Camrelizumab Plus Carboplatin and Pemetrexed as First-Line Treatment for Advanced Nonsquamous NSCLC: Extended Follow-Up of CameL Phase 3 Trial.

INTRODUCTION: In CameL phase 3 study (ClinicalTrials.gov: NCT03134872), addition of camrelizumab to first-line chemotherapy significantly improved the progression-free survival in patients with stages IIIB to IV nonsquamous NSCLC. Here, we present outcomes after a minimum follow-up of 43.9 months since last patient randomization. METHODS: Eligible patients were randomized 1:1 to 4 to 6 cycles of camrelizumab plus carboplatin and pemetrexed or chemotherapy alone every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only (n = 205 and 207, respectively). Total camrelizumab exposure was up to 2 years. RESULTS: As of January 31, 2022, camrelizumab plus chemotherapy exhibited substantially improved overall survival over chemotherapy alone (median, 27.1 versus 19.8 mo; hazard ratio = 0.72 [95% confidence interval: 0.57-0.92]). In the chemotherapy-alone group, 95 patients (45.9%) crossed over to camrelizumab monotherapy. After adjustment for crossover, the survival benefit with camrelizumab plus chemotherapy was more pronounced (adjusted hazard ratio = 0.55 [95% confidence interval: 0.42-0.71]). In camrelizumab plus chemotherapy group, 33 patients completed 2 years of camrelizumab. Objective response rate was 97.0%, with ongoing responses in 17 of the 32 responses (53.1%), and 93.9% (31 of 33) of the patients were alive at data cutoff. Safety profiles were consistent with the previous report, and no obvious evidence of cumulative toxicity was found with long exposure to camrelizumab. CONCLUSIONS: Camrelizumab plus carboplatin and pemetrexed provides long-term survival benefit over chemotherapy, with manageable toxicity and remarkable and durable response in patients receiving 2 years of camrelizumab, further supporting camrelizumab combination as first-line treatment for advanced nonsquamous NSCLC.

Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01).

PURPOSE: The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS: At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION: Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Efficacy and safety of pyrotinib in advanced lung adenocarcinoma with HER2 mutations: a multicenter, single-arm, phase II trial.

BACKGROUND: There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations. METHODS: In this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored. RESULTS: Seventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2-60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2-30.0), with median PFS of 5.6 months (95% CI, 2.8-8.4), and median OS of 10.5 months (95% CI, 8.7-12.3). The median duration of response was 9.9 months (95% CI, 6.2-13.6). All treatment-related adverse events (TRAEs) were grade 1-3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression. CONCLUSIONS: Pyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR1800020262.

Pyrotinib in Patients with HER2-Amplified Advanced Non-Small Cell Lung Cancer: A Prospective, Multicenter, Single-Arm Trial.

PURPOSE: In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with HER2-amplified non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with HER2 amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety. RESULTS: The enrolled cohort included 27 patients with HER2 amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0-69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0-9.6 months), and median OS was 12.5 months (95% CI, 8.2-16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%-40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of HER2 amplification was detected upon disease progression. CONCLUSIONS: Pyrotinib provided antitumor efficacy with a manageable safety profile in HER2-amplified patients with NSCLC.

Ensartinib in advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, two-staged, phase 1 trial.

