The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.
Humans ; Animals ; Mice ; Cisplatin/therapeutic use* ; Antineoplastic Agents/therapeutic use* ; Nasopharyngeal Carcinoma/drug therapy* ; Mice, Nude ; Nasopharyngeal Neoplasms/pathology* ; Tumor Microenvironment

OBJECTIVE: To evaluate pharmacokinetics (PK), efficacy, and safety of atezolizumab (anti-PD-L1) in high interest cancers in China, including esophageal cancer (EC), gastric cancer (GC), hepatocellular carcinoma (HCC), nasopharyngeal cancer (NPC), and non-small cell lung can-cer (NSCLC). METHODS: This phase I, open-label study was conducted at 6 Chinese sites from August 4, 2016 to April 15, 2019. The patients were ≥18 years old with a histologically documented incurable or metastatic solid tumor that was advanced or recurrent and had progressed since the last anti-tumor the-rapy. The PK phase characterized PK and safety of atezolizumab following multiple-dose administration when atezolizumab was administered as a single agent. The extension phase studied safety and efficacy of atezolizumab, as monotherapy (EC, GC, HCC, NPC) and with chemotherapy (NSCLC). RESULTS: This study enrolled 120 patients (PK phase: n=20; extension phase: n=20/cohort). Fourty-two patients (42.0%) were PD-L1 positive in atezolizumab monotherapy group (100 patients), of the 9 patients (9.0%) with microsatellite instability-high (MSI-H) tumors. Atezolizumab clearance was 0.219 L/d, and steady state was reached after 6 to 9 weeks (2-3 cycles) of repeated dosing. Objective response rates (ORRs) in EC, GC, HCC, NPC, and NSCLC were 10.0%, 15.0%, 10.0%, 5.0%, and 40.0%, respectively. In the patients with PD-L1 positive tumors, ORR was 11.9% with atezolizumab and 46.2% with atezolizumab plus gemcitabine and cisplatin. Two GC patients achieved durable response after pseudo-progression. The most common treatment-related adverse events in the atezolizumab monotherapy group were fatigue, anemia, fever, and decreased white blood cell count. The most common treatment-related adverse events in the combination group were anemia, decreased white blood cell count, and decreased appetite. No new safety signals were identified. CONCLUSION Atezolizumab's PK, efficacy, and safety were similar in Chinese patients vs. global patients in previous studies.
Adolescent ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Carcinoma, Hepatocellular/drug therapy* ; Cisplatin/therapeutic use* ; Humans ; Liver Neoplasms/drug therapy* ; Lung Neoplasms/pathology* ; Nasopharyngeal Neoplasms/drug therapy*

OBJECTIVETo compare the therapeutic effects, toxic side effects and influence on the immune function in patients treated with TPF [docetaxel (DOC) + cisplatin (DDP) + 5-fluorouracil (5-Fu)] induction chronochemotherapy and conventional chemotherapy for locally advanced nasopharyngeal (NPC).

METHODSSeventy patients with locally advanced nasopharyngeal carcinoma were treated in our department at their first visit from April 2013 to December 2013. They were divided randomly into two groups: the chronochemotherapy group (38 patients) and conventional chemotherapy group (32 patients). All of the patients were treated with TPF regimen with 2 cycles of induction chemotherapy in a 21-28-days/cycle. The chronochemotherapy group: DOC: 75 mg/m2, i. v. gtt, d1 (03: 30-04: 30); DDP: 75 mg/m2, 10 am-10 pm, c.i.v, d1-d5; 5-Fu: 750 mg·m(-2)·d(-1), 10 pm-10 am, c. i.v., d1-d5, both chemotherapies were administered by intravenous infusion using an automatic electric pump. The conventional chemotherapy group: Both DOC and DDP were administered intravenously at a dose of 75 mg/m2 on d1. 5-Fu was given at a dose of 750 mg/m2 for 24 hours from d1-d5 with continuous infusion in a total of 120 hours. In this procedure, prescribing the conventional intravenous infusion, intensity modulated radiation therapy was used after the induction chemotherapy. The prescribed nasopharyngeal lesion dose (GTVnx) was 69.96 Gy/33 fractions for the T1-T2 nasopharygeal cancer, while 73.92 Gy/33 fractions nasopharynx lesion dose (GTVnx) for the T3-T4 nasopharyngeal cancer. The planning target volume (PTV) of positive lymph node (PTVnd) dose was 69.96 Gy/33 fractions. Concurrent chemoradiotherapy: cisplatin 100 mg/m2, i. v. gtt. d1-d2, and there were two cycles in total and 21 days each cycle.

