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腫瘤和標靶治療 林鵬展醫師 (Peng-Chan Lin) 成大醫學院附設醫院. 癌症治療新紀元分子標靶治療 具專一性 正常細胞較不具破壞性 副作用較小.

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Presentation on theme: "腫瘤和標靶治療 林鵬展醫師 (Peng-Chan Lin) 成大醫學院附設醫院. 癌症治療新紀元分子標靶治療 具專一性 正常細胞較不具破壞性 副作用較小."— Presentation transcript:

1 腫瘤和標靶治療 林鵬展醫師 (Peng-Chan Lin) 成大醫學院附設醫院

2 癌症治療新紀元分子標靶治療 具專一性 正常細胞較不具破壞性 副作用較小

3 Chemotherapy and Cell Cycle

4 History of Cancer Chemotherapy

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7 Molecular Events in Cancer Aberrant Signal Transduction Secretion of Autocrine Growth Factors Secretion of Matrix Metalloproteinases Expression of Oncogenes Loss of Tumor Suppressor Genes Secretion of Angiogenic Growth Factors Dysregulation of Growth Factors or Receptors

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9 何謂標靶治療 ? 針對癌細胞特有的表面標記或訊息傳遞途 徑,以小分子化合物或單株抗體加以阻斷 腫瘤細胞增殖,促進癌細胞死亡,抑制血 管生成等,稱之「標靶治療」

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12 Colon Cancer

13 Lung Cancer Progression

14 標靶藥物之選擇 1. 肺癌 – Iressa,Tarceva,Avastin 2. 乳癌 - Herceptin,Lapatinib 3. 大腸癌 – Erbitux,Avastin 4. 腎細胞癌 – Sorafinib, Sutent, Affinitor 5. 肝癌 - Sorafinib 6. 頭頸癌 - Erbitux 7. 淋巴癌 – Mabthera 8. 白血病 - Mylotag 9. 胰臟癌 – Tarvceva 10. 慢性骨髓性白血病 – Glivec, Dastinib 11. 胃腸基質瘤 – Glivec,Sutent

15 標靶治療的種類 1. 阻斷癌細胞傳遞生物訊息的小分子代表藥物 2. 癌細胞表面抗原單株抗體的標靶治療 3. 抑制新生血管的標靶治療

16 阻斷癌細胞傳遞生物訊息的小分子 代表藥物 1. 艾瑞莎 (Gefitinib) 2. 得舒緩 (Tarceva) 3. 基立克 (Imatinib) 4. 雷莎瓦 (Sorafenib) 5. 舒癌特 (Sutent)

17 The Era of Molecular Therapy for personalizing lung cancer

18 EGFR A regulator of tumor growth. Frequently overexpressed in lung cancer.

19 EGF TGF-  Amphiregulin  -cellulin HB-EGFEpiregulin Heregulins HB-EGFHeregulins Tyrosine Kinase Domain ErbB-1 HER1 EGFRErbB-2 HER2 neu ErbB-3HER3ErbB-4HER4 Extracellular Intracellular No Known Ligands The ErbB Family and Ligands

20 EGFR Pathway Inhibition Ligand EGFR-TK P Ras/Raf/MAPK Signal transduction pathways Angiogenesis Cell proliferation Apoptosis Invasion and metastasis C225 BX-EGF EMD 7200 ZD 1839 OSI-774 CI-1033

21 MAPK MEK Gene transcription Cell cycle progression PI3-K RAS RAF SOS GRB2 PTEN Akt STAT R K pY R pY pY K Proliferation/Maturation Survival (Anti-apoptosis) AngiogenesisMetastasis DNA myc Myc cyclin D1 Cyclin D1 JunFos PP Chemotherapy/ Radiotherapy resistance 肺癌 -Activated EGFR-TK (Tarceva or Iressa)

22 EGFR mutations Somatic Found in 10-15% of Caucasians; 30-40% of Asians with NSCLC No-Smoker, Asia, female adenocarcinoma : 60% mt Smoker : 30% mt BAC nonmucinous (50%) Oncogenic in NIH3T3 cells and in mice Exquisite sensitivity to EGFR TKIs

23 肺癌 - 艾瑞莎 (Gefitinib) Gefitinib 為表皮細胞生長因子 (EGFR) tyrosine kinase( 能夠 把蛋白質中的 tyrosine 接上磷 酸根 (phosphorylation) 的酵素 ) 專一性抑制劑 → 抑制 tyrosine kinase 活性 → 阻止細胞內訊號 傳遞 → 抑制腫瘤生長、轉移及 血管增生。

