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1.  Primary concomitant EGFR T790M mutation predicted worse prognosis in non-small cell lung cancer patients 
OncoTargets and therapy  2014;7:513-524.
Purpose
We performed this analysis to improve the understanding of the clinicopathological characteristics and clinical outcome of non-small cell lung cancer (NSCLC) patients harboring the primary epidermal growth factor receptor (EGFR) T790M mutation along with activating EGFR mutation.
Methods
Resected tumors from 1903 NSCLC patients were analyzed for mutation in EGFR, as well as KRAS (Kirsten rat sarcoma viral oncogene homolog), BRAF (v-raf murine sarcoma viral oncogene homolog B), HER2 (human epidermal growth factor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha), and EML4 (echinoderm microtubule associated protein like 4)–ALK (anaplastic lymphoma receptor tyrosine kinase) fusion. Fluorescence in situ hybridization was performed to define EGFR and c-MET (met proto-oncogene gene amplification. Expression of PIK3CA and p-Akt (phosphorylated protein kinase B) were tested using immunohistochemistry. Clinical and pathological data, including sex, age at diagnosis, stage, tumor differentiation, smoking history, histological subtype, relapse-free and overall survival, were further analyzed.
Results
In all, 16 NSCLC patients were found to harbor primary EGFR T790M mutation, including 14 adenocarcinomas and two adenosquamous carcinomas, accounting for 2.04% of all the EGFR mutant cases and 0.84% of the total. No c-MET amplification was found to coexist with primary EGFR T790M. Fewer EGFR copy-number variations were found in samples harboring EGFR T790M mutations compared with those in patients with exon 19 deletions and L858R. Overall survival was significantly shorter for patients harboring EGFR T790M mutation than it was for patients with exon 19 deletions (logrank P=0.008). When taking patients harboring EGFR L858R or exon 19 deletions as one group, the overall survival was also significantly longer than that in patients with T790M mutation (logrank P=0.012). There was no significant difference in relapse-free survival among three subgroups of patients.
Conclusion
Our study described the clinicopathological and molecular characteristics of NSCLC patients harboring primary EGFR T790M mutations. Its value of being a predictor for worse prognosis was established. Primary EGFR T790M mutation is a rare event in NSCLC cases, but the therapeutic strategies for this subtype of patients should be precisely considered.
doi:10.2147/OTT.S60122
PMCID: PMC3979794
driver mutation; survival; clinicopathological profile; EGFR tyrosine kinase inhibitor; acquired resistance
2.  Role of capecitabine in treating metastatic colorectal cancer in Chinese patients 
OncoTargets and therapy  2014;7:501-511.
The China Food and Drug Administration approved the use of capecitabine in patients with metastatic colorectal cancer (mCRC) in 2004. This paper reviews the available information of capecitabine in Chinese patients with mCRC, focusing on its effectiveness and safety against mCRC. Identification of all eligible studies was made by searching the PubMed and Wanfang database from 2000 to 2013. Published data examining various aspects of clinical response and tolerability with capecitabine alone or in combination with other chemotherapeutic or biological agents for first- and second-line mCRC were examined. Capecitabine and its combination displayed high efficacy in Chinese patients with mCRC. Toxicities are generally manageable, and elderly patients can tolerate capecitabine well.
doi:10.2147/OTT.S38843
PMCID: PMC3979786
capecitabine; metastatic colorectal cancer; Chinese
3.  Downregulation of CD99 and upregulation of human leukocyte antigen class II promote tumor aggravation and poor survival in patients with osteosarcomas 
OncoTargets and therapy  2014;7:477-484.
Background
CD99 is involved in the intracellular transport of human leukocyte antigen class II (HLA-II) protein. The aim of this study was to clarify the clinical value of CD99 and HLA-II expression in primary osteosarcoma.
Methods
One hundred and thirty pairs of osteosarcoma and matched noncancerous bone tissues were evaluated by immunohistochemistry for CD99 and HLA-II expression.
Results
Compared with the noncancerous bone tissues, the expression levels of CD99 (tumor versus normal: 2.96±0.09 versus 5.89±1.26, P<0.001) and HLA-II (tumor versus normal: 5.01±1.39 versus 1.92±0.06, P<0.001) proteins were respectively downregulated and upregulated in osteosarcoma tissues. CD99 and HLA-II were highly expressed in 49/130 (37.69%) and 107/130 (82.31%) of osteosarcoma tissues, respectively. In addition, the osteosarcoma patients with downregulation of CD99 and upregulation of HLA-II more frequently showed the presence of metastasis and recurrence and poor response to chemotherapy. Moreover, there was a negative correlation between CD99 and HLA-II expression in osteosarcoma tissues (r=−0.69, P=0.01). The patients with low CD99 expression correlated with poor prognosis of osteosarcoma, as opposed to HLA-II. Patients with CD99-low/HLA-II-high expression had the lowest overall and disease-free survival rates, and conjoined expression of CD99/HLA-II was an independent prognostic indicator of osteosarcoma.
