Mini-Review Article

靶向基因异常治疗结肠癌及其转移进展

卷 22, 期 7, 2021

发表于: 19 November, 2020

页: [722 - 733] 页: 12

弟呕挨: 10.2174/1389450121666201119141015

价格: $65

conference banner
摘要

结直肠癌的发生涉及从遗传改变积累到遗传和表观遗传调节和染色体异常的各种过程。它还涉及致癌基因和肿瘤抑制基因的突变。基因组不稳定性在结直肠癌中起着至关重要的作用。现代生物学技术的进步和分子水平的研究已经确定了各种参与结直肠癌(CRC)的基因。KRAS、BRAF、PI3K和p53基因在CRC的不同阶段发挥重要作用。这些基因的改变导致结肠癌的发生、发展和转移。本文就KRAS、BRAF、PI3KCA和TP53基因在结直肠癌发病中的作用及其在结直肠癌各阶段的意义进行综述。它还提供了对作用于这些基因的特定调节器的见解。此外,这篇综述还讨论了这些基因在致癌过程中通路的机制,以及当前的分子和在不同临床评估阶段的治疗方案。

关键词: 转移性结肠癌,基因改变,BRAF基因,KRAS基因,P53基因,PI3K基因

图形摘要

[1]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020; 70(1): 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[3]
World Health Organization. Cancer Profile 2020.
[4]
American Cancer Society. Colorectal Cancer Facts & Figures 2017-2019 2017.
[5]
Bos JL. Ras oncogenes in human cancer: a review. Cancer Res 1989; 49(17): 4682-9.
[PMID: 2547513]
[6]
Abubaker J, Bavi P, Al-Haqawi W, et al. Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma. J Pathol 2009; 219(4): 435-45.
[http://dx.doi.org/10.1002/path.2625] [PMID: 19824059]
[7]
Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 2010; 28(3): 466-74.
[http://dx.doi.org/10.1200/JCO.2009.23.3452] [PMID: 20008640]
[8]
Porru M, Pompili L, Caruso C, Biroccio A, Leonetti C. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J Exp Clin Cancer Res 2018; 37(1): 57.
[http://dx.doi.org/10.1186/s13046-018-0719-1] [PMID: 29534749]
[9]
Huang D, Sun W, Zhou Y, et al. Mutations of key driver genes in colorectal cancer progression and metastasis. Cancer Metastasis Rev 2018; 37(1): 173-87.
[http://dx.doi.org/10.1007/s10555-017-9726-5] [PMID: 29322354]
[10]
Foley TM, Payne SN, Pasch CA, et al. Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations. Mol Cancer Res 2017; 15(3): 317-27.
[http://dx.doi.org/10.1158/1541-7786.MCR-16-0256] [PMID: 28184015]
[11]
Wang Y, Kaiser CE, Frett B, Li HY. Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators. J Med Chem 2013; 56(13): 5219-30.
[http://dx.doi.org/10.1021/jm3017706] [PMID: 23566315]
[12]
Siddiqui AD, Piperdi B. KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy. Ann Surg Oncol 2010; 17(4): 1168-76.
[http://dx.doi.org/10.1245/s10434-009-0811-z] [PMID: 19936839]
[13]
Arrington AK, Heinrich EL, Lee W, et al. Prognostic and predictive roles of KRAS mutation in colorectal cancer. Int J Mol Sci 2012; 13(10): 12153-68.
[http://dx.doi.org/10.3390/ijms131012153] [PMID: 23202889]
[14]
Krens LL, Baas JM, Gelderblom H, Guchelaar H-J. Therapeutic modulation of k-ras signaling in colorectal cancer. Drug Discov Today 2010; 15(13-14): 502-16.
[http://dx.doi.org/10.1016/j.drudis.2010.05.012] [PMID: 20594936]
[15]
Andreyev HJN, Norman AR, Cunningham D, Oates JR, Clarke PA. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst 1998; 90(9): 675-84.
[http://dx.doi.org/10.1093/jnci/90.9.675] [PMID: 9586664]
[16]
Reggiani Bonetti L, Barresi V, Bettelli S, Caprera C, Manfredini S, Maiorana A. Analysis of KRAS, NRAS, PIK3CA, and BRAF mutational profile in poorly differentiated clusters of KRAS-mutated colon cancer. Hum Pathol 2017; 62: 91-8.
[http://dx.doi.org/10.1016/j.humpath.2016.12.011] [PMID: 28025078]
[17]
Imamura Y, Lochhead P, Yamauchi M, Kuchiba A, Qian Rong. Analyses of clinicopathological, molecular, and prognostic associations of kras codon 61 and codon 146 mutations in colorectal cancer: Cohort study and literature review 2014. Mol Cancer 2014; 13: 135.
[18]
Thiel A, Ristimäki A. Toward a molecular classification of colorectal cancer: The Role of BRAF. Front Oncol 2013; 3(November): 281.
[http://dx.doi.org/10.3389/fonc.2013.00281] [PMID: 24298448]
[19]
Cope N, Candelora C, Wong K, et al. Mechanism of BRAF activation through biochemical characterization of the recombinant full-length protein. ChemBioChem 2018; 19(18): 1988-97.
[http://dx.doi.org/10.1002/cbic.201800359] [PMID: 29992710]
[20]
Barras D. BRAF Mutation in Colorectal Cancer: An Update. Biomark Cancer 2015.
[21]
Sale MJ, Minihane E, Monks NR, et al. Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors. Nat Commun 2019; 10(1): 5167.
[http://dx.doi.org/10.1038/s41467-019-12409-w] [PMID: 31727888]
[22]
Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010; 467(7315): 596-9.
[http://dx.doi.org/10.1038/nature09454] [PMID: 20823850]
[23]
Caputo F, Santini C, Bardasi C, et al. BRAF-mutated colorectal cancer: clinical and molecular insights. Int J Mol Sci 2019; 20(21): 5369.
[http://dx.doi.org/10.3390/ijms20215369] [PMID: 31661924]
[24]
Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer 2015; 51(5): 587-94.
[http://dx.doi.org/10.1016/j.ejca.2015.01.054] [PMID: 25673558]
[25]
Minoo P, Moyer MP, Jass JR. Role of BRAF-V600E in the serrated pathway of colorectal tumourigenesis. J Pathol 2007; 212(2): 124-33.
[http://dx.doi.org/10.1002/path.2160] [PMID: 17427169]
[26]
Ducreux M, Chamseddine A, Laurent-Puig P, et al. Molecular targeted therapy of BRAF-mutant colorectal cancer. Ther Adv Med Oncol 2019; 111758835919856494
[http://dx.doi.org/10.1177/1758835919856494] [PMID: 31244912]
[27]
Joerger AC, Fersht AR. The p53 pathway: origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem 2016; 85(1): 375-404.
[http://dx.doi.org/10.1146/annurev-biochem-060815-014710] [PMID: 27145840]
[28]
Mandinova A, Lee S W. The P53 pathway as a target in cancer therapeutics: obstacles and promise. Sci Transl Med 2011; 3(64): 64rv1-1.
[29]
Li X-L, Zhou J, Chen ZR, Chng WJ. P53 mutations in colorectal cancer - molecular pathogenesis and pharmacological reactivation. World J Gastroenterol 2015; 21(1): 84-93.
[http://dx.doi.org/10.3748/wjg.v21.i1.84] [PMID: 25574081]
[30]
Slattery ML, Mullany LE, Wolff RK, Sakoda LC, Samowitz WS, Herrick JS. The p53-signaling pathway and colorectal cancer: Interactions between downstream p53 target genes and miRNAs. Genomics 2019; 111(4): 762-71.
[http://dx.doi.org/10.1016/j.ygeno.2018.05.006] [PMID: 29860032]
[31]
Watanabe S, Tsuchiya K, Nishimura R, et al. TP53 mutation by CRISPR system enhances the malignant potential of colon cancer. Mol Cancer Res 2019; 17(7): 1459-67.
[http://dx.doi.org/10.1158/1541-7786.MCR-18-1195] [PMID: 30988165]
[32]
Bosari S, Viale G, Roncalli M, et al. Gene mutations. protein accumulation and compartmentalization in colorectal adenocarcinoma. Am J Pathol 1995; 147(3): 790-8.
[33]
Nakayama M, Oshima M. Mutant p53 in colon cancer. J Mol Cell Biol 2019; 11(4): 267-76.
[http://dx.doi.org/10.1093/jmcb/mjy075] [PMID: 30496442]
[34]
Willis A, Jung EJ, Wakefield T, Chen X. Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes. Oncogene 2004; 23(13): 2330-8.
[http://dx.doi.org/10.1038/sj.onc.1207396] [PMID: 14743206]
[35]
Cathomas G. PIK3CA in colorectal cancer. Front Oncol 2014; 4(4): 35.
[PMID: 24624362]
[36]
Papadatos-Pastos D, Rabbie R, Ross P, Sarker D. The role of the PI3K pathway in colorectal cancer. Crit Rev Oncol Hematol 2015; 94(1): 18-30.
[http://dx.doi.org/10.1016/j.critrevonc.2014.12.006] [PMID: 25591826]
[37]
Samuels Y, Ericson K. Oncogenic PI3K and its role in cancer. Curr Opin Oncol 2006; 18(1): 77-82.
[http://dx.doi.org/10.1097/01.cco.0000198021.99347.b9] [PMID: 16357568]
[38]
