疫苗與新藥開發 Vaccine and Drug Development--- 5 疫苗與新藥開發 Vaccine and Drug Development--- 5. Cancer Signals and Target therapy Ih-Jen SU 南臺科技大學-生物科技系 15 October, 2015

The Difference between Chemotherapy (化療) and Targeted Therapy (標靶療法) Mechanisms; efficacy, side effects Nonspecific, kill normal cells too, high side effect in BM, skin, immune, GI tract Specific signal molecule for specific cancers ; high efficacy, low side effect, kill cancer cells: a. Anti-cell proliferation: DNA, mitosis, cell cycle Tyrosine kinase inhibitors-HER2, Gleevec, Iressa ( EGFR ), VEGF-R Cytotoxicity : Protein synthesis, cytoskeleton ( tubulin ), DNA topoisomerase. Monoclonal Abs: anti-CD20. Combinations: CHOP Non-specific; high toxicity, less effective. Conjugated Mo Abs plus C/T drugs. Immunomodulators : Glycobiology. Matrix inhibitors. New delivery system.

Targeted therapy 癌症的標靶治療

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

Principal Targets of Genetic Damage Oncogenes 致癌基因 Apoptosis genes Normal Cell Cancer Cell 凋亡 Tumor suppressor genes 抑癌 DNA mismatch repair genes 錯誤配對修護 5

Oncogenes (致癌基因), Oncoproteins Growth factors: PDGF, FGF, TGF… Growth factor receptors: EGFR, PDGFR Signal-transducing proteins: RAS, RAF, β-catenin Transcription factors: MYC Cyclins and cyclin-dependent kinases

Growth factors and signal-transducing proteins

轉移癌標靶藥物之選擇

IPASS Studies : EGFR mutation

基立克 ( Gleevec; Imatinib)  慢性骨髓性白血病 ( chronic myelogenous leukemia )及胃腸基質瘤 ( gastric stromal tumor ) Gleevec能有效抑制激脢(kinase)群組，一種酵素群組， 其組成成分有百來個以上，當中的三個分子的活動。它可以對抗Bcr-Abl、c-Kit、PDGF-R 等標靶。因此，只要是與這三種酵素有關的癌症，Gleevec就有機會發揮抑制其擴散的作用。

bcr-abl Gene: The t(9;22) Translocation

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。

VEGF-A/Akt/mTOR Signals Involve in Oncogenic Pathways Induced by ER-localized Pre-S Mutants in GGHs

肝癌-Sorafenib (雷莎瓦) Multi-targeted tyrosine multikinase inhibitor Advanced renal cell carcinoma Advanced hepatocelluar carcinoma

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。

癌細胞表面抗原單株抗體的 標靶治療 Erbitux (爾必得舒) Herceptin (賀癌平): Breast cancer MabThera (莫須瘤)

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。

乳癌‐Trastuzumab (Herceptin) 2.和化療paclitaxel或docetaxel 併用，使用於未曾接受過化學治療之轉移性乳癌病患。

淋巴瘤‐Rituximab (MabThera)

淋巴瘤:CD20 Expression in B-Cell Development

使用標靶藥物於淋巴瘤有九成的反應率 MabThera Combination as Primary Treatment CR PR 100% 95% 97% 94% 100 89% 80 48 57 CR PR 86 60 80 76 40 49 37 20 13 14 15 FL D LC L CL L I n do le n t Ma n t le Coiffier et al. Blood 2000; Howard et al. Blood 1999; Keating et al. Blood 2000; Birhiray et al.Blood 2000; Jager et al. Blood 2000, Emmanouilides et al. Blood 1999

抑制腫瘤新生血管的標靶治療 Avastin (癌思停) 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，副作用低 常見的副作用為皮膚疹 副作用 治療建議 痤瘡樣紅疹 發炎後反應 皮膚乾 皮膚裂隙 甲溝炎 Topical antiacne creams (drying effect) Hydrocolloid dressing or propylene glycol ± acetylsalicyl Antiseptic soaks, silver nitrate (pyogenic granuloma) Pulse dye laser Emollients ± tetracyclines ± antihistamines Segaert S, et al. Ann Oncol. 2005;16:1425-1433.

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。

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.

The combination approach: Need for Rational Combination Molecular diversity of tumors may require a combination of agents to maximize therapeutic benefit Monoclonal antibody therapy Anti- angiogenesis therapy Molecular targeted therapy There is a potential role for agents with multiple targets Radiation therapy Priority research adressing best use of these agents, mainly in combination Chemotherapy

Major issue for targeted therapy: High cost, 600,000NTDs/course