Conclusion
These findings suggest for the first time that CD99 downregulation or HLA-II upregulation may be an important feature of human osteosarcoma. The combined detection of CD99/HLA-II coexpression may present a predictive and prognostic indicator in osteosarcoma.
doi:10.2147/OTT.S54765
PMCID: PMC3969338
CD99; HLA-II; osteosarcoma; immunohistochemistry; prognosis
4.  Potential of antibody–drug conjugates and novel therapeutics in breast cancer management 
OncoTargets and therapy  2014;7:491-500.
Progress in the treatment of cancer over the past decade has been slow. Targeting a mutated gene of an individual patient tumor, tumor-guided agents, and the first draft of the human genome sequence have created an overenthusiasm to achieve personalized medicine. However, we now know that this effort is misleading. Extreme interpatient and intratumor heterogeneity, scarce knowledge in how genome-wide mutational landscape and epigenetic changes affect transcriptional processes, gene expression, signaling transduction networks and cell regulation, and clinical assessment of temporary efficacy of targeted drugs explain the limitations of these currently available agents. Trastuzumab and a few other monoclonal antibodies or small-molecule tyrosine kinase inhibitors (TKIs) represent an exception to this rule. By blocking ligand-binding receptor in patients with human epidermal growth factor receptor 2 (HER2) amplification and overexpression, trastuzumab added to chemotherapy in HER2-positive patients has been proven to provide significant overall survival benefit in both metastatic and adjuvant settings. Lapatinib, a small-molecule dual inhibitor (TKI) of both HER2 and EGFR (epidermal growth factor receptor) pathways, has an antitumor activity translated into progression-free survival benefit in HER2-positive metastatic patients previously treated with a taxane, an anthracycline, and trastuzumab. Despite these advances, ~25% of patients with HER2-positive breast cancer experience recurrence in the adjuvant setting, while in the metastatic setting, median survival time is 25 months. In this review, we discuss the safety, efficacy, and limitations of the trastuzumab emtansine (T-DM1) conjugate in the treatment of HER2-positive metastatic breast cancer. We also highlight Phase III randomized trials, currently underway, using either the T-DM1 conjugate or various combinations of monoclonal antibodies and TKIs. Moreover, in contrast with all these agents developed on the basis of “central dogma” of simplified reductionist transcription and single gene–phenotype linear relationship, we summarize the emerging, amazing era of next-generation, transcriptional circuitry and intracellular signaling network-based drugs guided by the latest advances in genome science and dynamics of network biology.
doi:10.2147/OTT.S34235
PMCID: PMC3969339
trastuzumab emtansine; T-DM1; HER2 disease; targeted agents; cancer; genome; monoclonal antibodies
5.  Fractionated stereotactic radiosurgery with concurrent temozolomide chemotherapy for locally recurrent glioblastoma multiforme: a prospective cohort study 
OncoTargets and therapy  2014;7:485-490.
Local recurrence represents a significant challenge in the management of patients with glioblastoma multiforme. Salvage treatment options are limited by lack of clinical efficacy. Recent studies have demonstrated a significant response rate and acceptable toxicity with the use of fractionated stereotactic radiosurgery in this patient population. Our primary objective was to determine the efficacy and toxicity of fractionated stereotactic radiosurgery combined with concurrent temozolomide chemotherapy as a salvage treatment for recurrent glioblastoma multiforme. We prospectively collected treatment and outcome data for patients having fractionated stereotactic radiosurgery for locally recurrent glioblastoma multiforme after radical radiotherapy. Eligible patients had a maximum recurrence diameter of 60 mm without causing significant mass effect. The gross tumor volume was defined as the enhancing lesion on an enhanced fine-slice T1 (spin–lattice) magnetic resonance imaging, and a circumferential setup margin of 1 mm was used to define the planning target volume. All patients were treated using robotic radiosurgery with three dose/fractionation schedules ranging from 25 to 35 Gy in five fractions, depending on the maximum tumor diameter. Concurrent temozolomide 75 mg/m2 was prescribed to all patients. Tumor response was judged using the Macdonald criteria, and toxicity was assessed using the CTCAE (Common Terminology Criteria for Adverse Events). A total of 31 patients were enrolled in this study. The median overall survival was 9 months, and progression-free survival was 7 months. The 6-month progression-free survival was 60% with a 95% confidence interval of 43%–77%. The a priori stratification factor of small tumor diameter was shown to predict overall survival, while time to recurrence was not predictive of progression-free or overall survival. Three patients experienced grade 3 acute toxicity that responded to increased steroid dosing. One patient experienced a grade 4 acute toxicity that did not respond to increased steroids but did respond to anti-angiogenic therapy. Fractionated stereotactic radiosurgery with concurrent temozolomide has shown good short-term clinical and radiologic control with manageable acute toxicity. This regimen appears to provide superior efficacy to either temozolomide or fractionated radiosurgery alone. The results of this study support the continued evaluation of this regimen.
doi:10.2147/OTT.S60358
PMCID: PMC3969344
GBM; re-treatment; brain tumor; anti-angiogenic therapy
6.  Retreatment with bevacizumab in patients with gynecologic malignancy is associated with clinical response and does not increase morbidity 
OncoTargets and therapy  2014;7:469-476.