RESULTSSixty-six patients were evaluable for the response assessment. There were 36 patients in the chronochemotherapy group and 30 patients in the conventional chemotherapy group. After the induction chemotherapy, no CR case was found in both of the two groups. The PR was 80.6% in the chronochemotherapy group and 50.0% in the conventional chemotherapy group (P=0.009). After concurrent chemoradiotherapy, the CR rate in the chronocheotherapy group was 45.5%, significantly higher than 20.7% in the conventional chemotherapy group (P=0.040). Secondly, the incidence rates of adverse reactions including bone marrow suppression, nausea, vomiting, diarrhea, constipation, oral mucositis, fatigue, anorexia in the chrono-chemotherapy group were significantly lower than that in the conventional group (P<0.05 for all). Finally, compared the two groups, the CD4+ /CD8+ ratio was significantly lower in the chronochemotherapy group than that in the conventional chemotherapy group (P<0.05). The lymphocytes CD19+ and CD4+/CD8+ were decreased and CD3+, CD4+, CD8+, CD16++CD56+ were increased in the chronochemotherapy group, while only CD3+ and CD8+ were increased in the conventional chemotherapy group.

CONCLUSIONSCompared with the conventional chemotherapy, the chronochemotherapy may be more favorable in the treatment of NPC, with a better therapeutic effects and effectiveness than that of conventional chemotherapy after induction chemotherapy, with less side effects, and can improve the immune function in the patients.

Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; Carcinoma ; Chemoradiotherapy ; Cisplatin ; administration & dosage ; Drug Chronotherapy ; Fluorouracil ; administration & dosage ; Humans ; Induction Chemotherapy ; methods ; Nasopharyngeal Neoplasms ; drug therapy ; pathology ; radiotherapy ; Nausea ; Neoplasm Staging ; Radiotherapy, Intensity-Modulated ; Taxoids ; administration & dosage ; Treatment Outcome

OBJECTIVETo evaluate the efficacy and safety of gemcitabine combined with ifosfamide (GI regimen)in patients with recurrent or metastatic nasopharyngeal carcinoma after failure of platinum-based chemotherapy.

METHODSThe clinical data of 27 nasopharyngeal carcinoma patients, who received GI regimen between April 2005 and March 2014 after failure of prior platinum-based chemotherapy, were retrospectively reviewed,and relevant prognostic factors were explored.

RESULTSAll patients were evaluable for efficacy and toxicity. No patient achieved complete response (CR). Partial response (PR) was achieved in ten patients, stable disease (SD) in thirteen patients, progressive disease (PD) in four patients, with a response rate of 37.0% and an overall disease control rate (PR+SD) of 85.2%. For ten PR patients, the median duration of response was 5.5 months. The median progression-free survival of the whole group was 6.7 months, and the Kaplan-Meier estimate of median overall survival was 17.4 months. The 1-year survival rate was 72.6%. Toxicity was mainly hematological: Grade III or IV anemia, neutropenia and thrombocytopenia were found in 3.7%, 37.0% and 18.5% of all patients, respectively. Univariate and multivariate analyses indicated that dose intensity of gemcitabine was a significant prognostic factor for PFS, whereas salvage treatment after failure of GI regimen was a significant prognostic factor for OS.

CONCLUSIONSGemcitabine and ifosfamide combination is effective and well tolerated by patients with advanced nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Further clinical study is warranted.

