請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17978完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張正琪(Cheng-Chi Chang) | |
| dc.contributor.author | Yi-Xuan Chen | en |
| dc.contributor.author | 陳奕璇 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:47:35Z | - |
| dc.date.copyright | 2015-09-24 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-07-23 | |
| dc.identifier.citation | Awad, M. M., Sullivan, R. J. (2015). Dabrafenib in combination with trametinib for the treatment of metastatic melanoma. Expert Rev Clin Pharmacol, 8(1), 25-33. Bagnato, A., Rosano, L. (2008). The endothelin axis in cancer. Int J Biochem Cell Biol, 40(8), 1443-1451. Bhatia, S., Tykodi, S. S., Thompson, J. A. (2009). Treatment of metastatic melanoma: an overview. Oncology (Williston Park), 23(6), 488-496. Bollag, G., Tsai, J., Zhang, J., Zhang, C., Ibrahim, P., Nolop, K., Hirth, P. (2012). Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov, 11(11), 873-886. Carracedo, A., Ma, L., Teruya-Feldstein, J., Rojo, F., Salmena, L., Alimonti, A., . . . Pandolfi, P. P. (2008). Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest, 118(9), 3065-3074. Chang, J. W. (2010). Cutaneous melanoma: Taiwan experience and literature review. Chang Gung Med J, 33(6), 602-612. Cheung, M., Sharma, A., Madhunapantula, S. V., Robertson, G. P. (2008). Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development. Cancer Res, 68(9), 3429-3439. Corcoran, R. B., Dias-Santagata, D., Bergethon, K., Iafrate, A. J., Settleman, J., Engelman, J. A. (2010). BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal, 3(149), ra84. Curtin, J. A., Fridlyand, J., Kageshita, T., Patel, H. N., Busam, K. J., Kutzner, H., . . . Bastian, B. C. (2005). Distinct sets of genetic alterations in melanoma. N Engl J Med, 353(20), 2135-2147. Dean, M. (2009). ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia, 14(1), 3-9. Del Bufalo, D., Di Castro, V., Biroccio, A., Varmi, M., Salani, D., Rosano, L., . . . Bagnato, A. (2002). Endothelin-1 protects ovarian carcinoma cells against paclitaxel-induced apoptosis: requirement for Akt activation. Mol Pharmacol, 61(3), 524-532. Flaherty, K. T., Infante, J. R., Daud, A., Gonzalez, R., Kefford, R. F., Sosman, J., . . . Weber, J. (2012). Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med, 367(18), 1694-1703. Gibney, G. T., Zager, J. S. (2013). Clinical development of dabrafenib in BRAF mutant melanoma and other malignancies. Expert Opin Drug Metab Toxicol, 9(7), 893-899. Gray-Schopfer, V., Wellbrock, C., Marais, R. (2007). Melanoma biology and new targeted therapy. Nature, 445(7130), 851-857. Holohan, C., Van Schaeybroeck, S., Longley, D. B., Johnston, P. G. (2013). Cancer drug resistance: an evolving paradigm. Nat Rev Cancer, 13(10), 714-726. Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., . . . Garraway, L. A. (2010). COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature, 468(7326), 968-972. Kabbarah, O., Chin, L. (2005). Revealing the genomic heterogeneity of melanoma. Cancer Cell, 8(6), 439-441. Kainthla, R., Kim, K. B., Falchook, G. S. (2014). Dabrafenib for treatment of BRAF-mutant melanoma. Pharmgenomics Pers Med, 7, 21-29. Kefford, R., Beith, J. M., Van Hazel, G. A., Millward, M., Trotter, J. M., Wyld, D. K., . . . Clozel, M. (2007). A phase II study of bosentan, a dual endothelin receptor antagonist, as monotherapy in patients with stage IV metastatic melanoma. Invest New Drugs, 25(3), 247-252. Lahav, R. (2005). Endothelin receptor B is required for the expansion of melanocyte precursors and malignant melanoma. Int J Dev Biol, 49(2-3), 173-180. Long, G. V., Menzies, A. M., Nagrial, A. M., Haydu, L. E., Hamilton, A. L., Mann, G. J., . . . Kefford, R. F. (2011). Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol, 29(10), 1239-1246. Luke, J. J., Ott, P. A. (2014). New developments in the treatment of metastatic melanoma - role of dabrafenib-trametinib combination therapy. Drug Healthc Patient Saf, 6, 77-88. Madureira, P., de Mello, R. A. (2014). BRAF and MEK gene rearrangements in melanoma: implications for targeted therapy. Mol Diagn Ther, 18(3), 285-291. Maffei, R., Bulgarelli, J., Fiorcari, S., Martinelli, S., Castelli, I., Valenti, V., . . . Marasca, R. (2014). Endothelin-1 promotes survival and chemoresistance in chronic lymphocytic leukemia B cells through ETA receptor. PLoS One, 9(6), e98818. Menzies, A. M., Long, G. V. (2014). Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. Clin Cancer Res, 20(8), 2035-2043. Menzies, A. M., Long, G. V., Murali, R. (2012). Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Devel Ther, 6, 391-405. Miller, A. J., Mihm, M. C., Jr. (2006). Melanoma. N Engl J Med, 355(1), 51-65. Miller, A. J., Tsao, H. (2010). New insights into pigmentary pathways and skin cancer. Br J Dermatol, 162(1), 22-28. Mirzoeva, O. K., Das, D., Heiser, L. M., Bhattacharya, S., Siwak, D., Gendelman, R., . . . Korn, W. M. (2009). Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res, 69(2), 565-572. Montagut, C., Sharma, S. V., Shioda, T., McDermott, U., Ulman, M., Ulkus, L. E., . . . Settleman, J. (2008). Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res, 68(12), 4853-4861. Nazarian, R., Shi, H., Wang, Q., Kong, X., Koya, R. C., Lee, H., . . . Lo, R. S. (2010). Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature, 468(7326), 973-977. Ohashi, K., Sequist, L. V., Arcila, M. E., Lovly, C. M., Chen, X., Rudin, C. M., . . . Pao, W. (2013). Characteristics of lung cancers harboring NRAS mutations. Clin Cancer Res, 19(9), 2584-2591. Okazawa, M., Shiraki, T., Ninomiya, H., Kobayashi, S., Masaki, T. (1998). Endothelin-induced apoptosis of A375 human melanoma cells. J Biol Chem, 273(20), 12584-12592. Poulikakos, P. I., Persaud, Y., Janakiraman, M., Kong, X., Ng, C., Moriceau, G., . . . Solit, D. B. (2011). RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature, 480(7377), 387-390. Robert, C., Karaszewska, B., Schachter, J., Rutkowski, P., Mackiewicz, A., Stroiakovski, D., . . . Schadendorf, D. (2015). Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med, 372(1), 30-39. Saldana-Caboverde, A., Kos, L. (2010). Roles of endothelin signaling in melanocyte development and melanoma. Pigment Cell Melanoma Res, 23(2), 160-170. Scheier, B., Amaria, R., Lewis, K., Gonzalez, R. (2011). Novel therapies in melanoma. Immunotherapy, 3(12), 1461-1469. Sharma, S. V., Lee, D. Y., Li, B., Quinlan, M. P., Takahashi, F., Maheswaran, S., . . . Settleman, J. (2010). A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell, 141(1), 69-80. Shi, H., Hugo, W., Kong, X., Hong, A., Koya, R. C., Moriceau, G., . . . Lo, R. S. (2014). Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov, 4(1), 80-93. Shi, H., Kong, X., Ribas, A., Lo, R. S. (2011). Combinatorial treatments that overcome PDGFRbeta-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res, 71(15), 5067-5074. Singh, A., Settleman, J. (2010). EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene, 29(34), 4741-4751. Sladden, M. J., Balch, C., Barzilai, D. A., Berg, D., Freiman, A., Handiside, T., . . . Thompson, J. F. (2009). Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst Rev(4), CD004835. Stanisz, H., Stark, A., Kilch, T., Schwarz, E. C., Muller, C. S., Peinelt, C., . . . Bogeski, I. (2012). ORAI1 Ca(2+) channels control endothelin-1-induced mitogenesis and melanogenesis in primary human melanocytes. J Invest Dermatol, 132(5), 1443-1451. Sweetlove, M., Wrightson, E., Kolekar, S., Rewcastle, G. W., Baguley, B. C., Shepherd, P. R., Jamieson, S. M. (2015). Inhibitors of pan-PI3K Signaling Synergize with BRAF or MEK Inhibitors to Prevent BRAF-Mutant Melanoma Cell Growth. Front Oncol, 5, 135. Villanueva, J., Infante, J. R., Krepler, C., Reyes-Uribe, P., Samanta, M., Chen, H. Y., . . . Nathanson, K. L. (2013). Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep, 4(6), 1090-1099. Villanueva, J., Vultur, A., Herlyn, M. (2011). Resistance to BRAF inhibitors: unraveling mechanisms and future treatment options. Cancer Res, 71(23), 7137-7140. Villanueva, J., Vultur, A., Lee, J. T., Somasundaram, R., Fukunaga-Kalabis, M., Cipolla, A. K., . . . Herlyn, M. (2010). Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell, 18(6), 683-695. Vinogradov, S., Wei, X. (2012). Cancer stem cells and drug resistance: the potential of nanomedicine. Nanomedicine (Lond), 7(4), 597-615. Wang, R., Dashwood, R. H. (2011). Endothelins and their receptors in cancer: identification of therapeutic targets. Pharmacol Res, 63(6), 519-524. Whittaker, S., Kirk, R., Hayward, R., Zambon, A., Viros, A., Cantarino, N., . . . Marais, R. (2010). Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci Transl Med, 2(35), 35ra41. Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., . . . Masaki, T. (1988). A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature, 332(6163), 411-415. Zhang, P., Liu, W., Yuan, X., Li, D., Gu, W., Gao, T. (2013). Endothelin-1 enhances the melanogenesis via MITF-GPNMB pathway. BMB reports, 46(7), 364-369. Zhou, Y., Liu, B., Wang, M., Ni, J. (2014). Endothelin-1 gene polymorphisms and risk of chemoresistant pediatric osteosarcoma. Pediatr Blood Cancer, 61(4), 612-617. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17978 | - |
| dc.description.abstract | 對於BRAF有突變之已轉移黑色素細胞瘤，使用Dabrafenib (D) 及Trametinib (T) 合併治療是最新的標靶治療。雖然此種合併治療之臨床益處已被證實，但多數病人依舊產生抗藥性，然而其抗藥的分子機轉仍然未知。細胞實驗中，我們藉由將A375細胞暴露在逐漸提高的兩者藥物濃度的培養液中，以建立此兩者藥物單獨及合併治療之抗藥株(A375DR、A375TR、A375DTR)，並使用Western Blot及MTT assay來確認其抗藥性。此外我們利用基因晶片、重組蛋白、拮抗劑及knockdown系統找尋下游標的。而在動物實驗中，我們使用了nude mice，藉由打入A375細胞並每日灌食dabrafenib及trametinib來建立活體的抗藥株材料，當其腫瘤復發並長至1200 mm3時便犧牲，收集其血清及腫瘤，透過qRT-PCR、ELISA及IHC的方式進行後續研究。 研究結果顯示在抗藥株中內皮素-1的表現量大幅上升，此現象在合併使用兩種藥物的抗藥株(A375DTR)更為顯著，且進一步抑制內皮素-1的表現後，可使A375DTR的抗藥性消失。在A375DTR抗藥株中，Akt磷酸化的表現量透過內皮素-1/內皮素接受器B的訊息傳遞而上升。此外不論抑制Akt的磷酸化或阻斷內皮素接受器B皆使A375DTR的抗藥性回復。總結來說，我們推測內皮素-1及Akt的活化可能參與了黑色素細胞瘤經dabrafenib及trametinib合併治療後抗性之分子機轉，因此內皮素-1可能是合併使用此兩種標靶藥物產生抗性後的治療標的。 | zh_TW |
