胃肠间质瘤治疗中HSP90抑制剂的应用
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摘要
随着酪氨酸激酶受体抑制剂(TKI)伊马替尼等靶向治疗药物的发明,胃肠间质瘤(GIST的生存期大为改善,但GIST的原发和继发性耐药问题是限制其疗效的关键。热休克蛋白90(HSP90)抑制剂能绕过酪氨酸激酶受体,直接作用于其下游信号分子的保护伞HSP90,间接使其下游信号分子降解,中断异常活化的信号通路,从而抑制GIST的生长。近年来,HSP90抑制剂作为GIST三线治疗药物开始尝试应用于临床实验。研究表明,多种HSP90抑制剂对TKI多重耐药的GIST患者有较好疗效。随着药理学、分子生物学、生物信息学等学科的不断发展和相互促进,BEAMing技术等新一代测序技术的应用,HSP90抑制剂的应用前景会渐趋光明。
With the development of targeted therapeutics such as Tyrosine Kinase Receptor inhibitors(TKI) Imatinib, the treatment of rare diseases such as gastrointestinal stromal tumors(GIST) is certainly to the extent that there has been no cure for medicine, the drug has become ″drug to disease,″ but the problems of primary and secondary resistance to gastrointestinal stromal tumors and when it is possible to stop the drug are the key to limite the further improvement to fit sefficacy. Heat shock protein90(HSP90)inhibitor scan by pass tyrosine kinase receptors and directly act on the protective umbrella HSP90 of the down stream signaling molecules, indirectly degrading down stream signaling molecules and disrupting abnormally activated signaling pathways. This inhibits the growth of gastrointestinal stromal tumors. In recent years,HSP90 inhibitors have been used in clinical trials as a third-line treatment for gastrointestinal stromal tumors.With the continuous development and mutual promotion of pharmacology, molecular biology, bioinformatics and other disciplines, application of next-generation sequencing technology such as BEAMing technology,the application prospects of HSP90 inhibitors will gradually become brighter.
With the development of targeted therapeutics such as Tyrosine Kinase Receptor inhibitors(TKI) Imatinib, the treatment of rare diseases such as gastrointestinal stromal tumors(GIST) is certainly to the extent that there has been no cure for medicine, the drug has become ″drug to disease,″ but the problems of primary and secondary resistance to gastrointestinal stromal tumors and when it is possible to stop the drug are the key to limite the further improvement to fit sefficacy. Heat shock protein90(HSP90)inhibitor scan by pass tyrosine kinase receptors and directly act on the protective umbrella HSP90 of the down stream signaling molecules, indirectly degrading down stream signaling molecules and disrupting abnormally activated signaling pathways. This inhibits the growth of gastrointestinal stromal tumors. In recent years,HSP90 inhibitors have been used in clinical trials as a third-line treatment for gastrointestinal stromal tumors.With the continuous development and mutual promotion of pharmacology, molecular biology, bioinformatics and other disciplines, application of next-generation sequencing technology such as BEAMing technology,the application prospects of HSP90 inhibitors will gradually become brighter.
引文
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[12]Floris G,Sciot R,Wozniak A,et al.The Novel HSP90 inhibitor,IPI-493,is highly effective in human gastrostrointestinal stromal tumor xenografts carrying heterogeneous KIT mutations[J].Clinical cancer research,2011,17(17):5604-5614.
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[14]Fletcher J,Debiecrychter M,Swank S,et al.HSP90 inhibitor STA-9090 potently suppresses secondary KIT kinase-domain mutations responsible for gastrointestinal stromal tumor(GIST)progression during imatinib therapy[J].Proceedings,2010,
[15]Floris G,Debiec-Rychter M,Wozniak A,et al.The heat shock protein 90 inhibitor IPI-504 induces KIT degradation,tumor shrinkage,and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors[J].Molecular Cancer Therapeutics,2011,10(10):1897-1908.
[16]Solit DB,Ivy SP,Kopil C,et al.Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer[J].Clinical Cancer Research,2007,13(6):1775-1782.
[17]Smyth T,Van Looy T,Curry JE,et al.The HSP90 inhibitor,AT13387,is effective against imatinib-sensitive and-resistant gastrointestinal stromal tumor models[J].Molecular Cancer Therapeutics,2012,11(8):1799-1808.
[18]Wagner AJ,Chugh R,Rosen LS,et al.A phase I study of the HSP90inhibitor retaspimycin hydrochloride(IPI-504)in patients with gastrointestinal stromal tumors or soft-tissue sarcomas[J].Clinical cancer research,2013,19(21):6020-6029.