Purpose
Bevacizumab (Bev) is associated with improved progression-free survival in advanced epithelial ovarian cancer. The use of Bev in patients with gynecologic malignancy is increasing; however, little is known about cumulative toxicity and response in patients retreated with Bev. Our goal was to determine cumulative side effects and response in patients retreated with Bev.
Patients and methods
Women with recurrent gynecologic malignancy treated with Bev between January 2007 and March 2012 at a single institution were identified, including a subset who received Bev in a subsequent regimen. The primary outcome was Bev-associated toxicity, and the secondary outcome was response.
Results
Of 83 patients that received Bev for recurrent disease, 23 were retreated with Bev and four received Bev maintenance. Three patients (13%) developed grade 3 or 4 hypertension; all had a history of chronic hypertension. One (4.3%) patient developed grade 3 proteinuria, and one (4.3%) developed an enterovaginal fistula. Four patients discontinued Bev secondary to toxicity. Toxicity was not related to the cumulative number of cycles. Twenty-six percent of patients responded to Bev retreatment. On univariate analysis, there was a significant (P=0.003) overall survival advantage when the Bev-free interval was >9 months (95% confidence interval [CI] 4.9–43.7) compared to ≤9 months (95% CI 2.1–11.5), 24.3 months, and 6.8 months.
Conclusion
Retreatment of patients with recurrent gynecologic malignancy with Bev did not increase morbidity and was associated with treatment response. Physicians treating women with recurrent disease may consider a Bev-containing regimen even if prior regimen(s) included Bev. Future studies should prospectively evaluate the efficacy of this treatment strategy.
doi:10.2147/OTT.S57425
PMCID: PMC3968081
bevacizumab; gynecologic malignancy; cumulative toxicity; treatment response
7.  Clusterin: a key player in cancer chemoresistance and its inhibition 
OncoTargets and therapy  2014;7:447-456.
Clusterin is a heterodimeric disulfide-linked glycoprotein (449 amino acids) isolated in the rat prostate after castration. It is widely distributed in different tissues and highly conserved in species. There are two isoforms (1 and 2) with antagonistic actions regarding apoptosis. Clusterin is implicated in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement cascade, representing a truly multifunctional protein. Isoform 2 is overexpressed under cellular stress conditions and protects cells from apoptosis by impeding Bax actions on the mitochondrial membrane and exerts other protumor activities, like phosphatidylinositol 3-kinase/protein kinase B pathway activation, modulation of extracellular signal-regulated kinase 1/2 signaling and matrix metallopeptidase-9 expression, increased angiogenesis, modulation of the nuclear factor kappa B pathway, among others. Its overexpression should be considered as a nonspecific cellular response to a wide variety of tissue insults like cytotoxic chemotherapy, radiation, excess of free oxygen radicals, androgen or estrogen deprivation, etc. A review of the recent literature strongly suggests potential roles for custirsen in particular, and proapoptosis treatments in general, as novel modalities in cancer management. Inhibition of clusterin is known to increase the cytotoxic effects of chemotherapeutic agents, and custirsen, a second-generation antisense oligonucleotide that blocks clusterin, is being tested in a Phase III clinical trial after successful results were achieved in Phase II studies. A major issue in cancer evolution that remains unanswered is whether clusterin represents a driving force of tumorigenesis or a late phenomenon after chemotherapy. This review presents preclinical data that encourages trials in various types of cancer other than advanced castration-resistance prostate cancer and discusses briefly the appropriate timing for clusterin inhibition in the clinical context.
doi:10.2147/OTT.S58622
PMCID: PMC3964162  PMID: 24672247
custirsen; apoptosis; renal cell carcinoma; triple negative breast cancer; castration-resistance prostate cancer
8.  Oncogene mutational profile in nasopharyngeal carcinoma 
OncoTargets and therapy  2014;7:457-467.