Anemia ; chemically induced ; Antineoplastic Agents ; adverse effects ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Carcinoma ; Deoxycytidine ; administration & dosage ; adverse effects ; analogs & derivatives ; Disease-Free Survival ; Humans ; Ifosfamide ; administration & dosage ; adverse effects ; Induction Chemotherapy ; Kaplan-Meier Estimate ; Nasopharyngeal Neoplasms ; drug therapy ; mortality ; pathology ; Neutropenia ; chemically induced ; Platinum ; therapeutic use ; Remission Induction ; Salvage Therapy ; Survival Rate ; Thrombocytopenia ; chemically induced ; Treatment Failure

OBJECTIVETo compare the short-term efficacy and observe the tolerability and safety of recombinant human endostatin combined with induction chemotherapy followed by chemoradiotherapy for locally advanced nasopharyngeal carcinoma.

METHODSFifty-three patients with locally advanced nasopharyngeal carcinoma, who received recombinant human endostatin combined with induction chemotherapy followed by chemoradiotherapy, treated in our department from December 2011 to March 2013 were included in the study group of this study. Another 48 patients, who received induction chemotherapy followed by chemoradiotherapy alone in the same period, were chosen as a control group. The short-term outcome, overall survival (OS), progression-free survival (PFS), and acute side effects of the two groups were compared.

RESULTSThe complete remission rates of nasopharyngeal tumor in the study and control groups were 77.4% and 72.9%, respectively (P=0.154). The complete remission rates of patients with and without cervical lymph node metastasis were 75.5% and 62.6%, respectively, showing a significant difference (P=0.037). The 2-year OS, PFS, and DMFS rates for the study group were 82.3%, 77.2%, and 82.2%, respectively, versus 87.2%, 84.3% and 84.2% for the control group, showing a non-significant differences between the two groups (P=0.938, P=0.551, and P=0.725).

CONCLUSIONSThe short-term results of recombinant human endostatin (Endostar) combined with induction chemotherapy followed by concurrent chemoradiotherapy in the treatment of locally advanced nasopharyngeal carcinoma are slightly better than that of induction chemotherapy followed by concurrent chemoradiotherapy alone, with tolerable treatment-related toxicity and no more side effects.

Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoma ; Chemoradiotherapy ; Cisplatin ; Disease-Free Survival ; Endostatins ; therapeutic use ; Humans ; Induction Chemotherapy ; Lymphatic Metastasis ; Nasopharyngeal Neoplasms ; drug therapy ; radiotherapy ; Remission Induction

Carcinoma ; Dermatomyositis ; drug therapy ; Dexamethasone ; therapeutic use ; Humans ; Male ; Middle Aged ; Nasopharyngeal Neoplasms ; complications ; Paraneoplastic Syndromes ; drug therapy ; Prednisone ; therapeutic use

Radiotherapy is the primary treatment for nasopharyngeal carcinoma, and the disease control rate and survival time are able to be greatly improved by enhancing the radiosensitivity. Via mechanisms such as binding to target genes mRNA 3'untranslated region (3'UTR), microRNA (miRNA) inhibits translation, which therefore regulates transcription of target genes and thus affect target protein expression. Recent research showed that miRNAs play significant roles in improvement of radiosensitivity in nasopharyngeal carcinoma. This article reviews mechanism of miRNA action to strengthen radiosensitivity of nasopharyngeal carcinoma and the future of clinical practice of miRNA in this disease.
3' Untranslated Regions ; Carcinoma ; Humans ; MicroRNAs ; pharmacology ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms ; drug therapy ; radiotherapy ; RNA, Messenger ; Radiation Tolerance ; Radiation-Sensitizing Agents

