A Novel Combined Conjugate Therapeutic Cancer Vaccine, Recombinant EGF-CRM197, in Patients With Advanced Solid Tumors: A Phase I Clinical Study.

INTRODUCTION: The therapeutic cancer vaccine recombinant Epidermal Growth Factor (EGF)-CRM197 is a novel combined conjugate EGF with CRM197 as a carrier protein. Immunization with the EGF-CRM197 vaccine can induce high levels of neutralizing anti-EGF antibodies that inhibit EGF/EGFR signaling and thereby suppress growth of tumors that rely on this signaling pathway. Herein, we characterize the humoral immune responses elicited by the recombinant EGF-CRM197 vaccine in patients with advanced solid tumors in a phase I clinical trial and assess the safety, tolerability, and immunogenicity of this vaccine (CTR20190473). METHODS: A total of 16 subjects were enrolled in this study. Under 6 + 3 design, patients in each dosing cohort were administrated subcutaneously at a dosage of 0.4 mg, 0.8 mg, and 1.6 mg, respectively. The patients received vaccinations for immune induction (once a week for 4 consecutive weeks) and booster vaccinations (once every 4 weeks). Safety evaluation was performed 1 week after the immune induction. Booster vaccination was given until the occurrence of disease progression, intolerance, withdrawal of informed consent by the patient, or negative result of anti-EGF test after two booster vaccinations. RESULTS: Vaccination with EGF-CRM197 is safe and well-tolerated in patients with advanced solid tumors. Adverse reactions at the injection site were the most common adverse events (AEs) in recipients. No severe adverse reactions post vaccination were observed in the present study. Vaccinated patients developed a robust neutralizing antibody response triggered by EGF-CRM197 that significantly reduced the levels of EGF in serum. For lung cancer patients who were super good antibody responders (sGAR) to EGF-CRM197, the median progress-free survival (PFS) was 4.83 months, significantly longer than that of the good antibody responder (GAR) patients with lung cancer whose median PFS was 2.10 months (P=0.0018). The median overall survival (OS) of GAR lung cancer patients was 10.67 months while the OS) for sGAR lung cancer patients was not reached until analysis was performed. The median follow-up of the sGAR lung cancer patients was 14.6 months. CONCLUSION: Our study demonstrates that the recombinant EGF-CRM197 therapeutic cancer vaccine can induce a good immune response in patients with advanced solid tumors and is safe and well tolerated, which ensures further clinical development of the vaccine for extending the survival time of EGF-CRM197 sensitive patients with advanced solid tumors. CLINICAL TRIAL REGISTRATION: http://www.chinadrugtrials.org.cn, identifier CTR20190473, EGF-CRM197.

Docetaxel-mediated autophagy promotes chemoresistance in castration-resistant prostate cancer cells by inhibiting STAT3.

Signal transducer and activator of transcription (STAT)3 expression is correlated with neoplasm growth, metastasis, and prognosis; it has also been implicated in the regulation of autophagy, which may in turn contribute to tumor chemoresistance. However, it is unknown whether STAT3 is involved in cancer cell survival in response to chemotherapy. In this study, we show that autophagy is triggered during chemotherapy and that inhibiting autophagy increased chemosensitivity of castration-resistant prostate cancer (CRPC) cells. Meanwhile, docetaxel induced autophagy was inhibited by STAT3 activation, which increased mitochondrial damage and decreased CRPC cell viability. These results suggest that STAT3 contributes to CRPC cell survival and chemoresistance by modulating autophagy.

Inhibition of autophagy in hepatocarcinoma cells promotes chemotherapeutic agent-induced apoptosis during nutrient deprivation.

