Mechanisms of resistance to molecularly targeted drugs for oral squamous cell carcinoma and investigation of countermeasures

• Project/Area Number: 16K11732
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Tokai University
• Principal Investigator: YAMAZAKI Hiroshi 東海大学, 医学部, 准教授 (00338708)
• Co-Investigator(Kenkyū-buntansha): 森 泰昌 国立研究開発法人国立がん研究センター, 中央病院, 医員 (00296708)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 外科系歯学 / 臨床腫瘍学 / 口腔癌 / 口腔扁平上皮癌 / 分子標的薬 / 歯学 / 癌 / 遺伝子

Outline of Final Research Achievements

The expression of mutant epidermal growth factor receptor (EGFRvIII) was investigated in 96 patients with oral squamous cell carcinoma (OSCC) who underwent surgery. Biopsied tissue samples underwent reverse transcription polymerase chain reaction (PCR), Sanger sequencing, and digital PCR testing, as well as next-generation sequencing. The detection of EGFRvIII was not consistent among the cases, but at least 3 (3%) were considered definitely positive. In order to elucidate the functions of EGFRvIII, we used an OSCC cell line, prepared and evaluated cetuximab-resistant and EGFRvIII-transfected OSCC cell lines. We detected no changes in the protein expression of EGFRvIII, or the signal transduction pathway, in either line.

Academic Significance and Societal Importance of the Research Achievements

上皮成長因子受容体（EGFR）の抗体であるセツキシマブ（Cmab）は、局所進行あるいは再発転移口腔癌（OSCC）の標準治療に用いられている。そのため、Cmabに関するバイオマーカーの確立は重要であるが、現在のところ真に有用なバイオマーカーは存在せず、これを発見することはきわめて重要である。Cmabは野生型に対する抗体であり、変異型であるEGFRvⅢへの結合性は低いため、EGFRvⅢを指標としたネガティブセレクションの可能性が示唆されている。

Research Products

• [Journal Article] Altered DNA methylation is associated with aberrant stemness gene expression in early stage HNSCC (2019)
  • Author(s): Suzuki Takatsugu、Yamazaki Hiroshi、Honda Kazufumi、Ryo Eijitsu、Kaneko Akihiro、Ota Yoshihide、Mori Taisuke
  • Journal Title: International Journal of Oncology Volume: 55 Pages: 915-924
  • DOI: 10.3892/ijo.2019.4857
  • Peer Reviewed
• [Journal Article] New PCNT candidate missense variant in a patient with oral and maxillofacial osteodysplasia: a case report (2019)
  • Author(s): Aoyama KI, Kimura M, Yamazaki H, Uchibori M, Kojima R, Osawa Y, Hosomichi K, Ota Y, Tanaka M, Yamada S, Nishimura G.
  • Journal Title: BMC Medical Genetics Volume: 20 Issue: 1 Pages: 126-126
  • DOI: 10.1186/s12881-019-0858-z
  • Peer Reviewed / Open Access
• [Journal Article] Mandibular pain, trismus, and weight loss in a 75-year-old man. (2018)
  • Author(s): Yamazaki H, Suzuki T, Denda Y, Nakanishi Y, Uchibori M, Kojima R, Kondo Y
  • Journal Title: Oral Surg Oral Med Oral Pathol Oral Radiol Volume: 印刷中 Issue: 6 Pages: 451-456
  • DOI: 10.1016/j.oooo.2017.12.012
  • Peer Reviewed
• [Journal Article] A Case of Early Pneumoparotid Presenting with Oral Noises. (2018)
  • Author(s): Yamazaki H, Kojima R, Nakanishi Y, Kaneko A
  • Journal Title: J Oral Maxillofac Surg Volume: 76 Issue: 1 Pages: 67-69
  • DOI: 10.1016/j.joms.2017.05.039
  • Peer Reviewed
• [Journal Article] Lateral retropharyngeal lymph node metastasis from squamous cell carcinoma of the upper gingiva: a case report (2018)
  • Author(s): Yamazaki H, Sasaki M, Aoyama K, Suzuki T, Denda Y, Uchibori M, Nakanishi Y, Kojima R, Ota Y
  • Journal Title: MOLECULAR AND CLINICAL ONCOLOGY Volume: 8 Pages: 68-72
  • DOI: 10.3892/mco.2017.1496
  • Peer Reviewed / Open Access