OBJECTIVE: To study the expression of excision repair cross-complementing 1 (ERCC1) and the treatment of cisplatin-based chemotherapy in local advanced nasopharyngeal carcinoma (NPC). METHOD: The expression of ERCC1 protein in 107 cases with NPC and in 48 normal nasopharyngeal tissues adjacent to the cancer was detected by immunohistochemical method. RESULT: High expression of ERCC1 was observed in 52 cases with NPC, and 18 cases normal nasopharyngeal tissues, there was no statistically significant differences between them. The expression of ERCC1 protein was significant correlated with patient total TNM stage, but not significantly correlated with age, gender, histological type, T stage and N stage. The recent treatment efficiency in Low ER-CCl expression cases was higher than high expression cases. There was statistically significant difference between them. In 97 follow-up cases, 2 cases died, 5 cases with liver and lung metastasis, there was no statistically significant difference between them. CONCLUSION ERCC1 expression maybe regarded as indicator platinum based chemotherapy sensitivity prediction in nasopharyngeal carcinoma, and also helpful for formulating individualized treatment. The immunohistochemical detection is also simple and effective detection method for ERCC1 expression.
Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoma ; Cisplatin ; therapeutic use ; DNA-Binding Proteins ; biosynthesis ; Endonucleases ; biosynthesis ; Humans ; Lung Neoplasms ; secondary ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms ; drug therapy ; metabolism ; pathology

BACKGROUNDNasopharyngeal carcinoma (NPC) is a squamous-cell carcinoma especially prevailing among the natives of southern China. The regimen of concurrent chemoradiotherapy (CCRT) that include platinum and 5-fluorouracil (5-FU) is considered to be the standard treatment for NPC. However, its clinical use is limited by its toxicity. Our purpose was to evaluate the efficacy and safety of the regimen of CCRT with taxanes and platinum versus the regimen of CCRT with 5-FU and platinum in NPC treatment.

METHODSMedline, the Cochrane library, and the Chinese medical literature database were searched for eligible studies. Meta-analysis was performed using Review Manager (Version 5.2).

RESULTSSix random controlled trials (RCTs) including 514 patients met our criteria. Meta-analysis showed that the regimen of CCRT with taxanes and platinum had an improved significant difference in complete remission (CR) and less incidence rate in adverse reactions such as gastrointestinal impairment grades III-IV, liver and kidney impairment grades I-II, and radiodermatitis grades III-IV versus the conventional regimen of CCRT with 5-FU and platinum, while the longterm effectiveness rate of overall survival, locoregional failure-free survival, or distant metastasis failure-free survival between the two groups was therapeutic equivalence.

CONCLUSIONSThe regimen of CCRT with taxanes and platinum in NPC therapy may be more efficient and safe compared to the conventional modality of 5-FU and platinum in CCRT. However, we need more high-quality studies of multi-center and randomized double-blind clinical trials to further compare, analyze, and confirm the findings.

Carcinoma ; Chemoradiotherapy ; Fluorouracil ; administration & dosage ; therapeutic use ; Humans ; Nasopharyngeal Neoplasms ; drug therapy ; Platinum ; administration & dosage ; therapeutic use ; Taxoids ; administration & dosage ; therapeutic use ; Treatment Outcome

OBJECTIVE: To study the influence of PD173074 on proliferation and apoptosis of nasopharyngeal carcinoma. METHOD: With immunoblotting and RT-PCR, FGFR1 expression was detected in CNE, PONE1 and C666-1 cell lines. With MTT assay,the time-effect and dose-effect correlation between PD173074 and inhibition of CNE proliferation was evaluated. After PD173074 stimulation, the phosphorylation level of FGFR1 and AKT was detected with immunoblotting assay. Furthermore, influence of PD173074 on the activation of Caspase3 and Caspase9 was detected to study the underlying mechanism of why PD173074 could inhibit CNE proliferation. RESULT: FGFR1 has the highest expression in CNE cell line. Under incubation of 10 nmol/L PD173074 stimulation for 36 hours to 72 hours, the phosphorylation of FGFR1 and AKT was impaired significantly, which further reduced the proliferation of CNE. Moreover, PD173074 can activate the intrinsic apoptotic pathway by stimulating Caspase9,which activated Caspase3 and induced the apoptosis. CONCLUSION PD173074 could inhibit proliferation of nasopharyngeal carcinoma cell through reducing the phosphorylation of FGFR1 and AKT. Additionally, PD173074 can induce CNE apoptosis by activating intrinsic apoptotic pathway via cleaving Caspase9 and Caspase3.
Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Carcinoma ; Caspase 3 ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms ; drug therapy ; pathology ; Pyrimidines ; pharmacology