Novel Biomarker for Therapeutic Target in Lung squamous cell carcinoma

• Project/Area Number: 19K07706
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Gunma University
• Principal Investigator: Rokudai Susumu 群馬大学, 大学院医学系研究科, 講師 (20392334)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: p53 / p63 / 肺がん / 扁平上皮がん / Lung Cancer / Squamous Cell Carcinoma / TP53 / TP63 / Syntaxin Binding Protein / Lung cancer / Squamous cell carcinoma

Outline of Research at the Start

扁平上皮がんは有効な分子標的が少ないために難治療性である。肺扁平上皮がんの診断マーカーであるTP63は腫瘍性に関与していると考えられるが、その詳細な仕組みは解明されていない。これまでに申請者は、肺がんにおける新たながん悪性化遺伝子として、SNAREタンパクであるSTXBP遺伝子を同定し、p63の発現制御とがん悪性化に関与する仕組みを明らかにした。本研究は、p63やSTXBPの詳細ながん悪性化機構を解明し、バイオマーカーや分子標的治療の探索を行う。
本研究は、さらにp63関連遺伝子による扁平上皮がんの発生や進行について詳細を解明し、バイオマーカー探索、新規分子標的治療としての展開を目的とする。

Outline of Final Research Achievements

Lung squamous cell carcinoma is difficult to treat because molecular targeted therapies are not effective. The disruption of control of the ΔNp63 gene expression, which is a diagnostic marker for squamous cell carcinoma, is one of the causes of cancer development and progression. Through comprehensive screening using a next-generation sequencer, we clarified the molecular mechanism that causes the disruption of p63 expression control related to poor prognosis, and clarified the mechanism involved in malignant transformation of cancer. In addition, in squamous cell carcinoma of the head and neck, AKT3 in cancer-related fibroblastic cells (CAF) was revealed to be associated with immunosuppression of the microenvironment of CAF, and is a potential biomarker of CAF activity and immunosuppressive microenvironment. Possibly a therapeutic target that inhibits the tumor-promoting function of CAF.

Academic Significance and Societal Importance of the Research Achievements

肺扁平上皮がんの診断マーカーでもあるΔNp63の発現の増加は高頻度で認められ、90%以上の扁平上皮がんで陽性であり、p53のがん抑制機能を阻害することで、がんの発生や進行、治療への抵抗性を高めるものと考えられており、治療標的としての可能性を秘めていると考えられる。本研究では、p63遺伝子の制御に関与するがんの発生や進行の詳細な仕組みを解明し、分子標的治療の開発に繋がる可能性を検討した。p63の発現制御機構を利用した化合物スクリーニングを進めており、アカデミア創薬としての開発が期待される。

Research Products

• [Journal Article] AKT3 is a novel regulator of cancer-associated fibroblasts in head and neck squamous cell carcinoma (2021)
  • Author(s): Takahashi H, Rokudai S, Kawabata-Iwakawa R, Sakakura K, Oyama T, Nishiyama M, Chikamatsu K.
  • Journal Title: Cancers Volume: 13(6) Issue: 6 Pages: 1233-1233
  • DOI: 10.3390/cancers13061233
  • Peer Reviewed / Open Access
• [Journal Article] AKT3 is a key regulator of head and neck squamous cell carcinoma. Takahashi H, Rokudai S, Kawabata-Iwakawa R, Sakakura K, Oyama T, Nishiyama M, Chikamatsu K. (2021)
  • Author(s): Takahashi H, Rokudai S, Kawabata-Iwakawa R, Sakakura K, Oyama T, Nishiyama M, Chikamatsu K.
  • Journal Title: Cancer Science Volume: - Issue: 6 Pages: 2325-2334
  • DOI: 10.1111/cas.14911
  • Peer Reviewed / Open Access
• [Journal Article] Syntaxin binding proten 4 as a novel therapeutic target and an effective biomarker for better treatment selection in lung squamous cell carcinoma. (2020)
  • Author(s): Bilguun EO, Kaira K, Kawabata-Iwakawa R, Rokudai S, Shimizu K, Yokobori T, Oyama T, Shirabe K, Nishiyama M.
  • Journal Title: Research Square, Review Volume: -
  • DOI: 10.21203/rs.3.rs-39783/v1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinctive roles of syntaxin binding protein 4 and its action target, TP63, in lung squamous cell carcinoma: A theranostic study for the precision medicine (2020)
  • Author(s): Bilguun EO, Kaira K, Kawabata-Iwakawa R, Rokudai S, Shimizu K, Yokobori T, Oyama T, Shirabe K, Nishiyama M.
  • Journal Title: BMC Cancer Volume: 20(1) Pages: 1-14
  • Peer Reviewed / Open Access
• [Book] High-Throughput RNA Interference Screen Targeting Synthetic-Lethal Gain-of-Function of Oncogenic Mutant TP53 in Triple-Negative Breast Cancer (Reviews). (2020)
  • Author(s): Rokudai S.
  • Publisher: Springer Nature
• [Patent(Industrial Property Rights)] Method for manufacturing peripheral nerve cells. (2020)
  • Inventor(s): 西山正彦、六代範、吉山伸司
  • Industrial Property Rights Holder: 西山正彦、六代範、吉山伸司
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Overseas