんに対し,感受性が高いことが分かった.現在,多数の臨床試験が施行中であり,今後,期待される分子標的薬の1つである.(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00516&link_issn=&doc_id=20120625220019&doc_link_id=%2Fap7saisa%2F2012%2F0067s2%2F020%2F1534-1542%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fap7saisa%2F2012%2F0067s2%2F020%2F1534-1542%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Long-term outcome of induction chemoradiotherapy with docetaxel and cisplatin followed by surgery for non-small-cell lung cancer with mediastinal lymph node metastasis Reviewed

Shinichi Toyooka, Katsuyuki Kiura, Mitsuhiro Takemoto, Takahiro Oto, Nagio Takigawa, Toshiyoshi Fujiwara, Shinichiro Miyoshi, Hiroshi Date

INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY 14 ( 5 ) 565 - 569 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

The purpose of this study was to show the long-term outcome of induction chemoradiotherapy, using docetaxel and cisplatin with concurrent radiotherapy followed by surgery for non-small-cell lung cancer (NSCLC) with mediastinal nodal metastasis. Between January 2000 and July 2006, 22 consecutive NSCLC patients with pathologically proven mediastinal nodal metastasis were treated with tri-modality therapy. The regimen consisted of docetaxel and cisplatin plus concurrent radiation at a dose of 40-46 Gy. The induction therapy was followed by surgery 4-6 weeks later. The pulmonary resections were composed of a lobectomy in 19 patients, including 3 with a sleeve lobectomy, a bilobectomy in 2 patients and a left pneumonectomy in 1 patient. With a median follow-up duration of 8.7 years, the 3-year and 7-year overall survival (OS) rates for the entire population were 72.7 and 63.6%, respectively. Our results suggest that tri-modality therapy is promising for NSCLC patients with mediastinal nodal metastasis.

DOI： 10.1093/icvts/ivs028

DNA methylation status of REIC/Dkk-3 gene in human malignancies Reviewed

Tatsuro Hayashi, Hiroaki Asano, Shinichi Toyooka, Kazunori Tsukuda, Junichi Soh, Tadahiko Shien, Naruto Taira, Yuho Maki, Norimitsu Tanaka, Hiroyoshi Doihara, Yasutomo Nasu, Nam-ho Huh, Shinichiro Miyoshi

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 138 ( 5 ) 799 - 809 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The REIC (reduced expression in immortalized cells)/Dkk-3 is down-regulated in various cancers and considered to be a tumor suppressor gene. REIC/Dkk-3 mRNA has two isoforms (type-a,b). REIC type-a mRNA has shown to be a major transcript in various cancer cells, and its promoter activity was much stronger than that of type-b. In this study, we examined the methylation status of REIC/Dkk-3 type-a in a broad range of human malignancies.
We examined REIC/Dkk-3 type-a methylation in breast cancers, non-small-cell lung cancers, gastric cancers, colorectal cancers, and malignant pleural mesotheliomas using a quantitative combined bisulfite restriction analysis assay and bisulfate sequencing. REIC/Dkk-3 type-a and type-b expression was examined using reverse transcriptional PCR. The relationships between the methylation and clinicopathological factors were analyzed.
The rate of REIC/Dkk-3 type-a methylation ranged from 26.2 to 50.0% in the various primary tumors that were examined. REIC/Dkk-3 type-a methylation in breast cancer cells was significantly heavier than that in the other cell lines that we tested. REIC/Dkk-3 type-a methylation was inversely correlated with REIC/Dkk-3 type-a expression. There was a correlation between REIC/Dkk-3 type-a and type-b mRNA expression. REIC/Dkk-3 type-a expression was restored in MDA-MB-231 cells using 5-aza-2'-deoxycytidine treatment. We found that estrogen receptor-positive breast cancers were significantly more common among the methylated group than among the non-methylated group.
REIC/Dkk-3 type-a methylation was frequently detected in a broad range of cancers and appeared to play a key role in silencing REIC/Dkk-3 type-a expression in these malignancies.

