甲状腺癌靶向治疗研究进展

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
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
甲状腺癌靶向治疗研究进展 -一个转化医学的实例
上海市内分泌代谢病临床医学中心
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
乳头状癌（ATC）
滤泡状癌（FTC）
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)
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)
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
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
GTP
RAS
Mutation of RAS, RAF; amplification of PIK3CA, etc
PI3K AKT
Cell survival (anti-apoptosis)
Gene Transcription Cell Cycle Progression
Cell growth
Endocrine Review 2010 Metastasis
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 unpublished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
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
❖ 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
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
60
Sporadic
40
20
0Βιβλιοθήκη Baidu
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