[19]Kang YK,Ryu MH,Yoo C,et al.Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib(RIGHT):a randomised,placebocontrolled,phase 3 trial[J].The Lancet Oncology,2013,14(12):1175-1182.
[20]Demetri GD,Van Oosterom AT,Garrett CR,et al.Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib:a randomised controlled trial[J].The Lancet,2006,368(9544):1329-1338.
[21]Demetri GD,Reichardt P,Kang YK,et al.Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib(GRID):an international,multicentre,randomised,placebo-controlled,phase 3 trial[J].The Lancet,2013,381(9863):295-302.
[22]Demetri GLCA,Von Mehren M,Chmielowski B,et al.Final results from a Phase III study of IPI-504(retaspimycin hydrochloride)versus placebo in patients(pts)with gastrointestinal stromal tumors(GIST)following failure of tyrosine kinase inhibitor(TKI)therapies[C].Orlando:proceedings of the ASCO GI Cancers Symposium,2010:22-24.
[23]Sessa C,Shapiro GI,Bhalla KN,et al.First-in-human phase I doseescalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors[J].Clinical cancer research,2013,19(13):3671-3680.
[24]Bendell JC,Bauer TM,Lamar R,et al.A Phase 2 Study of the Hsp90 Inhibitor AUY922 as Treatment for Patients with Refractory Gastrointestinal Stromal Tumors[J].Cancer Invest,2016,34(6):265-270.
[25]Dickson MA,Okuno SH,Keohan ML,et al.Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors[J].Ann Oncol,2013,24(1):252-257.
[26]Shapiro GI,Kwak E,Dezube BJ,et al.First-in-human phase I dose escalation study of a second-generation non-ansamycin HSP90inhibitor,AT13387,in patients with advanced solid tumors[J].Clinical cancer research,2015,21(1):87-97.
[27]Wagner AJ,Agulnik M,Heinrich MC,et al.Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor,onalespib(AT13387),in combination with imatinib in patients with metastatic gastrointestinal stromal tumour[J].Eur J Cancer,2016,61:94-101.
[28]Lim KT,Tan KY.Current research and treatment for gastrointestinal stromal tumors[J].World J Gastroenterol,2017,23(27):4856-4866.
[29]Edris B,Willingham SB,Weiskopf K,et al.Anti-KIT monoclonal antibody inhibits imatinib-resistant gastrointestinal stromal tumor growth[J].Proc Natl Acad Sci USA,2013,110(9):3501-3506.
[30]Maier J,Lange T,Kerle I,et al.Detection of mutant free circulating tumor DNA in the plasma of patients with gastrointestinal stromal tumor harboring activating mutations of CKIT or PDGFRA[J].Clinical cancer research,2013,19(17):4854-4867.
[2]Mazur MT,Clark HB.Gastric stromal tumors.Reappraisal of histogenesis[J].American Journal of Surgical Pathology,1983,7(6):507.
[3]Kindblom LG,Remotti HE,Aldenborg F,et al.Gastrointestinal pacemaker cell tumor(GIPACT):gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal[J].American Journal of Pathology,1998,152(5):1259-1269.
[4]Demetri GD,Von Mehren M,Blanke CD,et al.Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors[J].The New England journal of medicine,2002,347(7):472-480.
[5]Casali PG,Le CA,Poveda VA,et al.Time to definitive failure to the first tyrosine kinase inhibitor in localized GI stromal tumors treated with imatinib as an adjuvant:A european organisation for research and treatment of cancer soft tissue and bone sarcoma group intergroup randomized trial in collaboration with the australasian Gastro-Intestinal trials group,UNICANCER,French Sarcoma Group,Italian Sarcoma Group,and Spanish Group for research on sarcomas[J].Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology,2015,33(36):4276-4283.
[6]Ritossa F.Discovery of the heat shock response[J].Cell Stress&Chaperones,1996,1(2):97-98.
[7]Usmani SZ,Chiosis G.HSP90 inhibitors as therapy for multiple myeloma[J].Clinical Lymphoma Myeloma&Leukemia,2011,11Suppl 1(Suppl 1):S77-81.
[8]Kang GH,Lee EJ,Jang KT,et al.Expression of HSP90 in gastrointestinal stromal tumours and mesenchymal tumours[J].Histopathology,2010,56(6):694-701.
[9]Brough PA,Aherne W,Barril X,et al.4,5-Diarylisoxazole Hsp90Chaperone Inhibitors:Potential Therapeutic Agents for the Treatment of Cancer[J].Journal of Medicinal Chemistry,2008,51(2):196-218.
[10]Verma S,Goyal S,Jamal S,et al.Hsp90:Friends,clients and natural foes[J].Biochimie,2016,127:227-240.