24 肺癌 - 得舒緩 (Tarceva)

25 肺 癌肺 癌

26 艾瑞莎 (Gefitinib)

27 IPASS study- 無病存活率

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29 IPASS study- 反應 率

30 NSCLC patients with EML4-ALK Adenocarcinoma Never or light former smokers EGFR and KRAS wild type Younger age Caucasian : 10-20%

31 艾瑞莎 (Gefitinib) and EGFR mutation

32 The Era of Molecular Therapy – CML and GIST

33 Courtesy of John K. Choi, MD, PhD, University of Pennsylvania. NormalChronic Phase CML 慢性骨髓性白血病 慢性骨髓性白血病 Comparative Peripheral Blood Smear

34 Melo. Blood. 1996;88:2375. Pasternak et al. J Cancer Res Clin Oncol. 1998;124:643. bcr-abl Gene: The t(9;22) Translocation

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36 慢性骨髓性白血病及胃腸基質瘤 慢性骨髓性白血病及胃腸基質瘤 - 基立克 (Imatinib)

37 Imatinib Mesylate: Mechanism of Action Imatinib mesylate occupies the ATP binding pocket of the Abl kinase domain P PPP ATP SIGNALING Imatinib mesylate Bcr-Abl Savage and Antman. N Engl J Med. 2002;346:683.

38 慢性骨髓性白血病

39 GIST: Diagnosis GIST have 2 major histologic patterns, which overlap with many non-GIST sarcomas and other malignancies –Spindle cell –Epithelioid In the past, GIST were usually classified as –Leiomyoma –Leiomyoblastoma –Leiomyosarcoma Many patients previously diagnosed with one of these tumors actually had a GIST Miettinen et al. Mod Pathol. 2000;13:1134. Fletcher et al. Hum Pathol. 2002;33:459.

40 胃腸道基質瘤簡介 胃腸道基質瘤細胞來源 胃腸基質瘤 胃腸黏膜下腫瘤 胃腸黏膜下肉瘤 胃腸平滑肌瘤 胃腸平滑肌肉瘤

41 病理診斷及腫瘤組織型態 紡錘狀細胞 ( 較常見 ) 及類上皮狀細胞 c-kit(+) 蛋白免疫染色陽性 desmin(-) 蛋白免疫染色陰性

42 Normal KIT Signaling PPP ADP P P PPP ATP SIGNALING Kinase domains SubstrateEffector The KIT kinase domain activates a substrate protein, eg, PI3 kinase, by phosphorylation Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314.

43 Heinrich et al. Hum Pathol. 2002;33:484. Corless et al. Proc Am Assoc Cancer Res. 2003;44. Abstract R4447. 胃腸基質瘤 GIST( 胃腸基質瘤 ) Membrane Cytoplasm Exon 11 (67.5%) Exon 9 (11%) Exon 13 (0.9%) Exon 17 (0.5%) Exon 12 (0.9%) Exon 18 (6.3%) KIT PDGFRA Overall mutation frequency: 87.4% Exon 14 (0.3%)

44 C- KIT Mutation Predicts Imatinib Mesylate Responsiveness KIT mutations are predictive of response to imatinib mesylate Exon 11 mutants respond best, Exon 9 increase Glivec Dose No mutation : Sutent Blanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2. 0 20 40 60 80 100 % of total KIT Exon 11 (n=85) KIT Exon 9 (n=23) No mutation (n=9) PD/NE SD PR

45 胃腸基質瘤

46 The Era of Molecular Therapy – Liver Cancer and Renal Cell Carcinoma

47 Sorafenib Targets both Cancer Cell Proliferation and Angiogenesis

48 肝癌 -Sorafenib( 雷莎瓦 ) 1. Multi-targeted tyrosine multikinase inhibitor: 2. Advanced renal cell carcinoma 3. Advanced hepatocelluar carcinoma

49 Sorafenib in Advanced Hepatocellular Carcinoma

50 腎細胞癌 - 舒癌特 (Sutent)  研究證實 Sutent 對於轉移性 腎細胞癌及惡性胃腸道基質 瘤有明顯的療效。  多重標靶治療的癌症藥物, 可同時作用於多種酪胺酸激 酶接受器,而抑制癌細胞血 管新生及癌細胞增殖,達到 抗癌的療效。