| dc.description.abstract | The combination of dabrafenib and trametinib is a targeted therapy for BRAF-mutated metastatic melanoma. Although this combination therapy has proven clinical benefits in cutaneous melanoma, some patients still develop resistance. However, the mechanism of the drug resistance is still unknown. In vitro, we established A375 drug resistant clones (A375DR, A375TR, and A375DTR cells) by chronically exposing A375 cells to dabrafenib and/or trametinib, and further confirmed the drug resistance by Western Blot and MTT assay. Besides, we found the downstream target(s) in drug resistance by microarray, recombinant protein, antagonists and knockdown system. In vivo, we also established A375 resistant tumors by oral gavage of dabrafenib and trametinib every day in a nude mice xenograft model. When the mice developed relapsed tumors after initial regression, we collected tumor and blood samples for further real-time RT-PCR, ELISA and immunohistochemistry studies. We demonstrated that endothelin-1 (ET-1) was increased in A375 drug resistance clones, especially A375DTR cells, and the drug resistance ability were decreased by ET-1 shRNA knockdown. Phosphorylation of Akt was increased through ET-1-ETBR signaling in A375DTR cells. Furthermore, inhibition of Akt phosphorylation or blockade of ETBR reversed the drug resistance ability of A375DTR cells. In conclusion, we demonstrated the molecular mechanism of acquired resistance to dabrafenib and trametinib co-treatment in cutaneous melanoma involves ET-1 and Akt activation. ET-1 may be a potential therapeutic target for acquired resistance to dabrafenib and trametinib co-treatment in cutaneous melanoma. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:47:35Z (GMT). No. of bitstreams: 1 ntu-104-R02450014-1.pdf: 1805814 bytes, checksum: 7749ff74ed682b5d021a8d2ce4768cb7 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 口試委員會審定書…………………………………………………………………….4 誌謝……………………………………………………………………………………. 5 中文摘要………………………………………………………………………………. 6 Abstract………………………………………………………………………………… 7 Introduction…………………………………………………………………………….9 Materials and Methods …………………………………………………………15 Results…………………………………………………………………………………. 24 Discussion………………………………………………………………………………32 References………………………………………………………………………………36 Figures…………………………………………………………………………………. 44 Figure 1. Establishment of A375 drug resistance clones……………………………..44 Figure 2. Identification of ET-1 as the major downstream effector in A375 drug resistant clones......………………………………………………………… 46 Figure 3.ET-1 decreased drug resistance ability through ETBR in A375DTRcells…... 49 Figure 4. ET-1 increased the drug resistance ability through Akt phosphorylation......... 50 Figure 5. ET-1 mRNA and protein was significantly increased inA375drug resistance clones in vivo……………………………………………………………………………… 53 Figure 6. Schematic of ET-1 axis signaling in acquired resistance to dabrafenib and trametinib co-treatment…………………………………………………………………… 56 Tables………………………………………………………………………………….. 57 | |
| dc.language.iso | en | |
| dc.title | 探討黑色素細胞瘤經dabrafenib及trametinib合併治療抗性之分子機轉 | zh_TW |
| dc.title | Identification of Molecular Mechanism of Acquired Resistance to Dabrafenib and Trametinib Co-treatment in Melanoma | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 朱家瑜(Chia-Yu Chu),楊慕華(Muh-Hwa Yang),江俊斌(Chun-Pin Chiang),林本仁(Ben-Ren Lin) | |
| dc.subject.keyword | dabrafenib,抗藥性,內皮素-1,黑色素細胞癌,trametinib, | zh_TW |
| dc.subject.keyword | dabrafenib,drug resistance,endothelin-1,melanoma,trametinib, | en |
| dc.relation.page | 59 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2015-07-23 | |
| dc.contributor.author-college | 牙醫專業學院 | zh_TW |
| dc.contributor.author-dept | 口腔生物科學研究所 | zh_TW |
| 顯示於系所單位： | 口腔生物科學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-104-1.pdf 未授權公開取用 | 1.76 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。