[11]Bauer S,Yu LK,Demetri GD,et al.Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor[J].Cancer research,2006,66(18):9153-9161.
[12]Floris G,Sciot R,Wozniak A,et al.The Novel HSP90 inhibitor,IPI-493,is highly effective in human gastrostrointestinal stromal tumor xenografts carrying heterogeneous KIT mutations[J].Clinical cancer research,2011,17(17):5604-5614.
[13]Muhlenberg T,Zhang Y,Wagner AJ,et al.Inhibitors of deacetylases suppress oncogenic KIT signaling,acetylate HSP90,and induce apoptosis in gastrointestinal stromal tumors[J].Cancer research,2009,69(17):6941-6950.
[14]Fletcher J,Debiecrychter M,Swank S,et al.HSP90 inhibitor STA-9090 potently suppresses secondary KIT kinase-domain mutations responsible for gastrointestinal stromal tumor(GIST)progression during imatinib therapy[J].Proceedings,2010,
[15]Floris G,Debiec-Rychter M,Wozniak A,et al.The heat shock protein 90 inhibitor IPI-504 induces KIT degradation,tumor shrinkage,and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors[J].Molecular Cancer Therapeutics,2011,10(10):1897-1908.
[16]Solit DB,Ivy SP,Kopil C,et al.Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer[J].Clinical Cancer Research,2007,13(6):1775-1782.
[17]Smyth T,Van Looy T,Curry JE,et al.The HSP90 inhibitor,AT13387,is effective against imatinib-sensitive and-resistant gastrointestinal stromal tumor models[J].Molecular Cancer Therapeutics,2012,11(8):1799-1808.
[18]Wagner AJ,Chugh R,Rosen LS,et al.A phase I study of the HSP90inhibitor retaspimycin hydrochloride(IPI-504)in patients with gastrointestinal stromal tumors or soft-tissue sarcomas[J].Clinical cancer research,2013,19(21):6020-6029.
[19]Kang YK,Ryu MH,Yoo C,et al.Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib(RIGHT):a randomised,placebocontrolled,phase 3 trial[J].The Lancet Oncology,2013,14(12):1175-1182.
[20]Demetri GD,Van Oosterom AT,Garrett CR,et al.Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib:a randomised controlled trial[J].The Lancet,2006,368(9544):1329-1338.
[21]Demetri GD,Reichardt P,Kang YK,et al.Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib(GRID):an international,multicentre,randomised,placebo-controlled,phase 3 trial[J].The Lancet,2013,381(9863):295-302.
[22]Demetri GLCA,Von Mehren M,Chmielowski B,et al.Final results from a Phase III study of IPI-504(retaspimycin hydrochloride)versus placebo in patients(pts)with gastrointestinal stromal tumors(GIST)following failure of tyrosine kinase inhibitor(TKI)therapies[C].Orlando:proceedings of the ASCO GI Cancers Symposium,2010:22-24.
[23]Sessa C,Shapiro GI,Bhalla KN,et al.First-in-human phase I doseescalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors[J].Clinical cancer research,2013,19(13):3671-3680.
[24]Bendell JC,Bauer TM,Lamar R,et al.A Phase 2 Study of the Hsp90 Inhibitor AUY922 as Treatment for Patients with Refractory Gastrointestinal Stromal Tumors[J].Cancer Invest,2016,34(6):265-270.
[25]Dickson MA,Okuno SH,Keohan ML,et al.Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors[J].Ann Oncol,2013,24(1):252-257.
[26]Shapiro GI,Kwak E,Dezube BJ,et al.First-in-human phase I dose escalation study of a second-generation non-ansamycin HSP90inhibitor,AT13387,in patients with advanced solid tumors[J].Clinical cancer research,2015,21(1):87-97.
[27]Wagner AJ,Agulnik M,Heinrich MC,et al.Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor,onalespib(AT13387),in combination with imatinib in patients with metastatic gastrointestinal stromal tumour[J].Eur J Cancer,2016,61:94-101.
[28]Lim KT,Tan KY.Current research and treatment for gastrointestinal stromal tumors[J].World J Gastroenterol,2017,23(27):4856-4866.
[29]Edris B,Willingham SB,Weiskopf K,et al.Anti-KIT monoclonal antibody inhibits imatinib-resistant gastrointestinal stromal tumor growth[J].Proc Natl Acad Sci USA,2013,110(9):3501-3506.
[30]Maier J,Lange T,Kerle I,et al.Detection of mutant free circulating tumor DNA in the plasma of patients with gastrointestinal stromal tumor harboring activating mutations of CKIT or PDGFRA[J].Clinical cancer research,2013,19(17):4854-4867.