Background: Ensartinib, a potent second-generation tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET and ROS1, was evaluated in a phase I clinical trial in patients with advanced, ALK-rearranged non-small cell lung cancer (NSCLC). Methods: Patients with advanced, ALK or ROS1-positive NSCLC were recruited from 2 centers in China. This study consisted of dose escalation and expansion stages. Patients were treated with oral ensartinib [dosage of escalation stage was from 150, 200, 225 to 250 mg per day, expansion stage was recommended phase II dose (RP2D)] in continuous 28-day cycles. The primary objectives were safety, dose limited toxicity (DLT), maximum tolerated dose (MTD), and RP2D based on tolerability. Key secondary objectives included pharmacokinetic (PK) and anti-tumor activity. Results: Forty-eight patients were enrolled, 37 (77.1%) were ALK TKI-naïve, 11 (22.9%) patients had previously received crizotinib, ceritinib or alectinib. Ensartinib was well tolerated and common treatment-related adverse events (TRAEs) included rash (87.5%), transaminase elevation (60.4%), pruritus (45.8%) and creatinine elevation (35.4%). The top 3 grade 3-5 TRAEs were rash (14.6%), elevated alanine aminotransferase (ALT) (12.5%) and aspartate transaminase (AST) (4.2%). Two DLTs were observed in 250 mg, so MTD and RP2D was 225 mg per day. Ensartinib was moderately absorbed (median Tmax: 3.00-4.00 h) and slowly eliminated (mean T1/2: 21.0-30.2 h). The area under the curve (AUC) of ensartinib reached saturation at 200 to 225 mg and no major accumulation after daily administration. For all patients, the objective response rate (ORR) and disease control rates (DCR) were 64.6 % and 81.3%, median progression-free survival (mPFS) was 16.79 months. In subgroup analysis, the ORR and mPFS was 81.3% and 45.5%, 25.73 and 4.14 months in TKI-naïve and -treated ALK+ patients, respectively. The intra-cranial ORR and mPFS for patients with measurable brain metastases were 66.7% and 22.90 months. ALK abundance may predict the efficacy of ensartinib. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed specific signaling pathways enrichment in long and short progression-free survival (PFS) groups. Conclusions: Ensartinib was well tolerated under 225 mg (MTD) and demonstrated promising anti-tumor activity in ALK+ NSCLC patients, including those with CNS metastases and those previously TKI-treated. Trial Registration: ClinicalTrials.gov NCT02959619.

Safety and efficacy of aprepitant as mono and combination therapy for the prevention of emetogenic chemotherapy-induced nausea and vomiting: post-marketing surveillance in China.

BACKGROUND: The goal of this study was to evaluate aprepitant usage in the context of routine clinical practice with dose/regimens at the discretion of prescribers for chemotherapy-induced nausea and vomiting (CINV) treatments. METHODS: In this single arm, multicenter prospective study 1,000 patients with solid malignancies were enrolled across 21 centers in China. The primary endpoint was the rate of adverse events (AEs), including drug related AEs and serious AEs (SAEs). Secondary efficacy endpoints included the proportion of patients achieving complete response (CR; no vomiting, no nausea, and no use of rescue medication) within 120 h after highly emetogenic chemotherapy, the rates of no nausea and no vomiting, as well as quality of life (QoL). Multivariable logistic regression analysis was carried out to determine factors associated with the overall (0-120 h), acute (0-24 h) and delayed (25-120 h) CR. RESULTS: Of the 1,000 highly emetogenic chemotherapy treated patients enrolled in the study ≥1 AE, ≥1 drug related AE, ≥1 SAE and drug related SAE rates in 998 patients were 45.9%, 2.5%, 4.0% and 0.1%, respectively. Approximately half of the patients (455/990, 46.0%) received aprepitant as part of a 3-drug anti-CINV regimen consistent with prescribing guidelines. The overall CR (0 to 120 h) for anti-emetic drug use was 41.0%, with an acute CR of 66.0% and a delayed CR of 46.5%. The rates of no vomiting and no nausea after solely aprepitant anti-emetic therapy from 0 to 120 h were 70.9% and 43.0%, for dual anti-emetic therapy 86.9% and 64.6%, and for triple therapy 86.4% and 69.5%, respectively. Multivariate regression analysis revealed that triple anti-emetic therapy (P=0.038), male gender (P<0.001) and a history of chemotherapy (P=0.016) were significantly associated with the overall acute CR. CONCLUSIONS: Especially as a combination treatment, aprepitant is safe and efficient for preventing CINV in patients receiving highly emetogenic chemotherapy.

Inhibition of DNA­PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC.

Lung cancer has the highest incidence and mortality rates among the malignant tumor types worldwide. Platinum­based chemotherapy is the main treatment for advanced non­small­cell lung cancer (NSCLC), and epidermal growth factor receptor­tyrosine kinase inhibitors (EGFR­TKIs) have greatly improved the survival of patients with EGFR­sensitive mutations. However, there is no standard therapy for treating patients who are EGFR­TKI resistant. Combining EGFR­TKIs and platinum­based chemotherapy is the most popular strategy in the clinical practice. However, the synergistic mechanism between EGFR­TKIs and platinum remains unknown. Therefore, the aim of the present study was to determine the synergistic mechanism of gefitinib (an EGFR­TKI) and cisplatin (a main platinum­based drug). MTT assay, apoptosis analysis, tumorsphere formation and an orthotropic xenograft mouse model were used to examine the combination effects of gefitinib and cisplatin on NSCLC. Co­immunoprecipitation and immunofluorescence were used to identify the underlying mechanism. It was found that gefitinib could selectively inhibit EGFR from entering the nucleus, decrease DNA­PK activity and enhance the cytotoxicity of cisplatin on NSCLC. Collectively, the results suggested that inhibition of DNA­dependent protein kinase by gefitinib may be due to the synergistic mechanism between gefitinib and cisplatin. Thus, the present study provides a novel insight into potential biomarkers for the selection of combination therapy of gefitinib and cisplatin.