Ikenoue T, Kanai F, Hikiba Y, et al. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 2005; 65(11): 4562-7.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-4114] [PMID: 15930273]
[39]
Liao X, Morikawa T, Lochhead P, et al. Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review. Clin Cancer Res 2012; 18(8): 2257-68.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-2410] [PMID: 22357840]
[40]
Velho S, Oliveira C, Ferreira A, et al. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer 2005; 41(11): 1649-54.
[http://dx.doi.org/10.1016/j.ejca.2005.04.022] [PMID: 15994075]
[41]
Ziv E, Bergen M, Yarmohammadi H, et al. PI3K pathway mutations are associated with longer time to local progression after radioembolization of colorectal liver metastases. Oncotarget 2017; 8(14): 23529-38.
[http://dx.doi.org/10.18632/oncotarget.15278] [PMID: 28206962]
[42]
Hertzman Johansson C, Egyhazi Brage S. BRAF inhibitors in cancer therapy. Pharmacol Ther 2014; 142(2): 176-82.
[http://dx.doi.org/10.1016/j.pharmthera.2013.11.011] [PMID: 24325952]
[43]
Coffee EM, Faber AC, Roper J, et al. Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer. Clin Cancer Res 2013; 19(10): 2688-98.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-2556] [PMID: 23549875]
[44]
Mao M, Tian F, Mariadason JM, et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res 2013; 19(3): 657-67.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1446] [PMID: 23251002]
[45]
Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012; 483(7387): 100-3.
[http://dx.doi.org/10.1038/nature10868] [PMID: 22281684]
[46]
Burkart J, Owen D, Shah MH, et al. Targeting BRAF Mutations in High-Grade Neuroendocrine Carcinoma of the Colon. J Natl Compr Canc Netw 2018; 16(9): 1035-40.
[http://dx.doi.org/10.6004/jnccn.2018.7043] [PMID: 30181415]
[47]
Ursem C, Atreya CE, Van Loon K. Emerging treatment options for BRAF-mutant colorectal cancer. Gastrointest Cancer 2018; 8: 13-23.
[http://dx.doi.org/10.2147/GICTT.S125940] [PMID: 29628780]
[48]
Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med 2019; 381(17): 1632-43.
[http://dx.doi.org/10.1056/NEJMoa1908075] [PMID: 31566309]
[49]
Leshchiner ES, Parkhitko A, Bird GH, et al. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. Proc Natl Acad Sci USA 2015; 112(6): 1761-6.
[http://dx.doi.org/10.1073/pnas.1413185112] [PMID: 25624485]
[50]
Mazhab-Jafari MT, Marshall CB, Smith MJ, et al. Oncogenic and RASopathy-associated K-RAS mutations relieve membrane-dependent occlusion of the effector-binding site. Proc Natl Acad Sci USA 2015; 112(21): 6625-30.
[http://dx.doi.org/10.1073/pnas.1419895112] [PMID: 25941399]
[51]
Fang Z, Marshall CB, Nishikawa T, et al. Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site. Cell Chem Biol 2018; 25(11): 1327-1336.e4.
[http://dx.doi.org/10.1016/j.chembiol.2018.07.009] [PMID: 30122370]
[52]
McCarthy MJ, Pagba CV, Prakash P, et al. Discovery of high-affinity noncovalent allosteric kras inhibitors that disrupt effector binding. ACS Omega 2019; 4(2): 2921-30.
[http://dx.doi.org/10.1021/acsomega.8b03308] [PMID: 30842983]
[53]
Knickelbein K, Zhang L. Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer. genes and diseases. Chongqing Medical University 2015; 4-12.
[54]
Laurent-Puig P, Pekin D, Normand C, et al. Clinical relevance of KRAS-mutated subclones detected with picodroplet digital PCR in advanced colorectal cancer treated with anti-EGFR therapy. Clin Cancer Res 2015; 21(5): 1087-97.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-0983] [PMID: 25248381]
[55]
Rowland A, Dias MM, Wiese MD, et al. Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours. Eur J Cancer 2016; 55: 122-30.
[http://dx.doi.org/10.1016/j.ejca.2015.11.025] [PMID: 26812186]
[56]
Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD. Biochemical and structural analysis of common cancer-associated kras mutations. Mol Cancer Res 2015; 13(9): 1325-35.
[http://dx.doi.org/10.1158/1541-7786.MCR-15-0203] [PMID: 26037647]
[57]
Janes MR, Zhang J, Li LS, et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell 2018; 172(3): 578-589.e17.
[http://dx.doi.org/10.1016/j.cell.2018.01.006] [PMID: 29373830]
[58]
Peyser BD, Hermone A, Salamoun JM, et al. Specific rita modification produces hyperselective cytotoxicity while maintaining in vivo antitumor efficacy. Mol Cancer Ther 2019; 18(10): 1765-74.
[http://dx.doi.org/10.1158/1535-7163.MCT-19-0185] [PMID: 31341033]
[59]
Wiegering A, Matthes N, Mühling B, et al. Reactivating p53 and inducing tumor apoptosis (rita) enhances the response of rita-sensitive colorectal cancer cells to chemotherapeutic agents 5-fluorouracil and oxaliplatin. Neoplasia 2017; 19(4): 301-9.
[http://dx.doi.org/10.1016/j.neo.2017.01.007] [PMID: 28284059]
[60]
Walter RFH, Werner R, Wessolly M, et al. Inhibition of mdm2 via nutlin-3a: a potential therapeutic approach for pleural mesotheliomas with mdm2-induced inactivation of wild-type p53. J Oncol 2018; 2018: 1986982.
[http://dx.doi.org/10.1155/2018/1986982] [PMID: 30112000]
[61]
Crane EK, Kwan S-Y, Izaguirre DI, et al. Nutlin-3a: A Potential Therapeutic Opportunity for TP53 Wild-Type Ovarian Carcinomas. PLoS One 2015; 10(8)e0135101
[http://dx.doi.org/10.1371/journal.pone.0135101] [PMID: 26248031]
[62]
He X, Kong X, Yan J, et al. CP-31398 prevents the growth of p53-mutated colorectal cancer cells in vitro and in vivo. Tumour Biol 2015; 36(3): 1437-44.
[http://dx.doi.org/10.1007/s13277-014-2389-8] [PMID: 25663456]
[63]
Takimoto R, Wang W, Dicker DT, Rastinejad F, Lyssikatos J, el-Deiry WS. The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein. Cancer Biol Ther 2002; 1(1): 47-55.
[http://dx.doi.org/10.4161/cbt.1.1.41] [PMID: 12174820]
[64]
Rao CV, Steele VE, Swamy MV, Patlolla JMR, Guruswamy S, Kopelovich L. Inhibition of azoxymethane-induced colorectal cancer by CP-31398, a TP53 modulator, alone or in combination with low doses of celecoxib in male F344 rats. Cancer Res 2009; 69(20): 8175-82.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1377] [PMID: 19826045]
[65]
Li H, Zhang J, Tong JHM, et al. Targeting the oncogenic p53 mutants in colorectal cancer and other solid tumors. Int J Mol Sci 2019; 20(23): 5999.
[http://dx.doi.org/10.3390/ijms20235999] [PMID: 31795192]
[66]
Jan R, Chaudhry GE. Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull 2019; 9(2): 205-18.
[http://dx.doi.org/10.15171/apb.2019.024] [PMID: 31380246]
[67]
Mateo J, Ganji G, Lemech C, et al. First-Time-in-human study of gsk2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2017; 23(19): 5981-92.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0725] [PMID: 28645941]
[68]
National Cancer Institute. Definition of PI3K-beta inhibitor GSK2636771 - NCI Drug Dictionary - National Cancer Institute https://www.cancer.gov/publications/dictionaries/cancer-drug/def/pi3k-beta-inhibitor-gsk2636771
[69]
Migliardi G, Sassi F, Torti D, et al. Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas. Clin Cancer Res 2012; 18(9): 2515-25.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-2683] [PMID: 22392911]
[70]
Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature 2007; 446(7132): 153-8.
[http://dx.doi.org/10.1038/nature05610] [PMID: 17344846]
[71]
City of Hope Medical Center. FOLFIRI and Panitumumab in Treating Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer https://clinicaltrials.gov/show/NCT02508077
[72]
Southwest Oncology Group. S1406 Phase II Study of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer https://clinicaltrials.gov/show/NCT02164916
[73]
Takeda. Panitumumab for Intravenous Infusion 100 mg and 400 mg Special Drug Use Surveillance Survey on Unresectable Advanced or Recurrent Colorectal Cancer With Wild-type KRAS Gene https://clinicaltrials.gov/show/NCT02089737
[74]
Pfizer. A Study Of PF-05212384 Plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS And NRAS Wild Type Metastatic Colorectal Cancer https://clinicaltrials.gov/show/NCT01925274
[75]
Merck KGaA Darmstadt Germany. Cetuximab in Refractory Colorectal Cancer With K-RAS Mutated and Favorable FcÎ3RIIa (CD32) Genotype https://clinicaltrials.gov/show/NCT01450319
[76]
SCRI Development Innovations. L. FOLFOXIRI Plus Panitumumab Patients With Metastatic KRAS Wild-Type Colorectal Cancer With Liver Metastases Only https://clinicaltrials.gov/show/NCT01226719
[77]
Memorial Sloan Kettering Cancer Center. Clinical And Translational Study Of MK-2206 In Patients With Metastatic KRAS-Wild-Type, PIK3CA-Mutated, Colorectal Cancer https://clinicaltrials.gov/show/NCT01186705
[78]
EMD Serono. MEK Inhibitor MSC1936369B Plus FOLFIRI in Second Line K-Ras Mutated Metastatic Colorectal Cancer (mCRC) https://clinicaltrials.gov/show/NCT01085331
[79]
Celgene Corporation. A Study to Assess the Efficacy and Safety of Lenalidomide in Combination With Cetuximab in Pre-treated Patients With KRAS Mutant Colorectal Cancer https://clinicaltrials.gov/show/NCT01032291
[80]
Merck KGaA, Darmstadt, G. EMD 525797 in Combination With Cetuximab and Irinotecan in K-ras Wild Type Metastatic Colorectal Cancer https://clinicaltrials.gov/show/NCT01008475
[81]
Amgen. ASPECCT: A Study of Panitumumab Efficacy and Safety Compared to Cetuximab in Patients With KRAS Wild-Type Metastatic Colorectal Cancer https://clinicaltrials.gov/show/NCT01001377
[82]
Massachusetts General Hospital. Panitumumab in Cetuximab Refractory KRAS Wild-Type Colorectal Cancer https://clinicaltrials.gov/show/NCT00842257
[83]
Amgen. PEAK: Panitumumab Plus mFOLFOX6 vs. Bevacizumab Plus mFOLFOX6 for First Line Treatment of Metastatic Colorectal Cancer (mCRC) Patients With Wild-Type Kirsten Rat Sarcoma-2 Virus (KRAS) Tumors https://clinicaltrials.gov/show/NCT00819780
[84]
Amgen. Panitumumab Combination Study With Rilotumumab or Ganitumab in Wild-type Kirsten Rat Sarcoma Virus Oncogene Homolog (KRAS) Metastatic Colorectal Cancer (mCRC) https://clinicaltrials.gov/show/NCT00788957
[85]
Merck KGaA, Darmstadt, G. Study Evaluating the Safety and Efficacy of FOLFIRI Plus Cetuximab or FOLFOX Plus Cetuximab as First-line Therapy in Subjects With KRAS Wild-type Metastatic Colorectal Cancer (APEC-Study) https://clinicaltrials.gov/show/NCT00778830
[86]
OHSU Knight Cancer Institute. Erlotinib and Chemotherapy for 2nd Line Treatment (Tx) of Metastatic Colorectal Cancer (mCRC) https://clinicaltrials.gov/show/NCT00642746
[87]
Novartis Pharmaceuticals. Efficacy and Safety of Everolimus in Patients With Metastatic Colorectal Cancer Who Have Failed Prior Targeted Therapy and Chemotherapy https://clinicaltrials.gov/show/NCT00419159
[88]
Edward Chu M. A Phase II Multicenter, Randomized, Placebo Controlled, Double Blinded Clinical Study of KD018 as a Modulator of Irinotecan Chemotherapy in Patients With Metastatic Colorectal Cancer https://clinicaltrials.gov/show/NCT00730158

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy