A novel metabolism-targeting therapy of pulmonary neuroendocrine tumors.

• Project/Area Number: 18K15965
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Miyagi Prefectural Hospital Organization Miyagi Cancer Center
• Principal Investigator: Morita Mami 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん薬物療法研究部, 特任研究員 (20647193)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 小細胞肺がん / 代謝 / 肺神経内分泌腫瘍 / 前臨床

Outline of Final Research Achievements

Small-cell lung cancer (SCLC) accounts for about 15% of human lung cancers, and patient prognosis in these cases is poorer than that of patients with other lung cancers. Although recent genomic studies show simultaneous bi-allelic inactivation of TP53 and RB1 in human SCLC, these studies reveal few driver mutations in SCLC that could be therapeutically targeted.
In this study, we tried to develop a novel strategy to treat SCLC by targeting their metabolic vulnerability. We found that SCLC survival and/or proliferation are highly dependent on the NAD biosynthesis, hence vulnerable upon inhibition of the pathway. We have (1) validated the efficacy of the NAD-targeting therapy in mouse preclinical models, (2) evaluated the molecular details of SCLC metabolic vulnerability, (3) evaluated SCLC dependency to three NAD precursors in culture.

Academic Significance and Societal Importance of the Research Achievements

小細胞肺がんの代謝ターゲット治療の有用性を、マウス前臨床モデルにて示した。肺がんの～15%を占める肺神経内分泌腫瘍（小細胞肺がんを含む）においては、腺癌の場合のような明確で標的化が可能なドライバー変異が存在しない。故に、これら難治肺がんに対しては、ドライバー変異以外の要素を創薬開発する戦略が求められている。これらの肺がんは、発見時には外科的治療のタイミングを逸していることが多く、その文脈でも、新たな分子標的治療を開発する意義は大きい。