Long-term safety of icotinib in patients with non-small cell lung cancer: a retrospective, real-world study.

BACKGROUND: Lung cancer is a global health problem with a high mortality, and the development of target therapy has led to a revolution in the treatment of lung cancer in recent years. Favorable efficacy and safety of icotinib have been demonstrated in patients with non-small cell lung cancer (NSCLC). Currently, minimal data are available to describe the long-term safety of icotinib in NSCLC patients. METHODS: We reviewed the safety data from 1,321 advanced NSCLC patients who were treated with icotinib. The primary endpoint was the long-term safety, defined as any adverse drug reactions (ADRs) occurred after 6 months of icotinib administration. RESULTS: Fewer ADRs were noticed over 6 month administration of icotinib than within 6 months in overall population (24.3% vs. 65.4%), and elderly patients (23.6% vs. 66.9%). The majority of ADRs were grade 1-2 in severity over 6 month exposure of icotinib in overall population as well as elderly patients. In overall population, the most common ADRs of icotinib during long-term use were rash (16.4%) and diarrhea (5.3%), while the incidences were 31.8% and 13.2% in the induction period, respectively. In elderly population, the most common ADRs of icotinib during long-term use were rash (15.7%) and diarrhea (4.7%), while the incidences were 27.8% and 14.9% in the induction period, respectively, and more inching was observed in the induction period as compared with long term use (6.3% vs. 0.3%). CONCLUSIONS: There was an evidence of decreased frequency of icotinib-induced ADRs over time, and icotinib was well-tolerated in elderly NSCLC patients.

MicroRNA-30a targets BECLIN-1 to inactivate autophagy and sensitizes gastrointestinal stromal tumor cells to imatinib.

Gastrointestinal stromal tumors (GISTs), the most widespread type of sarcoma, contain driver gene mutations predominantly of receptor tyrosine kinase and platelet-derived growth factor receptor alpha. However, the inevitable development of resistance to imatinib (IM) cannot be fully attributed to secondary driver gene mutations. In this study, we investigated the role of microRNA-30a in sensitization of GIST cells to IM in vivo and in vitro. Higher levels of miR-30a were detected in GIST-T1 cells, which were more sensitive to IM than GIST-882 cells. IM treatment also reduced miR-30a levels, indicating the possible role of miR-30a in GIST IM resistance. Subsequently, miR-30a was confirmed to be an IM sensitizer via a mechanism that was attributed to its involvement in the regulation of cell autophagy. The interaction of miR-30a and autophagy in IM treated GIST cells was found to be linked by beclin-1. Beclin-1 knockdown increased IM sensitivity in GIST cell lines. Finally, miR-30a was confirmed to enhance IM sensitivity of GIST cells in mouse tumor models. Our study provides evidence for the possible role of miR-30a in the emergence of secondary IM resistance in GIST patients, indicating a promising target for overcoming this chemoresistance.

Influence of different drug delivery methods for Endostar combined with a gemcitabine/cisplatin regimen in locally advanced or metastatic lung squamous cell carcinoma: A retrospective observational study.

Continuous endovenous administration of Endostar (CE) gradually replaced drip intravenous administration of Endostar (DE) in lung squamous cell carcinoma (SCC) treatment presently, but the efficacy and safety of CE and DE which is better in advanced lung SCC are yet unclear. To evaluate the feasibility of CE as an alternative to DE with gemcitabine/cisplatin (GP) chemotherapy. Data were collected from patients admitted with locally advanced or metastatic lung SCC from January 2011 to April 2015, including the patients' characteristics, the therapeutic regimen, the treatment effectiveness, and toxicity. There are 71 patients with pathologically confirmed lung SCC retrospectively assigned to a treatment (CE) group of 48 patients and a control (DE) group of 23 patients. The response of each tumor to the therapy was assessed every 2 cycles by a chest and upper abdomen computed tomography for the comparison of curative effects and adverse reactions. Compared with the DE group, the response rate and disease control rate were noninferior in the CE group. The median progression-free survival and overall survival in the CE and DE groups were no significantly difference (5.5 vs 5.5 months, P = .141; 22.9 vs 14.3 months, P = .053). Increased progression-free survival (PFS) for patients in CE group was observed across 3 subgroups analyzed. There was a 35.7% reduction in the total dose of Endostar per cycle in the CE group compared with that in the DE group. Thus, in combination with GP chemotherapy, CE could be a suitable alternative to DE in locally advanced or metastatic SCC patients, resulting in less hemoptysis, less treatment time, and lower costs.

Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer.

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 µg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC.

Intercalating and maintenance gefitinib plus chemotherapy versus chemotherapy alone in selected advanced non-small cell lung cancer with unknown EGFR status.

Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) are standard treatment for advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation. However, EGFR mutation testing is not attainable in approximately 20% of patients. The current study examined intercalating and maintaining gefitinib treatment in stage IIIB/IV non-squamous NSCLC, never or former light smoking patients with unknown EGFR mutation status. Briefly, 219 patients who achieved stable disease (SD) with gemcitabine (1250 mg/m2) plus carboplatin (5 AUC) were randomized at 1:1 ratio to continue chemotherapy (n = 110) or intercalating gefitinib (250 mg/day on days 15-25 of each cycle until disease progress (n = 109). Progression-free survival (PFS) was 9.7 vs. 4.2 month in the gefitinib vs. control arm (HR: 0.41, 95% CI: 0.31-0.56; P < 0.001). Overall survival (OS) was also longer in the gefitinib arm (20.1 vs. 15.4 months; HR: 0.68; 95% CI 0.48-0.97; P = 0.0323). Adverse events, including diarrhea, dermal reaction and thrombocytopenia, were more common in the gefitinib arm. In conclusion, intercalating and maintenance gefitinib treatment is a viable option for advanced NSCLC patients with unknown EGFR mutation status in subpopulations with high EFGR mutation rate.

Interferon-α reduces the gefitinib sensitivity of human non-small cell lung cancer.

AIM OF THE STUDY: Many studies have shown that interferon-α (IFN-α) enhances the antiproliferative effect of gefitinib in some solid tumours. We aimed to determine the effect of combining IFN-α with gefitinib in human non-small cell lung cancer (NSCLC) cell lines (A549, H1299, HCC827) with different EGFR and K-Ras gene statuses. MATERIAL AND METHODS: An MTT assay was used to assess cell proliferation. Apoptosis was detected by an Annexin V/propidium iodide assay using flow cytometry, and western blotting was used to determine the expression of epidermal growth factor receptor/phosphorylated epidermal growth factor receptor (EGFR/p-EGFR) and signal transducers and activators of transcription 3/phosphorylated signal transducers and activators of transcription 3 (STAT3/p-STAT3). RESULTS: There was an additive interaction when gefitinib was combined with IFN-α in all cell lines; however, there was antagonism when gefitinib followed IFN-α pretreatment in three cell lines. Notably, IFN-α pretreatment significantly reduced the gefitinib sensitivity of HCC827 cells. Surprisingly, while IFN-α inhibited STAT3 phosphorylation in cell lines, gefitinib could do so. CONCLUSIONS: The results might confirm the hypothesis that IFN-α induces gefitinib sensitivity of NSCLC, and IFN-α inhibits phosphorylation of STAT3, which may be dependent on EGFR signal activation playing a role in the reduction of gefitinib sensitivity after IFN-α treatment in NSCLC cell lines.

Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α.

OBJECTIVE: To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms. METHODS: Three colon cancer cell lines (RKO, LoVo, and SW480) were used as in vitro models. 5-Fluorouracil (5-FU) and oxaliplatin were used as chemotherapeutic drugs. Cell viability and apoptosis were tested to evaluate the sensitivity of colon cancer cells to chemotherapy. The transcription and expression levels of hypoxia-inducible factor-1α (HIF-1α), multidrug resistance gene 1 (MDR1), and vascular endothelial growth factors (VEGF) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting. Cycloheximide and MG132 were used to inhibit protein synthesis and degradation, respectively. In vitro tube formation assay was used to evaluate angiogenesis. RESULTS: We demonstrated the chemosensitizing effects of ursolic acid with 5-FU and oxaliplatin in three colon cancer cell lines under hypoxia. This effect was correlated to its inhibition of MDR1 through HIF-1α. Moreover, ursolic acid was capable of inhibiting HIF-1α accumulation with little effects on its constitutional expression in normoxia. In addition, ursolic acid also down-regulated VEGF and inhibited tumor angiogenesis. CONCLUSIONS: Ursolic acid exerted chemosensitizing effects in colon cancer cells under hypoxia by inhibiting HIF-1α accumulation and the subsequent expression of the MDR1 and VEGF.