51 腎細胞癌

52 Herceptin ( 賀癌平 ) MabThera( 莫須瘤 ) 癌細胞表面抗原單株抗體的標靶 治療 1. Erbitux ( 爾必得舒 ) 2. Herceptin ( 賀癌平 ) 3. MabThera( 莫須瘤 )

53 Molecular Therapy – Change the Strategies of Colorectal Cancer Treatment

54 大腸直腸癌細胞膜上的上皮生長因子接受器 (EGFR) 可以將血 液中導致癌細胞生長、繁殖、以及抗凋亡的訊號傳遞到細胞內 標靶藥物治療: 抑制腫瘤生長的訊號傳遞

55 標靶藥物治療:臨床對抗多種癌症 Erbitux® 「爾必得舒」是一種單株抗體,也是上皮生 長因子接受器( EGFR )的阻斷劑。可有效抑制大腸直 腸癌細胞的生長,並增強癌細胞對化療藥物的效果

56 Treatment of Colon Cancer with Liver Metastasis Liver Metastasis Resectable 15-20% Non Resectable 80-85% Location Number Size Resectable 10-20(?)% Downsizing Survival Benefit 30-40%(?) at 5 years Neoadjuvant Chemotherapy Adjuvant HAI or Chemotherapy Biological agents Surgical techniques

57 ERBITUX: liver metastases only : Response rates 0 10 20 30 40 50 60 43 59 Percentage (%) CRYSTAL 25% Relative increase 0 10 20 30 40 50 60 61 Percentage (%) OPUS 33% Relative increase FOLFIRI alone ERBITUX + FOLFIRI 37 p = 0.027 FOLFOX alone ERBITUX + FOLFOX 77% Kras Wt

58 2.5 1.5 6 4.3 0 1 2 3 4 5 6 7 Surgery with curative intent No residual tumor after resection Percentage (%) *CMH test n=599 / group p=0.0034* odds ratio 3.0 [95% CI: 1.4 - 6.5] FOLFIRI alone Cetuximab + FOLFIRI 4.5 9.8 0 1 2 3 4 5 6 7 8 9 10 Percentage (%) n=134 / n=122 No residual tumor in patients with liver metastases ITT population (pre-planned) Liver metastases only population (exploratory) CRYSTAL Trial: Surgery with Curative Outcome

59 ERBITUX: CELIM Trial – liver only Surgery with Curative Outcome 0 20 40 60 70 80 90 79% 43% Percentage (%) Resection Rate 34% Response Rate R0 Resection KRAS WT

60 大腸直腸癌 基因檢測,個人化標靶藥物治療 KRAS 基因檢測,能夠預測標靶治療在大腸直腸癌的效果, 是個人化癌症治療的典範 約有 30-50% 的大腸直腸癌病人,會產生 K-RAS 基因的突 變, 其他病人的 KRAS 基因則未發生突變。

61 The Era of Molecular Therapy for breast cancer

62 Microarray- New Breast Cancer Subtypes Luminal A 51% Luminal B 16% HER2+/ER- 7% Basal-like 20% Unclassified 6%

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64 乳癌 - 乳癌 -HER2 Proto-Oncogene

65 乳癌 乳癌 : HER2 IHC Stain and FISH

66 乳癌 -Trastuzumab (Herceptin) 例如約 25% 至 30% 的原發性乳癌 病人中有過度 HER2 表現的現象 ,這些病人會比腫瘤細胞無過度 HER2 表現的病人的存活時間短 。 1998 年核准的 Herceptin 即為一 單株抗體,它可選擇性地與 HER2 結合而抑制此蛋白質的過 度表現。

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68 Disease Free Survival

69 The Era of Molecular Therapy for NHL

70 淋巴瘤 - 淋巴瘤 - CD20 Expression in B Cell Development

71 淋巴瘤 -Rituximab (MabThera) 會選擇抗 CD20 單株抗體來治療 復發性低惡性度非何杰金氏淋巴 瘤,其原因有二:第一、超過百 分之九十之低惡性度非何杰金氏 淋巴瘤都是 B- 細胞,它們都含有 CD20 抗原。第二、 CD20 抗原雖 然存在於幾乎所有的 B- 淋巴球的 表面上,但是在較為早期之造血 幹細胞、早期前 B- 細胞( early pre-B cell )以及抗原呈現細胞( antigen-presenting cells )之表 面並不含有 CD20 抗原,因此這 項治療並不會影響造血功能。