Autophagy is a lysosome-dependent process involved in protein and organelle degradation. It has been suggested that autophagy is activated in nutrient-deficient condition and plays an important role in protecting cells from nutrient shortage. However, the effect of autophagy on chemotherapy during nutrient deficiency has been rarely researched. In the present study, we discovered that hepatocarcinoma cells exhibit chemoinsensitivity accompanied by the activation of autophagy when cultured in nutrient-deprived medium. Inhibition of autophagy by 3-methyladenine or siRNA­targeted Beclin 1 increased the nutrient deprivation­induced apoptosis and chemosensitivity in hepatocarcinoma cells. Furthermore, decreased mitochondrial mass was detected when cells underwent autophagy. The present study suggests that induction of autophagy confers a survival advantage for hepatocarcinoma cells during nutrient deprivation, not only rescuing cells from nutrient deficiency-induced cell apoptosis, but also protecting cells from chemotherapy-induced cell death. Combined usage of the inhibition of autophagy and conventional chemotherapeutic agents could be an effective therapy for hepatocarcinoma during nutrient deprivation.

Prognostic role of vascular endothelial growth factor in prostate cancer: a systematic review and meta-analysis.

The objective of this study was to perform a meta-analysis and literature review on the predictive role of vascular endothelial growth factor (VEGF) in prostate cancer. A detailed literature search was performed using PubMed and Embase databases for related research publications written in English. Methodological quality of the studies was also evaluated. Data was collected from studies comparing overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), biomedical failure (BF) and cancer-specific survival (CSS) in patients with elevated VEGF levels and those having lower levels. The hazard ratio (HR) and its 95% confidence interval (CI) were used to assess the strength of associations. A total of 12 studies (n = 1,737) were included in this meta-analysis (4 for OS, 3 for CSS, 2 for DFS, 4 for BF, and 4 for PFS). For OS, DFS and PFS, the pooled HR for VEGF was not statistically significant at 1.30 (95% CI, 0.74-2.29), 0.80 (95% CI, 0.57-1.13) and 1.04 (95% CI, 0.93-1.16), respectively. However, for CSS and BF, the pooled HR was 2.32 (95% CI, 1.20-4.46) and 1.30 (95% CI, 1.06-1.59), respectively. Our results demonstrate that VEGF may have a critical prognostic value in patients with prostatic cancer.

WITHDRAWN: Hypoxia-induced STAT3 contributes to chemoresistance and epithelial-mesenchymal transition in prostate cancer cells.

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Prognostic role of C-reactive protein in prostate cancer: a systematic review and meta-analysis.

Several studies have reported that C-reactive protein (CRP), an inflammation biomarker, may be associated with the prognosis of prostate cancer (PCa). The objective of this systematic review is to summarize the predictive role of CRP for survival in PCa as reported in previous studies. Related studies were identified, and evaluated for quality through multiple search strategies. Data was collected from studies comparing overall and cancer-specific survival (CSS) in patients with elevated CRP levels and those having lower levels. However, for progression-free survival (PFS), data were collected according to the log of CRP. The hazard ratio (HR) and its 95% confidence interval (CI) were used to assess the strength of associations. A total of nine studies (n = 1,497) were evaluated in this meta-analysis (five for overall survival (OS), four for CSS and two for PFS). For OS and PFS, the pooled HR of CRP was statistically significant at 1.51 (95% CI, 1.28-1.79) and 1.50 (95% CI, 1.25-1.81), respectively. For CSS, the pooled HR was 1.91 (95% CI, 1.36-2.69) with higher CRP expression in PCa, which strongly indicates poorer survival in PCa. This study demonstrates that CRP may have a critical prognostic value in patients with prostatic cancer.

Prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabin-based chemotherapy: a meta-analysis.

BACKGROUND: The potential prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabine-based chemotherapy is variably reported. OBJECTIVE: The objective of this study was to conduct a systematic review of literature evaluating human equilibrative nucleoside transporter1 expression as a prognostic factor in pancreatic cancer receiving gemcitabine-based chemotherapy and to conduct a subsequent meta-analysis to quantify the overall prognostic effect. METHODS: Related studies were identified and evaluated for quality through multiple search strategies. Only studies analyzing pancreatic cancer receiving gemcitabine-based chemotherapy were eligible for inclusion. Data were collected from studies comparing overall, disease-free and progression-free survival (OS, DFS and PFS) in patients with low human equilibrative nucleoside transporter1 levels and those having high levels. The hazard ratio (HR) and its 95% confidence interval (95%CI) were used to assess the strength of associations. Hazard ratios greater than 1 reflect adverse survival associated with low human equilibrative nucleoside transporter1 levels. RESULTS: A total of 12 studies (n = 875) were involved in this meta-analysis (12 for OS, 5 for DFS, 3 for PFS). For overall and disease-free survival, the pooled HRs of human equilibrative nucleoside transporter1 were significant at 2.93 (95% confidence interval [95% CI], 2.37-3.64) and 2.67 (95% CI, 1.87-3.81), respectively. For progression-free survival, the pooled HR in higher human equilibrative nucleoside transporter1 expression in pancreatic cancer receiving gemcitabine-based chemotherapy was 2.76 (95% CI, 1.76-4.34). No evidence of significant heterogeneity or publication bias was seen in any of these studies. CONCLUSION: These results support the case for a low human equilibrative nucleoside transporter1 level representing a significant and reproducible marker of adverse prognosis in pancreatic cancer receiving gemcitabine-based chemotherapy.

The association of UGT1A1*6 and UGT1A1*28 with irinotecan-induced neutropenia in Asians: a meta-analysis.

BACKGROUND: The UGT1A1*28 polymorphism is known as a biomarker of irinotecan-induced neutropenia in Caucasians. However, in Asians, the UGT1A1*28 mutation is much less frequent. METHODS: A meta-analysis was performed to assess the association of the UGT1A1*6 and UGT1A1*28 with neutropenia in Asians. RESULTS: In a combination test of the two variations, patients with severe neutropenia displayed a 155% higher mutational load than those that were not neutropenic (ORG = 2.55; 95% CI: 1.82-3.58). CONCLUSIONS: In Asians, a combination test of UGT1A1*6 and UGT1A1*28 might be a potential biomarker of irinotecan-induced neutropenia, an observation that will need additional trials for confirmation.

[Impact of NF-kappaB inhibitor on STAT3 translocation in PC-3 prostate cancer cell line].

OBJECTIVE: To observe the changes in the expressions of STAT3 and NF-KB in PC-3 cells after IL-6 stimulation and to verify the effects of the NF-KB inhibitor caffeic acid phenethyl ester (CAPE) on the expressions of p-STAT3 and IL-6 in the PC-3 prostate cancer cell line. METHODS: PC-3 prostate cancer cells were treated with IL-6 at 20 ng/ml for 5, 10, 20, 30 and 45 min. The protein and mRNA expressions of STAT3 and NF-kappaB were measured by Western blot and real time PCR, respectively, and the cell cycle was detected by flow cytometry. The PC-3 cells were exposed to TNF-alpha or TNF-alpha + CAPE, followed by determination of the IL-6 expression in the supernatant of the cells by ELISA and the expression of p-STAT3 by Western blot. RESULTS: After IL-6 stimulation, both the expression of p-STAT3 protein and the proliferation index of the PC-3 cells were significantly increased, and so were the expressions of IL-6 and p-STAT3 protein in the supernatant after TNF-alpha treatment (P < 0.05). TNF-alpha + CAPE induced statistically lower expressions of IL-6 and p-STAT3 than TNF-alpha alone (P < 0.05). CONCLUSION: CAPE can inhibit IL-6 secretion induced by TNF-alpha in PC-3 cells and thus suppress STAT3 translocation. Therefore, by inhibiting the expression of NF-kappaB and affecting STAT3 and other related cell signaling pathways, CAPE may become a new therapeutic option for prostate cancer.