Icotinib plus gemcitabine for metastatic pancreatic cancer: a case report.

A large majority of patients diagnosed with pancreatic cancer have advanced metastatic disease with unresectable malignancies. Despite treatment advances, the survival benefit from chemotherapeutic regimens and targeted drugs is limited. Moreover, their application is limited in China because of high toxicity and cost. Recently, inhibitors of epidermal growth factor receptor activity have shown promise for the treatment of solid cancers when used in combination with standard therapy. However, these drugs have not been evaluated extensively for the treatment of pancreatic cancer. Here, we report the treatment of a 64-year-old male with metastatic pancreatic cancer using a novel regimen of icotinib with gemcitabine. Marked shrinkage of the mass was observed after two treatment cycles, and partial remission was achieved. The abdominal pain was relieved. The adverse effects were tolerable and treatment cost was acceptable. This is the first reported case for the treatment of advanced pancreatic cancer with icotinib plus gemcitabine and demonstrates a promising therapeutic alternative.

Estrogen receptor-α36 is involved in pterostilbene-induced apoptosis and anti-proliferation in in vitro and in vivo breast cancer.

Pterostilbene (trans-3,5-dimethoxy-4'-hudroxystilbene) is an antioxidant primarily found in blueberries. It also inhibits breast cancer regardless of conventional estrogen receptor (ER-α66) status by inducing both caspase-dependent and caspase-independent apoptosis. However, the pterostilbene-induced apoptosis rate in ER-α66-negative breast cancer cells is much higher than that in ER-α66-positive breast cancer cells. ER-α36, a variant of ER-α66, is widely expressed in ER-α66-negative breast cancer, and its high expression mediates the resistance of ER-α66-positive breast cancer patients to tamoxifen therapy. The aim of the present study is to determine the relationship between the antiproliferation activity of pterostilbene and ER-α36 expression in breast cancer cells. Methyl-thiazolyl-tetrazolium (MTT) assay, apoptosis analysis, and an orthotropic xenograft mouse model were used to examine the effects of pterostilbene on breast cancer cells. The expressions of ER-α36 and caspase 3, the activation of ERK and Akt were also studied through RT-PCR, western blot analysis, and immunohistochemical (IHC) staining. ER-α36 knockdown was found to desensitize ER-α66-negative breast cancer cells to pterostilbene treatment both in vitro and in vivo, and high ER-α36 expression promotes pterostilbene-induced apoptosis in breast cancer cells. Western blot analysis data indicate that MAPK/ERK and PI3K/Akt signaling in breast cancer cells with high ER-α36 expression are mediated by ER-α36, and are inhibited by pterostilbene. These results suggest that ER-α36 is a therapeutic target in ER-α36-positive breast cancer, and pterostilbene is an inhibitor that targets ER-α36 in the personalized therapy against ER-α36-positive breast cancer.

Critical appraisal of the role of gefitinib in the management of locally advanced or metastatic non-small cell lung cancer.

Past studies have demonstrated that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors can significantly improve clinical outcomes in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and sensitive EGFR gene mutations. Gefitinib (Iressa(®)), the first oral EGFR tyrosine kinase inhibitor, has been shown to be more effective and better tolerated than chemotherapy either in first-line or second-line treatment for patients with advanced NSCLC harboring sensitive EGFR mutations. Conversely, among patients with wild-type EGFR, gefitinib is inferior to standard chemotherapy in both the first-line and second-line settings. Further, gefitinib is effective in patients with brain metastases because of its low molecular weight and excellent penetration of the blood-brain barrier. In this review, we summarize the current data from clinical trials with gefitinib and appraise its role in the management of locally advanced or metastatic NSCLC.

Osteopontin-enhanced hepatic metastasis of colorectal cancer cells.

Liver metastasis is a major cause of mortality from colorectal cancer (CRC). However, mechanisms underlying this process are largely unknown. Osteopontin (OPN) is a secreted phosphorylated glycoprotein that is involved in tumor migration and metastasis. The role of OPN in cancer is currently unclear. In this study, OPN mRNA was examined in tissues from CRC, adjacent normal mucosa, and liver metastatic lesions using quantitative real-time PCR analysis. The protein expression of OPN and its receptors (integrin αv and CD44 v6) was detected by using an immunohistochemical (IHC) method. The role of OPN in liver metastasis was studied in established colon cancer Colo-205 and SW-480 cell lines transfected with sense- or antisense-OPN eukaryotic expression plasmids by flow cytometry and cell adhesion assay. Fluorescence redistribution after photobleaching (FRAP) was used to study gap functional intercellular communication (GJIC) among OPN-transfected cells. It was found that OPN was highly expressed in metastatic hepatic lesions from CRC compared to primary CRC tissue and adjacent normal mucosa. The expression of OPN mRNA in tumor tissues was significantly related with the CRC stages. OPN expression was also detected in normal hepatocytes surrounding CRC metastatic lesions. Two known receptors of OPN, integrin αv and CD44v6 proteins, were strongly expressed in hepatocytes from normal liver. CRC cells with forced OPN expression exhibited increased heterotypic adhesion with endothelial cells and weakened intercellular communication. OPN plays a significant role in CRC metastasis to liver through interaction with its receptors in hepatocytes, decreased homotypic adhesion, and enhanced heterotypic adhesion.

Combination chemotherapy with paclitaxel, cisplatin and fluorouracil for patients with advanced and metastatic gastric or esophagogastric junction adenocarcinoma: a multicenter prospective study.

OBJECTIVE: To evaluate the efficacy and toxicity of the combination regimen of paclitaxel, cisplatin and 5-FU (PCF) as first-line or second-line therapy in patients with advanced gastric and esophagogastric junction (EGJ) adenocarcinoma in China. METHODS: The patients were treated with paclitaxel 150 mg/m(2) on d1; fractionated cisplatin 15 mg/m(2) and continuous infusion 5-FU 600 mg/(m(2)·d) intravenously on d1-d5 of a 21-d cycle until disease progression or unacceptable toxicities. RESULTS: Seventy-five patients have been enrolled, among which, 41 received PCF regimen as the first-line therapy (group A) and 34 received the regimen as the second-line therapy (group B) with the median age of 59 years old and Karnofsky performance status (KPS) score ≥80. Toxicities were analyzed in all 75 patients. Seventy-one patients were evaluable for efficacy. The median overall survival (mOS) was 12.0 months (95% CI: 7.9-16.2 months) in group A and 7.3 months (95% CI: 4.3-10.3 months) in group B, respectively. The median progression-free survival (mPFS) was 5.7 months (95% CI: 4.1-7.2 months) and 5.0 months (95% CI: 3.1-6.9 months), respectively. The response rate (CR+PR) was 40% (16/40; 95% CI: 24.9-56.7%) in group A and 22.6% (7/31; 95% CI: 9.6-41.1%) in group B. Major grade 3 or 4 adverse events include neutropenia (41.3%), febrile neutropenia (9.3%), nausea/anorexia (10.7%), and vomiting (5.3%). There was no treatment-related death. CONCLUSIONS: The combination chemotherapy with PCF is active and tolerable as first-line and second-line therapy in Chinese patients with advanced gastric and EGJ adenocarcinoma. The response and survival of PCF are same as those of DCF, but the tolerance is much better.

Endostar enhances the antineoplastic effects of combretastatin A4 phosphate in an osteosarcoma xenograft.

Vascular-targeting agents (VTAs) can be divided into two groups: anti-angiogenesis agents and vascular disrupting agents (VDAs). The purpose of this study was to evaluate the antineoplastic activity of a combination of the anti-angiogenesis agent, Endostar, and the VDA combretastatin, A4 phosphate (CA4P). This study is the first to evaluate the activity of this combination against tumors and the first to investigate the activity of the combination against osteosarcoma. Endostar combined with CA4P had a good anti-tumor effect with no significant toxicity, and was at least not inferior to adriamycin, which is the main drug for osteosarcoma. The use of VDAs combined with anti-angiogenic drugs can result in significantly enhanced anti-tumor effects, providing a novel approach to cancer treatment, which could effectively complement standard treatments. It is believed that this exciting new treatment has the potential to transform the management of cancer.