DOI： 10.1007/s00432-012-1158-6

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer Reviewed

LUNG CANCER 76 ( 1 ) 32 - 38 2012.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC. The methylation of miR-34a and miR-34b/c was observed in 4 (36%) and 7 (64%) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4(15%) and 18 (67%), respectively. In contrast, 13 (28%) miR-34a methylated cases and 12 (26%) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC (p < 0.001). The expressions of miR-34s were reduced in methylated cell lines and tumors and restored after 5-aza-2'-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis. We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The transfection of miR-34b/c to two SCLC cell lines (H1048 and SBC5) resulted in the significant inhibition of cell growth, migration, and invasion, compared with control transfectants. Our results indicate that the aberrant methylation of miR-34b/c plays an important role in the pathogenesis of SCLC, implying that miR-34b/c may be a useful therapeutic target for SCLC. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2011.10.002

Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer Reviewed

Tsuyoshi Ueno, Kazunori Tsukuda, Shinichi Toyooka, Midori Ando, Munenori Takaoka, Junichi Soh, Hiroaki Asano, Yuho Maki, Takayuki Muraoka, Norimitsu Tanaka, Kazuhiko Shien, Masashi Furukawa, Tomoki Yamatsuji, Katsuyuki Kiura, Yoshio Naomoto, Shinichiro Miyoshi

LUNG CANCER 76 ( 1 ) 26 - 31 2012.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

The anti-tumor activity of a newly developed Hsp90 inhibitor, NVP-AUY922 (AUY922), against non-small cell lung cancer (NSCLC) was examined. Twenty-one NSCLC cell lines were used, the somatic alterations of which were characterized. Cell proliferation was analyzed using a modified MTS assay. Expression of the client proteins was assessed using Western blotting. The cell cycle was analyzed using flow cytometry. The IC50 value of AUY922 for the NSCLC cell lines ranged from 5.2 to 860 nM (median, 20.4 nM). Based on previous data, cells with an IC50 of less than 50 nM were classified as sensitive cells and 19 of the 21 NSCLC cell lines were judged to be sensitive. The IC50 of five malignant pleural mesothelioma (MPM) cell lines revealed that the MPM cells had a significantly higher IC50 value (median, 89.2 nM; range, 22.2-24, 100 nM) than the NSCLC cells (p = 0.015). There was significant depletion of both the total and phosphorylated client proteins - EGFR, MET, HERZ and ART - at low drug concentrations (50-100 nM) in drug-sensitive cell lines. Cell-cycle analysis was performed for two sensitive cell lines, H1975 and H838. Following AUY922 treatment, an increase in the sub-G(0)-G(1) cell population, as well as appearance of cleaved PARP expression, indicated the induction of apoptosis. In conclusion, AUY922 was effective against most NSCLC cell lines, independent of the type of known molecular alteration, and appears to be a promising new drug for the treatment of NSCLC. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2011.09.011

EGFRチロシンキナーゼ阻害剤に対する耐性機構と克服

肺切除術後の肺嚢胞における対側性気胸二症例報告(Contralateral pneumothorax in bullous lung after pneumonectomy: Report of two cases)

古川公之, 宗淳一, 豊岡伸一, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 26 ( 3 ) P30 - 10 2012.4

非小細胞肺癌に対する新たな個別化治療戦略 REIC/Dkk-3遺伝子治療の可能性

宗淳一, 豊岡伸一, 田中則光, 渡部昌実, 山本寛斉, 阪口政清, 許南浩, 那須保友, 公文裕巳, 三好新一郎

日本呼吸器外科学会雑誌 26 ( 3 ) P17 - 01 2012.4

宗淳一, 豊岡伸一, 上野剛, 三好新一郎

肺癌 52 ( 2 ) 131 - 135 2012.4

Language：Japanese Publisher：(NPO)日本肺癌学会

本邦の肺腺癌の約40%に認められるepidermal growth factor receptor(EGFR)変異肺癌に対する有効な治療法の開発は、肺癌治療成績の向上において重要である。EGFR変異肺癌にはEGFRチロシンキナーゼ阻害剤(EGFR-TKI)が高い感受性を示すが、遺伝子変異がもたらすEGFR変異蛋白に対するEGFR-TKIとアデノシン3リン酸(ATP)の親和性の関係を知ることは感受性・耐性の原因を理解する上で大切である。また、薬剤に対する獲得耐性の機構としては、T790M変異に代表されるEGFR遺伝子の2次変異とMET遺伝子増幅などのキナーゼ乗り換え耐性の2つに大別される。EGFR-TKI耐性肺癌の克服には、これら耐性化機構の理解に基づいた新規薬剤および治療法の開発が不可欠である。多くの薬剤が開発されているが、heat shock protein 90(Hsp90)阻害剤は、変異型EGFR・MET・AKTなどの複数のクライアント蛋白の安定化を阻害することで抗腫瘍効果を示すため、様々な機構を持つEGFR-TKI耐性肺癌への治療効果が期待され、現在臨床試験が行われている。(著者抄録)