72 使用標靶藥物於淋巴瘤有九成的反應率

73 抑制新生血管的標靶治療 1. Avastin 癌思停

74 大腸直腸癌細胞的轉移需要血管新生、抑制血管新生 可以抑制癌細胞生長和轉移 標靶藥物治療: 抑制腫瘤生長的新生血管

75 Antibodies that neutralize the ligand or the receptor Small molecules that block ligand binding sites on receptors Small molecules that inhibit tyrosine kinase activity of the receptor Soluble decoy receptors that capture ligands Lymphangio- genesis Angiogenesis Vasculogenesis VEGFR2 VEGFR3 Lymphangio- genesis Angiogenesis Vasculogenesis VEGFR-2 VEGFR-3 Lymphangio- genesis Angiogenesis Vasculogenesis VEGFR-2 VEGFR-3 VEGF Small molecule Soluble receptor Antibody VEGF VEGF-C Lymphangio- genesis Angiogenesis Vasculogenesis VEGFR2 VEGFR3 Strategies to Inhibit VEGFR Signaling

76 標靶藥物治療: 臨床對抗多種癌症 Avastin 「癌思停」是一種單 株抗體,也是血管生長因子 (VEGF )的阻斷劑。

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79 標靶治療,提昇整體存活 大腸直腸癌 Bevacizumab + IFL for Metastatic CRC: Phase III AVF2107g Trial Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

80 大腸直腸癌 標靶治療,提昇整體存活 Avastin 「癌思停」,顯示可以提昇整體存活 率二成以上 1. Hurwitz H, et al. N Engl J Med. 2004;350:2335-42. 2. Kabbinavar F, et al. J Clin Oncol. 2003;21:60-65. 3. Kabbinavar F, et al. J Clin Oncol. 2005; 23:3706-3712. 4. Mass RD, et al. ASCO 2004. Abstract 3616. 5. TBC

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83 標靶治療副作用

84 標靶療法常見的副作用  皮疹 -Iressea, Tarceva, Erbitux…  高血壓 -Avastin  心臟衰竭 -Herceptin  間質性肺炎 -Iressea,Tarceva…

85 EGFR inhibitor-induced skin reactions (A) Papular lesions on the chest; (B) papulopustular eruption on the back; (C) close-up of follicular pustules; (D) confluent pustules on the nose A CD B Segaert S, Van Cutsem E. Ann Oncol 2005;16:1425–1433

86 皮膚乾燥 標靶藥物會使皮膚變得乾燥、角質增厚脫 皮,表皮細胞壞死,皮膚乾燥,掉屑 臉部發生嚴重、上下肢,甚至全身 ( 冬季尤 其明顯 ) 平均 4~35% 發生率 用藥後 1-4 星期出現

87 標靶藥物 , 副作用低 常見的副作用為皮膚疹 1 2 3 4 5 6 7 8 9 副作用 發炎後反應 痤瘡樣紅疹 甲溝炎 皮膚乾 Topical antiacne creams (drying effect) ± tetracyclines ± antihistamines Pruritus Pulse dye laser EmollientsHydrocolloid dressing or propylene glycol ± acetylsalicyl Antiseptic soaks, silver nitrate (pyogenic granuloma) 皮膚裂隙 Segaert S, et al. Ann Oncol. 2005;16:1425-1433. 治療建議

88 皮疹處理 皮疹 – 使用溫和的乳液或凡士林維持皮膚的 保溼度。 使用溫和不刺激的清潔產品清洗出現紅疹 的皮膚區域。 盡量避免化妝、外出時需使用防曬乳。

89 心臟毒性 使用 Herceptin 與 Tykerb 藥物 開始治療前,應先評估病患左心室博出率 (LLVEF) ,若治療期間發生充血性心衰竭 (CHF) 需暫停藥物,立即就醫,並且 LVEF 下降介於 20-40%. 應立即停藥 當 LVEF 回復至正常值, 可由較低劑量重新開 始

90 心臟毒性 : 心臟衰竭 Endothelial cells Neuregulin/Heregulin Apoptosis Myofibrillar Disarray Cardiac myocyte Stress (Anthracyclines) Ventricular Dysfunction Heart Failure X erb B2 Trastuzumab erb B4

91 間質性肺炎 極少數病患服用 Iressa( 約 l % ) 及 Tarceva( 約 0.6 % ) 會發生 導致肺部症狀 ( 呼吸困難、咳嗽、發燒 )

92 高血壓、靜脈栓塞、蛋白尿、出血 Avastin 、 Sutent 、 Nexavar 等藥物

93 Toxicities of Sorafenib 皮膚問題 Dermatologic toxicities – 手足紅腫脫皮反應 (46%) Hand-foot skin reaction – 紅疹 (20%) Rash  其他不良反應 Other adverse events – 腹瀉、腹痛、高血壓 Diarrhea, fatigue, abdominal pain, hypertension

94 入境時必須按指紋

95 Thanks for Your Attention


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