Nasopharyngeal carcinoma (NPC) is a common tumor in Southern China, but the oncogene mutational status of NPC patients has not been clarified. Using time-of-flight mass spectrometry, 238 mutation hotspots in 19 oncogenes were examined in 123 NPC patients. The relationships between mutational status and clinical data were assessed with a χ2 or Fisher’s exact test. Survival analysis was performed using the Kaplan–Meier method with the log-rank test. In 123 patients, 21 (17.1%) NPC tumors were positive for mutations in eight oncogenes: six patients had PIK3CA mutations (4.9%), five NRAS mutations (4.1%), four KIT mutations (3.3%), two PDGFRA mutations (1.6%), two ABL mutations (1.6%), and one with simultaneous mutations in HRAS, EGFR, and BRAF (1%). Patients with mutations were more likely to relapse or develop metastasis than those with wild-type alleles (P=0.019). No differences or correlations were found in other clinical characteristics or in patient survival. No mutations were detected in oncogenes AKT1, AKT2, CDK, ERBB2, FGFR1, FGFR3, FLT3, JAK2, KRAS, MET, and RET. These results demonstrate an association between NPC and mutations in NRAS, KIT, PIK3CA, PDGFRA, and ABL, which are associated with patient relapse and metastasis.
doi:10.2147/OTT.S58791
PMCID: PMC3964172  PMID: 24672248
NPC; oncogene; mutation
9.  Gastrointestinal tract metastasis from tubulolobular carcinoma of the breast: a case report and review of the literature 
OncoTargets and therapy  2014;7:435-440.
Metastasis of breast cancer into the gastrointestinal tract happens rarely. The diagnosis of this kind of disease is difficult because of the nonspecific symptoms and the long interval between primary manifestations and recurrence. Awareness of this condition may lead to an accurate diagnosis and an earlier initiation of systemic treatment, thus avoiding unnecessary surgical intervention. In this paper, we report a rare case of a patient with tubulolobular carcinoma metastases to the colon, presenting with abdominal pain, discomfort, and weight loss. The patient underwent radical mastectomy and received postoperative radiotherapy and chemotherapy. Ten years later, she presented with gastrointestinal tract symptoms. Surgery combined with systemic treatment was chosen for the colon lesion. Immunohistochemical staining suggested a breast origin. The patient was still living 24 months after the diagnosis of the metastasis. This is the fourth case report in our literature review.
doi:10.2147/OTT.S57831
PMCID: PMC3964157  PMID: 24672246
breast cancer; tubulolobular carcinoma; metastasis; gastrointestinal tract
10.  Cancer cell-oriented migration of mesenchymal stem cells engineered with an anticancer gene (PTEN): an imaging demonstration 
OncoTargets and therapy  2014;7:441-446.
Background
Mesenchymal stem cells (MSCs) have been considered to hold great potential as ideal carriers for the delivery of anticancer agents since the discovery of their tumor tropism. This study was performed to demonstrate the effects of phosphatase and tensin homolog (PTEN) engineering on MSCs’ capacity for cancer cell-oriented migration.
Methods
MSCs were engineered with a PTEN-bearing plasmid and the expression was confirmed with Western blotting. A human glioma cell line (DBTRG) was used as the target cell; DBTRG cell-oriented migration of MSCs was monitored with a micro speed photographic system.
Results
The expression of transfected PTEN in MSCs was identified by immunoblotting analysis and confirmed with cell viability assessment of target cells. The DBTRG cell-oriented migration of PTEN-engineered MSCs was demonstrated by a real-time dynamic monitoring system, and a phagocytosis-like action of MSCs was also observed.
Conclusion
MSCs maintained their capacity for cancer cell-directed migration after they were engineered with anticancer genes. This study provides the first direct evidence of MSCs’ tropism post-anticancer gene engineering.
doi:10.2147/OTT.S59227
PMCID: PMC3962313  PMID: 24669193
gene therapy; mesenchymal stem cells; phosphatase and tensin homolog; cancer
12.  Additive effect by combination of Akt inhibitor, MK-2206, and PDGFR inhibitor, tyrphostin AG 1296, in suppressing anaplastic thyroid carcinoma cell viability and motility 
OncoTargets and therapy  2014;7:425-432.
The phosphatidylinositol-3-kinase/Akt pathway and receptor tyrosine kinases regulate many tumorigenesis related cellular processes including cell metabolism, cell survival, cell motility, and angiogenesis. Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid cancer with no effective systemic therapy. It has been shown that Akt activation is associated with tumor progression in ATC. Here we observed the additive effect between an Akt inhibitor (MK-2206) and a novel platelet-derived growth factor receptor inhibitor (tyrphostin AG 1296) in ATC therapy. We found an additive effect between MK-2206 and tyrphostin AG 1296 in suppressing ATC cell viability. The combination of MK-2206 and tyrphostin AG 1296 induces additive apoptosis, additive suppression of the Akt signaling pathway, as well as additive inhibition of cell migration and invasion of ATC cells. Furthermore, the combination of MK-2206 and tyrphostin AG 1296 induced additive suppression of ATC tumor growth in vivo. In summary, our studies suggest that the combination of Akt and receptor tyrosine kinase inhibitors may be an efficient therapeutic strategy for ATC treatment, which might shed new light on ATC therapy.
doi:10.2147/OTT.S57324
PMCID: PMC3961587  PMID: 24665203
anaplastic thyroid carcinoma; Akt inhibitor; PDGFR inhibitor; synergy; additive effect; viability; motility
13.  A rehabilitation program for lung cancer patients during postthoracotomy chemotherapy 
OncoTargets and therapy  2014;7:415-423.
Objective
The objective of this pilot study was to describe the effects of a 16-week home-based rehabilitative exercise program on cancer-related fatigue (CRF), other symptoms, functional status, and quality of life (QOL) for patients with non-small cell lung cancer (NSCLC) after thoracotomy starting within days after hospital discharge and continuing through the initiation and completion of chemotherapy.
Materials and methods
Five patients with NSCLC completed the Brief Fatigue Inventory (measuring CRF severity) and the MD Anderson Symptom Inventory (measuring symptom severity) before and after thoractomy, and at the end of each week of the 16-week exercise program. Additionally, the Medical Outcomes Study Short Form-36 (measuring physical and mental functional status) and the Quality of Life Index (measuring QOL) were completed before and after thoracotomy, after weeks 3, 6, 12, and 16 (the end of the exercise program). Further, the 6-minute walk test (measuring functional capacity) was administered before thoracotomy, prior to the initiation of chemotherapy and/or radiation therapy, and at the end of the 16-week exercise program, after completion of chemotherapy.
Results
Participants had a mean age of 63 years and a mean of five comorbid conditions; the exercise program was initiated within 4 days after hospital discharge. Participants’ CRF severity scores were reduced to mild levels, while the mean number of symptoms decreased from 9 postthoracotomy to 6 after the exercise program, with mean levels of severity and interference decreasing to below prethoracotomy levels. Likewise, participants’ functional status and QOL after completing the exercise program improved to near or above prethoracotomy levels.
Conclusion
The home-based, light-intensity exercise program for NSCLC patients receiving and completing adjuvant chemotherapy postthoracotomy showed promising trends in improving CRF severity, other symptom severity, functional status, and QOL. Further testing via a two-arm randomized controlled trial is being conducted.
doi:10.2147/OTT.S57262
PMCID: PMC3956688  PMID: 24648745
lung cancer; exercise; cancer-related fatigue; symptoms; functional status; quality of life
14.  Clinical effectiveness, toxicity, and failure patterns of helical tomotherapy for postoperative oral cavity cancer patients 
OncoTargets and therapy  2014;7:405-414.
Background
The outcome of postoperative high- and intermediate-risk oral cavity cancer (OCC) patients receiving helical tomotherapy (HT) remains limited.
Materials and methods
Between November 2006 and November 2012, 53 postoperative high- and intermediate-risk OCC patients treated with HT were enrolled.
Results
The 4-year locoregional, local, and regional control rates were 66%, 76.4%, and 94.3%, respectively. The 4-year locoregional control rates of oral tongue and buccal mucosa cancer were 88.3% and 37.1%, respectively (P=0.012). Eleven (20.8%) patients experienced locoregional failure. In-field failure occurred in six of 53 (11.3%) in the primary area and three of 53 (5.7%) in the regional lymph-node area. No marginal failure was noted. Two of 53 (3.8%) experienced out-of-field failure. The rates of grade 3 dermatitis, mucositis, and dysphagia were 11%, 34%, and 13%, respectively. No grade 3 xerostomia was noted. Grade 2 xerostomia was 33% at month 6 and declined to 0 at month 48. A rate of 56% of grade 2 trismus at month 6 was noted, and declined to around 30% after 2 years. No grade 3 trismus was noted after 2 years.
Conclusion
HT as a postoperative modality provided satisfying results, especially for xerostomia and trismus, and was impressive in high- and intermediate-risk OCC patients receiving postoperative HT.
doi:10.2147/OTT.S59998
PMCID: PMC3956740  PMID: 24648744
concurrent chemoradiation; helical tomotherapy; locoregional control rate; oral cavity cancer; trismus
15.  Clinical efficacy and safety of imatinib in the management of Ph+ chronic myeloid or acute lymphoblastic leukemia in Chinese patients 
OncoTargets and therapy  2014;7:395-404.
Imatinib mesylate is considered the standard first-line systemic treatment for patients with chronic myeloid leukemia (CML) and functions by targeting BCR-ABL tyrosine kinases. Imatinib has substantially changed the clinical management and improved the prognosis of CML and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL). Here, we review the pharmacology, mode of action, and pharmacokinetics of imatinib; Chinese efficacy studies in CML and Ph+ ALL; safety and tolerability; patient-focused perspectives, such as quality of life, patient satisfaction, acceptability, and adherence; and uptake of imatinib.
doi:10.2147/OTT.S38846
PMCID: PMC3949731  PMID: 24623982
imatinib; Philadelphia chromosome-positive acute lymphocytic leukemia; chronic myeloid leukemia; safety; clinical efficacy
16.  The predictive role of pretreatment epidermal growth factor receptor T790M mutation on the progression-free survival of tyrosine-kinase inhibitor-treated non-small cell lung cancer patients: a meta-analysis 
OncoTargets and therapy  2014;7:387-393.
Purpose
Subclones bearing the epidermal growth factor receptor (EGFR) T790M mutation concomitant with deletional mutation in exon 19 (Del19) or a point mutation in exon 21 (L858R) have been reported in non-small cell lung cancer patients before any EGFR tyrosine-kinase inhibitor (TKI) treatment. The effect of pretreatment T790M mutation on the survival of patients with both mutations treated with EGFR TKI is still being debated.
Methods
A meta-analysis was undertaken to pool eligible trials to better elucidate whether pretreatment T790M mutation predicts a poorer outcome of EGFR TKI treatment. Hazard ratios and their 95% confidence intervals for progression-free survival (PFS) were extracted and used under the random-effects model.
Results
A total of 246 patients with activating EGFR mutation such as Del19 or L858R participated in four selected trials from 350 articles. The overall incidence of patients with pretreatment T790M mutation was 43.10% (106/246), ranging from 34.88% to 80.00% in the individual trials. The combined hazard ratio for PFS in all four eligible studies was 2.602 (95% confidence interval 1.011–6.695; P=0.047), indicating a shorter PFS in patients who had the T790M mutation before receiving EGFR TKI treatment. Heterogeneity testing indicated significant heterogeneity but the absence of publication bias.
Conclusion
The meta-analysis reported here found that pretreatment T790M mutation had a negative impact on the PFS of non-small cell lung cancer patients with a Del19 or L858R EGFR mutation who received EGFR TKI treatment.
doi:10.2147/OTT.S58870
PMCID: PMC3949752  PMID: 24623981
EGFR; primary resistance; TKI; Del19; L858R; prediction
17.  Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer 
OncoTargets and therapy  2014;7:375-385.
The fusion of echinoderm microtubule-associated protein-like 4 with anaplastic lymphoma kinase (ALK) was identified as a transforming gene for lung cancer in 2007. This genetic rearrangement accounts for 2%–5% of non-small-cell lung cancer (NSCLC) cases, occurring predominantly in younger individuals with adenocarcinoma who are never- or light smokers. A small-molecule tyrosine-kinase inhibitor of ALK, crizotinib, was rapidly approved by the US Food and Drug Administration on the basis of its pronounced clinical activity in patients with ALK rearrangement-positive NSCLC. Next-generation ALK inhibitors, such as alectinib, LDK378, and AP26113, are also being developed in ongoing clinical trials. In addition, the improvement and validation of methods for the detection of ALK rearrangement in NSCLC patients will be key to the optimal clinical use of ALK inhibitors. We here summarize recent progress in the development of new ALK inhibitors and in the molecular diagnosis of ALK rearrangement-positive NSCLC.
doi:10.2147/OTT.S38868
PMCID: PMC3949762  PMID: 24623980
ALK; rearrangement; NSCLC; ALK inhibitor; targeted therapy; diagnosis
18.  Clinical impact of targeted therapies in patients with metastatic clear-cell renal cell carcinoma 
OncoTargets and therapy  2014;7:365-374.
Introduction
The aim of this retrospective clinical study was to assess, in the context of the recent evolution of systemic therapies, the potential effect of targeted therapies on overall survival (OS) of patients with metastatic clear-cell renal cell carcinoma (mccRCC) in daily practice.
Patients and methods
All consecutive patients with histologically confirmed mccRCC who received systemic therapy between January 2000 and December 2010 in two oncology treatment centers in our Franche-Comté region in eastern France were included in the analysis. The primary end point was OS. The analysis of prognostic factors was performed using a two-step approach: univariate then multivariate analysis with a stepwise Cox proportional hazards regression model.
Results
For the entire cohort of 111 patients, the median OS was 17 months (95% confidence interval [CI]; 13–22 months) and the two-year OS was 39%. Three prognostic factors were independent predictors of long survival: prior nephrectomy (hazard ratio =0.38 [0.22–0.64], P<0.0001); systemic therapy by targeted therapy (hazard ratio =0.50 [0.31–0.80], P=0.005); and lack of liver metastasis (hazard ratio =0.43 [0.22–0.82], P=0.002). Median OS was 21 months [14–29 months] for patients who received at least one targeted therapy compared with 12 months [7–15 months] for patients who were treated only by immunotherapy agents (P=0.003).
Conclusion
Our results suggest that targeted therapies are associated with improved OS in comparison with cytokines, which is in line with other publications.
doi:10.2147/OTT.S56370
PMCID: PMC3942215  PMID: 24600236
angiogenesis; immunotherapy; metastatic renal cell carcinoma; mTOR; survival; targeted therapy
19.  Cyclooxygenase-2 inhibitor is a robust enhancer of anticancer agents against hepatocellular carcinoma multicellular spheroids 
OncoTargets and therapy  2014;7:353-363.
Purpose
Celecoxib, an inhibitor of cyclooxygenase-2 (COX2), was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs), as well as elucidate the underlying mechanisms.
Methods
The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway.
Results
MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 μmol/L) plus 5-fluorouracil (8.1 × 10−3 g/L) or sorafenib (4.4 μmol/L) increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR) and phosphorylated (p)-AKT expression. Gefitinib (5 μmol/L), which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 μmol/L) plus celecoxib (21.8 μmol/L) increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited.
Conclusion
Celecoxib combined with 5-fluorouracil or sorafenib or gefitinib may be superior to single-agent therapy in HepG2 MCSs. Our results provided molecular evidence to support celecoxib combination-treatment strategies for patients with human hepatocellular carcinoma. MCSs provided a good model to evaluate the interaction of anticancer drugs.
doi:10.2147/OTT.S56115
PMCID: PMC3938498  PMID: 24591842
hepatocellular carcinoma; celecoxib; multicellular spheroids; 5-fluorouracil; sorafenib; gefitinib
20.  Isotype-specific inhibition of the phosphatidylinositol-3-kinase pathway in hematologic malignancies 
OncoTargets and therapy  2014;7:333-342.
In the last decade, the advent of biological targeted therapies has revolutionized the management of several types of cancer, especially in the realm of hematologic malignancies. One of these pathways, and the center of this review, is the phosphatidylinositol-3-kinase (PI3K) pathway. The PI3K pathway seems to play an important role in the pathogenesis and survival advantage in hematologic malignancies, such as leukemia, lymphoma, and myeloma. The objectives of the present review, hence, are to describe the current knowledge on the PI3K pathway and its isoforms, and to summarize preclinical and clinical studies using PI3K inhibitors, focusing on the advances made in hematologic malignancies.
doi:10.2147/OTT.S34641
PMCID: PMC3937185  PMID: 24591840
phosphatidylinositol-3-kinase pathway; inhibitors; leukemia; lymphoma; myeloma
21.  ABCC4 is required for cell proliferation and tumorigenesis in non-small cell lung cancer 
OncoTargets and therapy  2014;7:343-351.
Background
Multidrug resistance protein 4 (MRP4), also known as ATP-cassette binding protein 4 (ABCC4), is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, which are capable of pumping a wide variety of drugs out of the cell. However, little is known about the function of ABCC4 in the proliferation of lung cancer cells.
Methods
ABCC4 mRNA and protein levels in lung cancer cell lines were measured by real-time polymerase chain reaction and Western blot, respectively. A lentivirus-mediated RNA interference technique was used to inhibit ABCC4 mRNA expression in A549 and 801D cells. The function of ABCC4 in cell growth was investigated by MTS and colony formation assays. The role of ABCC4 in cell cycle progression was evaluated by flow cytometry and Western blot analysis. ABCC4 mRNA levels in 30 pairs of tumors and corresponding matched adjacent normal tissues from non-small cell lung cancer patients were detected by real-time polymerase chain reaction.
Results
ABCC4 was highly expressed in lung cancer cell lines. ABCC4 expression was markedly downregulated in A549 and 801D cells using the RNA interference technique. Suppression of ABCC4 expression inhibited cell growth. The percentage of cells in G1 phase was increased when ABCC4 expression was suppressed. Phosphorylation of retinoblastoma protein was weakened, originating in the downregulation of ABCC4. ABCC4 mRNA was highly expressed in lung cancer tissue and lung cancer cell lines.
Conclusion
ABCC4 may play an important role in the control of A549 and 801D cell growth. ABCC4 is a potential target for lung cancer therapy.
doi:10.2147/OTT.S56029
PMCID: PMC3937249  PMID: 24591841
ABCC4; cell proliferation; lung cancer; cell cycle
22.  miR-7 inhibits colorectal cancer cell proliferation and induces apoptosis by targeting XRCC2 
OncoTargets and therapy  2014;7:325-332.
Background
Analysis using publicly available algorithms predicts that X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2), a key component in the homologous recombination repair pathway, is a potential target of micro-ribonucleic acid-7 (miR-7). Some studies have shown that both miR-7 and XRCC2 are associated with cancer development. For this purpose, we searched for the possible relationship between miR-7 and XRCC2 in the development of colorectal cancer (CRC).
Methods
miR-7 expression was assessed in CRC specimens and cell lines using real-time polymerase chain reaction (PCR). Luciferase reporter assay was used to confirm the target associations. The effect of miR-7 on cell proliferation and apoptosis was confirmed in vitro by the methylthiazol tetrazolium (MTT) assay, colony formation assay, and flow cytometry. Gene and protein expression were examined using real time PCR and western blotting, respectively.
Results
miR-7 was downregulated in CRC specimens and cell lines, and targeted the 3′ untranslated region of XRCC2. miR-7 overexpression reduced cyclin D1 expression and increased p21, caspase-3, and BAX expression, which subsequently inhibited CRC cell proliferation and induced CRC cell apoptosis. However, XRCC2 can repress the inhibitory effects of miR-7 on proliferation.
Conclusion
Our findings suggest that miR-7 plays a protective role by inhibiting proliferation and increasing apoptosis of CRC cells. It may identify new targets for anti-cancer treatment.
doi:10.2147/OTT.S59364
PMCID: PMC3933726  PMID: 24570594
MiRNA; DNA; overexpression; downregulated
23.  Ipilimumab in the treatment of metastatic melanoma: management of adverse events 
OncoTargets and therapy  2014;7:203-209.
Recently, “ipilimumab,” an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, has been demonstrated to improve overall survival in metastatic melanoma. “CTLA-4” is an immune-checkpoint molecule that downregulates pathways of T-cell activation. Ipilimumab, by targeting CTLA-4, is able to remove the CTLA-4 inhibitory signal, allowing the immune system to react to cancer cells. Due to its immune-based mechanism of action, ipilimumab causes the inhibition of CTLA-4-mediated immunomodulatory effects, the enhancement of antitumor specific immune response mediated by the weakening of self-tolerance mechanisms while exacerbating the development of autoimmune diseases and immune-related adverse events, including dermatitis, hepatitis, enterocolitis, hypophysitis, and uveitis.
doi:10.2147/OTT.S57335
PMCID: PMC3933725  PMID: 24570590
melanoma; T-cells; CTLA-4; autoimmunity; adverse events
24.  Synergism from the combination of ulinastatin and curcumin offers greater inhibition against colorectal cancer liver metastases via modulating matrix metalloproteinase-9 and E-cadherin expression 
OncoTargets and therapy  2014;7:305-314.
Liver metastasis is a major cause of mortality in colorectal cancer (CRC). The current study was to investigate the ability of ulinastatin (UTI) and curcumin (CUR) to inhibit CRC liver metastases via modulating matrix metalloproteinase-9 (MMP-9) and E-cadherin expression. Human CRC HCT-116 cells were treated with compounds individually and in combination in order to understand the effect on cell migration and invasion. The HCT-116 cell line was established to stably express luciferase and green fluorescent protein (GFP) by lentiviral transduction (HCT-116-Luc-GFP). We identified an anti-metastasis effect of UTI and CUR on a CRC liver metastasis mouse model. Tumor development and therapeutic responses were dynamically tracked by bioluminescence imaging. Expression of MMP-9 and E-cadherin in metastatic tumors was detected by immunohistochemical assay. Results of wound healing and cell invasion assays suggest that treatment with UTI, CUR, and UTI plus CUR, respectively, significantly inhibit HCT-116 cell migration and invasion. Furthermore, results of CRC hepatic metastasis on a nude mouse model showed that treatment with UTI, CUR alone, and a combination notably inhibited hepatic metastases from CRC and prolonged survival of tumor-bearing mice, especially in the UTI plus CUR group. These results suggest that the combination of UTI and CUR together may offer greater inhibition against metastasis of CRC.
doi:10.2147/OTT.S57126
PMCID: PMC3933719  PMID: 24570592
hepatic metastasis; bioluminescence imaging; therapy
25.  Recent advances in the ARID family: focusing on roles in human cancer 
OncoTargets and therapy  2014;7:315-324.
The human AT-rich interaction domain (ARID) family contains seven subfamilies and 15 members characterized by having an ARID. Members of the ARID family have the ability to regulate transcription and are involved in cell differentiation and proliferation. Accumulating evidence suggests that ARID family members are involved in cancer-related signaling pathways, highly mutated or differentially expressed in tumor tissues, and act as predictive factors for cancer prognosis or therapeutic outcome. Here we review the molecular biology and clinical studies concerned with the role played by the ARID family in cancer. This may contribute to our understanding of the initiation and progression of cancer from a novel point of view, as well as providing potential targets for cancer therapy.
doi:10.2147/OTT.S57023
PMCID: PMC3933769  PMID: 24570593
AT-rich interaction domain; human cancer; cancer-related signaling pathway; therapy; potential targets

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