基于分子标志物的肺癌转化性
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基于分子标志物的肺癌转化性 研究进展
张绪超
广东省医学科学院 & 广东省人民医院 广东省肺癌研究所 华南临床基因检测中心
OUTLINE
1. 分子标志物核心地位与临床试验 2. 相对全面的分子分型和靶向治疗策略 3. 联合治疗及积极发现特殊患者进行转化研
究 4. 液相活检（liquid biopsy）的应用 5. 免疫靶点治疗的机制深入
• NCI NCORP: Lung_MAP, ALCHEMIST, and MATCH trials
• China: lung cancer cluster trial
2011 ASCO blueprint for transforming clinical and translational cancer research
•Bert Vogelstein et al. Cancer Genome Landscapes. 1546 (2013); 339 Science •S. Thiagalingam et al., Nat. Genet. 13, 343 (1996)
基于分子靶点的临床和转化性研究
- 基于驱动分子变异的新药研发/基于分子靶点筛查的临床试验 - 多臂临床试验
LUNG-MAP: Phase II/III Biomarker-driven Master Protocol for
Second Line Therapy of Squamous Cell Lung Cancer (SCCA)
Common Broad Platform CLIA Biomarker Profiling*
2013 WCLC, Vali Papadimitrakopoulou
The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials, or
ALCHEMIST
ALCHEMIST - Screening component (A151216) – Coordinated by the Alliance for Clinical Trials in Oncology; Principal Investigators: Pasi A. Janne, M.D., Ph.D., and Geoffrey Oxnard, M.D., Dana-Farber Cancer Institute, Boston. http://www.cancer.gov/clinicaltrials/NCT02194738
CT*
PNDo-nL-1 match drug
PI3Ki
CT*
Cdk4/6 i
CT*
FGFRi+CT CT*
HGFi+E E*
Endpoint (Interim PFS)
OS
Endpoint (Interim PFS)
OS
Endpoint (Interim PFS)
OSBiblioteka Baidu
Endpoint (Interim PFS)
PIB3Kiomarker A M:PIK3CA mut
CMD:CKC4N/6BDio1m, Cadrkke6raΒmpl, CDKN2 del, mut
FBGioFmRarker C M: FGFR ampl, mut, fusion
Non-match
HGFBiomarker D
M:c-Met Expr
生物标志物：分子时代肺癌转化性研究的核心
From AACR progress 2013
致癌信号通路的活化：癌基因、抑癌 基因的变异
原癌基因 • 基因突变 癌基因
(proto-oncogene•) 扩活增化
• 易位融合
(oncogene)
• 表观遗传修饰
• 缺失（LOH）
•…
抑癌基因
(tumor suppressor gene, TSG)
失活
功能缺失
Diagnostic
to indicate if an individual is ill or carrier of defected genes
biomarker
Prognostic
to show the effects of tumor on the outcome of a patient, with no relationship with intervention
OS
TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib *Archival FFPE tumor, fresh CNB if needed
Final agent and specific protocol arms TBA Nov 7, 2013-Friends Brookings Meeting, Washington D.C.
•Mut-Driver gene：containing driver mutation
Q：– o免ncog疫ene治, we疗sim中ply reDquririevtheatr>2g0%eonf tehe/mrecourdtead tion 定义的界限？ mutations in the gene are at recurrent positions and are
missense – that >20% of the recorded mutations in the gene are inactivating
•Epi-Driver gene：epigenetic deregulation
– Criteria for distinguishing epigenetic changes that exert a selective growth advantage from those that do not (passenger epigenetic changes) have not yet been formulated.
Predictive
to show the effects of intervention on the tumors
“Driver gene” vs “Druggable target”
The driver versus-passenger concept was originally used to distinguish mutations that caused a selective growth advantage from those that did not.
张绪超
广东省医学科学院 & 广东省人民医院 广东省肺癌研究所 华南临床基因检测中心
OUTLINE
1. 分子标志物核心地位与临床试验 2. 相对全面的分子分型和靶向治疗策略 3. 联合治疗及积极发现特殊患者进行转化研
究 4. 液相活检（liquid biopsy）的应用 5. 免疫靶点治疗的机制深入
• NCI NCORP: Lung_MAP, ALCHEMIST, and MATCH trials
• China: lung cancer cluster trial
2011 ASCO blueprint for transforming clinical and translational cancer research
•Bert Vogelstein et al. Cancer Genome Landscapes. 1546 (2013); 339 Science •S. Thiagalingam et al., Nat. Genet. 13, 343 (1996)
基于分子靶点的临床和转化性研究
- 基于驱动分子变异的新药研发/基于分子靶点筛查的临床试验 - 多臂临床试验
LUNG-MAP: Phase II/III Biomarker-driven Master Protocol for
Second Line Therapy of Squamous Cell Lung Cancer (SCCA)
Common Broad Platform CLIA Biomarker Profiling*
2013 WCLC, Vali Papadimitrakopoulou
The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials, or
ALCHEMIST
ALCHEMIST - Screening component (A151216) – Coordinated by the Alliance for Clinical Trials in Oncology; Principal Investigators: Pasi A. Janne, M.D., Ph.D., and Geoffrey Oxnard, M.D., Dana-Farber Cancer Institute, Boston. http://www.cancer.gov/clinicaltrials/NCT02194738
CT*
PNDo-nL-1 match drug
PI3Ki
CT*
Cdk4/6 i
CT*
FGFRi+CT CT*
HGFi+E E*
Endpoint (Interim PFS)
OS
Endpoint (Interim PFS)
OS
Endpoint (Interim PFS)
OSBiblioteka Baidu
Endpoint (Interim PFS)
PIB3Kiomarker A M:PIK3CA mut
CMD:CKC4N/6BDio1m, Cadrkke6raΒmpl, CDKN2 del, mut
FBGioFmRarker C M: FGFR ampl, mut, fusion
Non-match
HGFBiomarker D
M:c-Met Expr
生物标志物：分子时代肺癌转化性研究的核心
From AACR progress 2013
致癌信号通路的活化：癌基因、抑癌 基因的变异
原癌基因 • 基因突变 癌基因
(proto-oncogene•) 扩活增化
• 易位融合
(oncogene)
• 表观遗传修饰
• 缺失（LOH）
•…
抑癌基因
(tumor suppressor gene, TSG)
失活
功能缺失
Diagnostic
to indicate if an individual is ill or carrier of defected genes
biomarker
Prognostic
to show the effects of tumor on the outcome of a patient, with no relationship with intervention
OS
TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib *Archival FFPE tumor, fresh CNB if needed
Final agent and specific protocol arms TBA Nov 7, 2013-Friends Brookings Meeting, Washington D.C.
•Mut-Driver gene：containing driver mutation
Q：– o免ncog疫ene治, we疗sim中ply reDquririevtheatr>2g0%eonf tehe/mrecourdtead tion 定义的界限？ mutations in the gene are at recurrent positions and are
missense – that >20% of the recorded mutations in the gene are inactivating
•Epi-Driver gene：epigenetic deregulation
– Criteria for distinguishing epigenetic changes that exert a selective growth advantage from those that do not (passenger epigenetic changes) have not yet been formulated.
Predictive
to show the effects of intervention on the tumors
“Driver gene” vs “Druggable target”
The driver versus-passenger concept was originally used to distinguish mutations that caused a selective growth advantage from those that did not.