| Project/Area Number |
17K15032
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (B)
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
Tumor therapeutics
|
|---|
| Research Institution | Kindai University |
|---|
Principal Investigator |
TANAKA Kaoru 近畿大学, 医学部, 講師 (80548628)
|
|---|
| Project Period (FY) |
2017-04-01 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
|
|---|
| Keywords | 分子標的治療 / ALK阻害剤 / 薬剤耐性 / 非小細胞肺癌 |
|---|
| Outline of Final Research Achievements |
Between November 2016 and May 2019, 16 EML4-ALK fusion gene-positive patients were enrolled following disease progression on first- or second-generation ALK inhibitors. Blood samples were collected in all patients, and re-biopsy was performed in 12 patients. Paired samples of pre- and post-ALK-TKI treatment were collected in 10 patients and next-generation sequencing was performed. Among the 12 patients undergoing ALK-TKI-resistant biopsies, 6 (50.0%) had secondary mutations. The most common ALK resistance mutation was G1202R (2 cases), and the remaining ALK resistance mutations included: G1269A, L1196M, V1180L, and F1174L. The characteristics of patients with secondary mutations were mostly males (83.3%), non-smokers (50%), or light smokers (33.3%), and all patients pretreated with alectinib. Of the 4 patients (66.7%) with secondary mutations were treated with lorlatinib, a third-generation ALK-TKI, and all patients had a response to lorlatinib.
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究ではALK陽性肺癌に対するTKI耐性獲得機序の研究体制を構築し、G1269A、L1196M、G1202R、V1180L、F1174Lの5つの既知の二次耐性遺伝子変異を確認。少数例ではあるが耐性機序と患者背景や治療歴の関連を検証し、2次耐性変異検出例への第3世代ALK-TKIの治療効果確認することが出来た。
ALK陽性肺癌は症例数が少なく、ALK-TKIのPFSが長く耐性化するまでの期間が長い。また、高い治療効果のために標的病変が消失しており耐性後の組織検体採取が困難である。そのような背景を鑑みると、本研究で得られた結果は将来の肺癌治療の基礎データとして国民に還元し得る重要なものである。
|
