甲状腺癌靶向治疗研究进展

PDGF PDGFR
FGF FGFR
HGF MET
Rearrangement of NTRK1, RET; mutation of RET, EGFR; amplification of EGFR, KIT, MET; overexpression of VEGFR, FGFR, MET etc
RAF ERK
乳头状癌（ATC）
滤泡状癌（FTC）
未分化癌（ATC）
甲状腺髓样癌（MTC）
甲状腺癌临床与病理特点
类型 乳头状癌 滤泡状癌 低分化癌 未分化癌 髓样癌
百分比 85-90% <10%
<7% 2% 3%
男女比 1:2-1:4 1:2-1:3 1:0.4-1:2 1:1.5 1:1-1:1.2
年龄 20-50 40-60 50-60 60-80 30-60
No Metastasis
Distant Metastasis
Annals of Surgery 2007
非常有必要探讨新的治疗方案 探讨甲癌的发病机制
甲癌遗传学研究进展
Nature Review Cancer 2006
Thyroid, 2009 vol. 19, pp. 1351-61
Somatic Mutations Play Role in Patient Survival Outcome and are Likely Drivers of Metastasis
❖ Tumor stage at diagnosis is a key indicator of survival
❖ Distance metastases is found in ~10% of thyroid cancer patients
❖ Presence of metastasis is associated with the worst possible survival outcome
Angiogenesis
Cancer Res 2002
The relative IC50 of tyrosine kinase inhibitor (TKIs) targets in a cell-free assay system (nM)
Endocrine Review 2010
Response Evaluation Criteria in Solid Tumors (RECIST)
甲状腺癌靶向治疗研究进展
-一个转化医学的实例
叶蕾
上海市内分泌代谢病临床医学中心 上海交通大学医学院附属瑞金医院内分泌科
发病率增长速度排肿瘤第一位
美国1975-2007年发病 率增长2.5倍
我国的沿海地区十年 增长三倍
瑞金医院以每年200例 的速度递增
SEERS， 2010
甲状腺癌病理分类
C细胞 滤泡细胞
恶性肿瘤的分子靶向治疗
1961 费城染色体 1984 Bcl-Abl 基因 1996 Imatinib 2009 FDA批准近30种分子靶向治疗药物
CA Cancer J Clin 2009
甲状腺癌相关分子通路及药物靶点
GDNF RET
EGF EGFR
VEGF VEGFR
Overexpression of EGF,VEGF, etc
Lessons from Chernobyl
Oncogene (2009) 27, S9–S18
碘摄入异常也会影响 甲癌的发生
Cancer Epidemiology, Biomarkers & Prevention 2001
Association of High Iodine Intake with the T1799A BRAF Mutation in Papillary Thyroid Cancer
Papillary Thyroid Carcinoma
Medullary Thyroid Carcinoma
The presence of activated BRAF reduces survival
Kim et al. Clin Endocrinol 65: 364 (2006)
Gagel et al. unpublished
J Clin Endocrinol Metab. May 2009, 94(5):1612–1617
甲癌其他的高危因素
Cancer Epidemiology, Biomarkers & Prevention Vol. 10, 979–985, September 2001
甲状腺癌的传统治疗模式
手术
GTP
RAS
Mutation of RAS, RAF; amplification of PIK3CA, etc
PBiblioteka Baidu3K AKT
Cell survival (anti-apoptosis)
Gene Transcription Cell Cycle Progression
Cell growth
Endocrine Review 2010 Metastasis
60
Sporadic
40
20
0
0
5
10
15
20
25
30
Years from Diagnosis
Cupisti et al. Annals of Surgery (2007) vol. 246, pp. 815-21
The Need for NonSurgical Treatments
❖ Surgical success is highly dependent on the timing of thyroidectomy
淋巴转移 <50% <5% 30-80% 40% 50%
远处转移 5-7% 20%
30-80% 40% 50%
5年存活率 >90% >90% 50% 1-17% 80%
多数预后良好 部分预后不良
Nature Review Cancer 2006
放射线是甲状腺癌最为明确的高危因素
RADIATION RESEARCH 141, 259–277 (1995)
放射性碘
对晚期甲状腺癌无有效治疗措施
Surgical Timing – MTC Provides a Worst and Best Case Scenario
Roman et al. Cancer (2006) vol. 107, pp. 2134-42
Survival (%)
100
80
Hereditary MTC