The Study Of Overcoming Resistance Of Crizotinib By CT-707 And The Biomarkers Related To Tumorigenesis And Development Of Cancer

This study mainly researched on the diagnosis and therapy in the non-small cell lung cancer(NSCLC)and prostate cancer(PCa),respectively.The contents are divided into two sections as followed:Section 1.CT-707 Overcomes Resistance of crizotinib through activating PDPK1-AKT1 pathway by torgeting FAKCrizotinib established the position of anaplastic lymphoma kinase-tyrosine kinase inhibitors(ALK-TKI)in the treatment of non-small cell lung cancer(NSCLC)while a challenge for patients to continue to benefit was the therapy-resistance.CT-707 is a ALK/FAK/IGFR-1 inhibitor.H3122CR(crizotinib resistance,CR)and H2228CR NSCLC cell lines were generated in from the parental cell line H3122 and H2228 with ALK-positive,respectively.We investigated that CT-707 exerted antitumor effects against H3122CR in vitro and in vivo.Importantly,our study provided evidence that CT-707 overcomes resistance to crizotinib through activating PDPK1-AKT1 pathway by targeting FAK.Meanwhile,using an in-vivo H3122CR xenograft model we found CT-707 significantly inhibited tumor growth without obvious side effects.These findings indicate that CT-707 may be a promising therapeutic agent against crizotinib-resistance in NSCLC.Section 2.The Study on Biomarkers Related to Tumorigenesis and Development of cancerIn this part,we evaluated the genomic patterns of prostate cancer in National Cancer Center in China as well as the prognostic value of biomarkers in peripheral blood of patients with PCa.What is more,a meta-analysis of Anti-p53 autoantibody as the diagnostic biomarker for non-small cell lung cancer was made.The specific research contents as followed:Chapter 1:The genomic patterns of prostate cancer in National Cancer Center of ChinaThis study prospectively collected 156 patients with increased-tPSA from October 2014 to June 2017 in National Cancer Center in China with treatment-naive tumor tissues and paired blood.We conducted whole genome seq-uence in 27qualified samples and chose 11 with high-concerntration of tumour for transcriptome sequence.We identified 112,528 somatic mutations with an average of 32 nonsilent mutations per tumor.Four mutational signatures were extracted from the samples based on the somatic single-nucleotide-variants byNMF.Apreviously unreported signature B was presented at 92.6%(25/27)samples with a strong link to several hotspot mutations of SPOP,suggesting that it could play a substantial role in PCa.Copy number variations analysis showed high level amplification in chromosomal region 8q24.21(22%).We found that the anplification gene(ZBTB7B and SLC4A4)were overexpressed(P<0.001)while the deletion gene(TBX18,CYSLTR2 and EFNA5)were lower expressed(P<0.05)than normal which indicating that the five genes may relate to tumorigenesis.Six structure signatures were extracted from the samples based on the structure-variants by NMF.More importantly,four classifications(C1:translocation,7.41%;C2:tandem duplicator,25.93%;C3:small deletor with segment length<lkb,33.33%;C4:large deletor with segment length>lkb,33.33%)with different phenotypes and characteristics based on six structural variation(SV)signatures were identified for the first time in PCa.The genomic characteristics such as cluster C3 and C4,possibly interpret the pathogenesis and carcinogenesis.Our study reveals potentially disease relevant genomic alteration patterns of Chinese PCa.Chapter 2:The application of peripheral blood biomarkers in the differential diagnosis of prostate cancer and value to evaluate malignancyThis study aimed to evaluate the difference of the application of peripheral blood biomarkers in the differential diagnosis of prostate cancer.Clinical data of 126 patients with prostate cancer(PCa)and 34 patients with benign prostatic hyperplasia(BPH)in National Cancer Hospital between January 2015 and December 2016 was retrospectively collected.The results of ROC curve showed that the AUC of tPS A,fPSA/tPSA and PLR were the largest.The results of Logistic regression and ROC curve analysis of combined markers showed that the diagnostic efficiency of tPSA and fPSA/tPS A combined analysis was the best with AUC=0.76.Differences between different degree of malignant group analysis results showed that in 126 patients with PCa,PLR and NLR in peripheral blood have a significant difference among different tPSA and clinical classification(P<0.05).There was no obvious difference in LDH among different degree of malignant group.Our results suggested that combined-analysis of tPSA and fPSA/tPSA had the best diagnostic efficiency for BPH and PCa.PLR and NLR in peripheral blood can assist tPSA,Gleason scoring and clinical staging to assess the malignancy of prostate cancer and have some suggestive effects on evaluating malignancy.Chapter 3:Anti-p53 autoantibody as the diagnostic biomarker for non-small cell lung cancer:a meta-analysisThis meta-analysis aims to summarize the most studied autoantibody(p53)and determine the overall diagnostic accuracy in NSCLC.In a fixed-or random-effects model,the pooled diagnostic sensitivity,specificity,positive likelihood ratio,negative likelihood ratio,and diagnostic odds ratio for anti-p53 autoantibody were 0.21[95%confidence interval(CI):0.19-0.23],0.98(95%CI:0.97-0.99),18.04(95%CI:11.3-28.8),0.79(95%CI:0.72-0.86),and 23.29(95%CI:14.38-37.71),respectively.The AUC for anti-p53 autoantibody was 0.8015(standard error:0.1053).The anti-p53 autoantibody may be used as a reference index for the diagnosis of NSCLC with a high pooled specificity,PLR and DOR.But when used alone,has limited utility as a cancer biomarker because of its low sensitivity.