Login Register Cart 0
Mini-Review Article

Target Genetic Abnormalities for the Treatment of Colon Cancer and Its Progression to Metastasis

Author(s): Tushar Baviskar, Munira Momin, Jingwen Liu, Bin Guo and Lokesh Bhatt*

Volume 22, Issue 7, 2021

Published on: 19 November, 2020

Page: [722 - 733] Pages: 12

DOI: 10.2174/1389450121666201119141015

Price: $65

Abstract

Colorectal carcinogenesis involves various processes from the accumulation of genetic alterations to genetic and epigenetic modulations and chromosomal abnormalities. It also involves mutations in oncogenes and tumour suppressor genes. Genomic instability plays a vital role in CRC. Advances in modern biological techniques and molecular level studies have identified various genes involved in colorectal cancer (CRC). KRAS, BRAF, PI3K, and p53 genes play a significant role in different phases of CRC. Alteration of these genes leads to development or progression and metastasis colon cancer. This review focuses on the role of KRAS, BRAF, PI3KCA, and TP53 genes in carcinogenesis and their significance in various stages of CRC. It also provides insights on specific modulators acting on these genes. Further, this review discusses the mechanism of the pathways involving these genes in carcinogenesis and current molecules and treatment options under various stages of clinical evaluation.

Keywords: Metastatic colon cancer, Genetic alterations, BRAF gene, KRAS gene, P53 gene, PI3K gene.

« Previous Next »
Graphical Abstract

[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
Article Metrics
65
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy