Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs

Beijing, China

Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs

Beijing, China
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Song W.-Y.,Peking Union Medical College | Song W.-Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Liu P.,Peking Union Medical College | Zhang Y.,Peking Union Medical College | And 9 more authors.
Chinese Journal of New Drugs | Year: 2017

Objective: To establish an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for determining the concentrations of sabarubicin and its metabolite M3 in human urine for a phase I clinical pharmacokinetic study in Chinese small cell lung cancer (SCLC) patients. Methods: Liquid-liquid extraction by chloroform was used to isolate sabarubicin and M3, using doxorubicin hydrochloride as the internal standard (IS). The optimal chromatographic behavior was achieved on an ACQUITY UPLC BEH Shield RP18 (100 mm×2.1 mm, 1.7 μm) column using a mixture of 0.1% formic acid water and acetonitrile (90∶10, v/v) as the mobile phase. The flow rate was 0.3 mL·min-1. ESI+ detection was performed in MRM mode using target ions at m/z 644.2→130.2 for sabarubicin, m/z 646.2→130.1 for M3 and m/z 544.3→397.1 for doxorubicin. Results: The calibration curve exhibited excellent linearity over the range of 2~200 ng·mL-1 for both sabarubicin and M3, with reproducible coefficients of correlation greater than 0.99. No endogenous interference was observed at the retention time of the analytes and the carry-over effect was found to be negligible from previous concentrated samples. The method was validated with respect to selectivity, extraction recovery, matrix effect, intra- and inter-day precision, accuracy, and stabilities, all of which met the requirements of FDA and CFDA guidelines, and this method has already been used to detect the concentrations of sabarubicin and M3 in Chinese patients. Conclusion: We developed a sensitive, accurate and rapid method to quantify sabarubicin and M3 in human urine, which can fulfill the requirements of the clinical pharmacokinetic study of sabarubicin. © 2017, Chinese Journal of New Drugs Co. Ltd. All right reserved.

Park K.,Sungkyunkwan University | Tan E.-H.,National Cancer Center | O'Byrne K.,Queensland University of Technology | Zhang L.,Sun Yat Sen University | And 20 more authors.
The Lancet Oncology | Year: 2016

Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with, number NCT01466660. Findings: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Funding: Boehringer Ingelheim. © 2016 Elsevier Ltd.

Shi Y.,Peking Union Medical College | Shi Y.,National Center for Anticancer Drugs Clinical Study | Shi Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Xing P.,Peking Union Medical College | And 13 more authors.
Thoracic Cancer | Year: 2015

Background: The treatment status of small cell lung cancer (SCLC) in Mainland China has never been reported; therefore, this study is the first multicenter survey investigating the status of epidemiology and treatment options of SCLC in Mainland China. Methods: Two questionnaires were designed to obtain information in 12 medical centers in five major Chinese cities. The hospital information questionnaire was designed to outline SCLC patients' characteristics and treatment preferences in each medical institution, and the patient information questionnaire collected detailed treatment information of 298 SCLC cases in these hospitals. Results: SCLC represented 13.7% and 18.3% of all lung cancer patients in 2005 and 2010, respectively. Clinical management of SCLC follows mainstream clinical guidelines in general. The most widely applied first-line treatment mode for limited-stage patients was combined chemoradiotherapy (66.2%), while 77.0% of the extensive-stage patients received chemotherapy alone as initial treatment. Etoposide with cisplatin or carboplatin were the most accepted first-line chemotherapy regimens. The objective response rate was 58.3% after first-line chemotherapy and 23% of the patients who responded well to first-line treatment received prophylactic cranial irradiation. As for second-line chemotherapy, single regimen topotecan or a combined regimen containing topotecan were preferred (53.0%). Conclusions: The treatment options indicated in our study are in accordance with the international clinical guidelines, which is valuable for the improvement of future guidelines, health care standard, and even the better distribution of health care resources in China. © 2015 The Authors. Thoracic Cancer published by Tianjin Lung Cancer Institute and Wiley Publishing Asia Pty Ltd.

Shen Y.,Peking Union Medical College | Shen Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Wang J.,Peking Union Medical College | Wang J.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | And 8 more authors.
PLoS ONE | Year: 2013

Mutations in KRAS oncogene are recognized biomarkers that predict lack of response to anti- epidermal growth factor receptor (EGFR) antibody therapies. However, some patients with KRAS wild-type tumors still do not respond, so other downstream mutations in BRAF, PIK3CA and NRAS should be investigated. Herein we used direct sequencing to analyze mutation status for 676 patients in KRAS (codons 12, 13 and 61), BRAF (exon 11 and exon 15), PIK3CA (exon 9 and exon 20) and NRAS (codons12, 13 and 61). Clinicopathological characteristics associations were analyzed together with overall survival (OS) of metastatic colorectal cancer patients (mCRC). We found 35.9% (242/674) tumors harbored a KRAS mutation, 6.96% (47/675) harbored a BRAF mutation, 9.9% (62/625) harbored a PIK3CA mutation and 4.19% (26/621) harbored a NRAS mutation. KRAS mutation coexisted with BRAF, PIK3CA and NRAS mutation, PIK3CA exon9 mutation appeared more frequently in KRAS mutant tumors (P = 0.027) while NRAS mutation almost existed in KRAS wild-types (P<0.001). Female patients and older group harbored a higher KRAS mutation (P = 0.018 and P = 0.031, respectively); BRAF (V600E) mutation showed a higher frequency in colon cancer and poor differentiation tumors (P = 0.020 and P = 0.030, respectively); proximal tumors appeared a higher PIK3CA mutation (P<0.001) and distant metastatic tumors shared a higher NRAS mutation (P = 0.010). However, in this study no significant result was found between OS and gene mutation in mCRC group. To our knowledge, the first large-scale retrospective study on comprehensive genetic profile which associated with anti-EGFR MoAbs treatment selection in East Asian CRC population, appeared a specific genotype distribution picture, and the results provided a better understanding between clinicopathological characteristics and gene mutations in CRC patients. © 2013 Shen et al.

Yang L.,CAS Beijing National Laboratory for Molecular | Cui X.,CAS Beijing National Laboratory for Molecular | Cui X.,Peking Union Medical College | Zhang N.,Peking Union Medical College | And 8 more authors.
Analytical and Bioanalytical Chemistry | Year: 2015

Abnormal lipid metabolism is a common feature in most solid tumors, and occurs in early stages of the tumor progression. As benign breast tumor is different from malignant tumor of breast cancer, it is particularly important to take benign breast tumor into consideration when investigating cancer biomarkers. In this study, by using a normal-phase/reversed-phase two-dimensional liquid chromatography-mass spectrometry (NP/RP 2D LC-MS) method, we conducted comprehensive lipid profiling in human plasma obtained from six benign breast tumor patients and five breast cancer patients, as well as nine healthy controls. As a result, 512 lipid species were successfully identified. Principal component analysis allowed clear separation of the three groups. Quantitative analysis revealed that many lipid contents were similar in benign and malignant breast tumors compared with controls, and these were proposed as potential breast tumor biomarkers other than breast cancer biomarkers. Two phosphatidylinositol (PI) species, including PI (16:0/16:1) and PI (18:0/20:4), could differentiate between benign and malignant breast tumors, as well as breast cancer patients and healthy controls, indicating that they could be utilized as potential breast cancer biomarkers. In addition, PI (16:0/18:1), phosphatidylglycerol (36:3), and glucosylceramide (d18:1/15:1) were demonstrated to be potential biomarkers to evaluate the level of malignancy of breast tumor. Taken together, our results indicate the usefulness of lipid profiling in the discrimination between patients with breast cancer and non-carcinoma lesions, which might provide assistance in clinical diagnosis.[Figure not available: see fulltext.] © 2015 Springer-Verlag Berlin Heidelberg

Zhang Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Song Y.-Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Song W.-Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Shi Y.-K.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | And 2 more authors.
Chinese Journal of New Drugs | Year: 2016

Objective: To investigate the influence of EDTA-K2 or lithium heparin anticoagulant plasma, different extraction agents and liquid chromatograph methods on matrix effects of sabarubicin and M3 during analysis by high performance liquid chromatography mass spectrometry. Methods: Prepared plasma samples of sabarubicin and M3 at 3 concentrations in plasmas containing different anticoagulants were extracted by ethyl-acetate or chloroform. Gradient elution or isocratic elution composed of A: 0.1% formic acid water and B:acetonitrile were adopted, and a gradient elute were developed. Detection was performed by electrospray ionization (ESI) in the positive ionization mode by multiple reaction monitoring (MRM) of the transitions at m/z 644→130 for sabarubicin, m/z 646→333.2 for M3 and m/z 544→360 for internal standard doxorubicin. Post-extraction spiking method was adopted to investigate the impacts of these conditions on matrix effects of sabarubicin and M3. Results: At lower concentration, the matrix effects of sabarubicin and M3 in EDTA-K2 anticoagulant plasma were respectively 123% and 110%, while it is 143% and 160% in in lithium heparin anticoagulant plasma. There was a statistically significant difference between anticoagulant plasmas (sabarubixin:P<0.05, M3:P<0.05). Matrix effects for chloroform extracted sabarubicin and M3 at 3 concentrations in lithium heparin anticoagulant plasma were 142%, 94% and 78% for sabarubicin, and 123%, 102% and 89% for M3, respectively. After adoption of gradient elute, the matrix effects were 108%, 81% and 73% for sabarubicin, and 93%, 83% and 73% for M3, at 3 concentrations. The matrix effects in ultimate method were 85.4% and 98.7% for sabarubicin and M3 at low concentration, and 88.5% and 96.0% at high concentration. Conclusion: The matrix effects are more serious for sabarubicin and M3 in lithium heparin anticoagulant plasma, which have large difference in multi-concentration. Improvement of pretreatment method and liquid chromatograph method could decrease matrix effects. © 2016, Chinese Journal of New Drugs Co. Ltd. All right reserved.

Worden F.,University of Michigan | Fassnacht M.,University of Würzburg | Shi Y.,Peking Union Medical College | Shi Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | And 15 more authors.
Endocrine-Related Cancer | Year: 2015

Effective adverse event (AE) management is critical to maintaining patients on anticancer therapies. The DECISION trial was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial which investigated sorafenib for treatment of progressive, advanced, or metastatic radioactive iodine-refractory, differentiated thyroid carcinoma. Four hundred and seventeen adult patients were randomized (1:1) to receive oral sorafenib (400 mg, twice daily) or placebo, until progression, unacceptable toxicity, noncompliance, or withdrawal. Progression-free survival, the primary endpoint of DECISION, was reported previously. To elucidate the patterns and management of AEs in sorafenib-treated patients in the DECISION trial, this report describes detailed, by-treatment-cycle analyses of the incidence, prevalence, and severity of hand-foot skin reaction (HFSR), rash/desquamation, hypertension, diarrhea, fatigue, weight loss, increased serum thyroid stimulating hormone, and hypocalcemia, as well as the interventions used to manage these AEs. By-cycle incidence of the above-selected AEs with sorafenib was generally highest in cycle 1 or 2 then decreased. AE prevalence generally increased over cycles 2-6 then stabilized or declined. Among these AEs, only weight loss tended to increase in severity (from grade 1 to 2) over time; severity of HFSR and rash/desquamation declined over time. AEs were mostly grade 1 or 2, and were generally managed with dose interruptions/reductions, and concomitant medications (e.g. antidiarrheals, antihypertensives, dermatologic preparations). Most dose interruptions/reductions occurred in early cycles. In conclusion, AEs with sorafenib in DECISION were typically grade 1 or 2, occurred early during the treatment course, and were manageable over time. © 2015 Society for Endocrinology.

Yao J.,Peking Union Medical College | Yao J.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Liu L.,Beijing University of Chemical Technology | Yang M.,Beijing University of Chemical Technology
Gene | Year: 2014

Aim: Interleukin-23 (IL-23) and IL-23 receptor (IL23R) play an important role during the T-helper 17 (Th17) cell-mediated inflammatory process as well as pathogenesis of multiple cancers. Several IL-23R single nucleotide polymorphisms (SNPs), especially rs6682925, rs10889677 and rs1884444 polymorphisms, are considered to have significant impacts on susceptibility of multiple cancers. A number of case-control studies have explored the role these genetic polymorphisms in development of carcinogenesis, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically investigate the associations between the three genetic variants and multiple cancer risk. Methods: A total of ten studies are eligible (12,211 patients and 14,650 controls). Pooled odds ratios (ORs) and the 95% confidence interval (95% CI) were appropriately calculated using either fixed-effect model or random-effect model. Results: Significant associations between rs6682925 or rs10889677 polymorphism and cancer risk were found (OR. = 1.11, 95% CI. = 1.03-1.21, P= 0.007; or OR. = 0.85, 95% CI. = 0.71-0.92, P= 0.001). However, there was no such association between rs1884444 genotypes and cancer susceptibility (P>. 0.05). Conclusion: These findings reveal that the IL-23R rs6682925 and rs10889677 genetic variants play a more important part in pathogenesis of multiple cancers. © 2013 Elsevier B.V.

Han X.,Peking Union Medical College | Han X.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Liu M.,CAS Beijing Institute of Genomics | Liu M.,University of Chinese Academy of Sciences | And 8 more authors.
Current Cancer Drug Targets | Year: 2015

The epidermal growth factor receptor-tyrosine kinase inhibitors (EGFRTKI), such as gefitinib and erlotinib have improved the survival of patients with nonsmall cell lung cancer (NSCLC). Unfortunately, acquired resistance will eventually develop in most patients who initially respond to the therapy. Currently known molecular mechanisms for such an acquired resistance may interpret only about 70% of clinical cases. In this study, using NSCLC cell model H1650, we constructed a gefitinib resistant cell line H1650GR through long term drug exposure with increased doses. RNA sequencing and whole genome SNP array were applied to investigate the transcriptome and genome alterations possibly involved in gefitinib resistance. By comparing the expression profiles between H1650GR and H1650 cells, we identified a large set of differentially expressed genes (DEGs), including FOXM1. In the PI3K/AKT pathway, AKT activity was predicted to be inhibited. However, genes that play important roles in gefitinib-induced apoptosis, including TP53, FOXO3 and BAD, were not up-regulated. Ingenuity Pathway Analysis (IPA) canonical pathway analysis showed that p53 signaling was inhibited in H1650GR cells, with down-regulation of pro-apoptosis genes FAS, PUMA, NOXA, and upregulation of anti-apoptosis genes BIRC5/Survivin. Besides, a large number of immune response-related genes were differently expressed, the role of which in gefitinib resistance requires further investigation. Whole genome copy number alterations (CNAs) were also analyzed and NOXA was located in the H1650GR unique copy number loss region, 18q21. Our results suggested that the much higher EGFR-TKI resistance in H1650GR may be produced by the integration of multi-aspect factors. © 2015 Bentham Science Publishers.

Yang J.,Peking Union Medical College | Yang J.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | Shi Y.,Peking Union Medical College | Shi Y.,Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs | And 12 more authors.
Thoracic Cancer | Year: 2014

Background: This study was conducted to evaluate the efficacy and safety of paclitaxel-carboplatin combined with intercalated gefitinib in patients with advanced, untreated, nonsquamous non-small cell lung cancer. Methods: A total of 29 patients were enrolled in the study. All patients were Chinese, with a histology type of adenocarcinoma, without a smoking history, and as a result of the limited tissue sample, an epidermal growth factor receptor (EGFR) mutation test could not be performed. All patients received chemotherapy of paclitaxel-carboplatin every 21 days for four cycles, and gefitinib (250mg/day) was administered on days eight to 17 of the chemotherapy cycle. If the patient responded to chemotherapy, maintenance therapy of 250mg of gefitinib could be administered daily. Results: All of the 29 patients received at least one cycle of chemotherapy and gefitinib, and 25 patients received four cycles of therapy. Eighteen patients selected maintenance therapy with gefitinib. The objective response rate was 74.1% (95% confidence interval, 53.7% to 88.9%). No complete response was achieved. The median progression-free survival was 16 months, however, the median overall survival was not available by the conclusion of the study. The major adverse event was hematologic toxicity. Conclusions: The regimen of paclitaxel-carboplatin combined with intercalated gefitinib showed a high response rate and a favorable safety profile. Gefitinib maintenance therapy was proven to be beneficial. This study proposes a good pattern of chemotherapy combined with EGFR tyrosine kinase inhibitors. © 2013 Tianjin Lung Cancer Institute and Wiley Publishing Asia Pty Ltd.

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