Showing papers in "OncoTargets and Therapy in 2016"

PD-L1 expression in human cancers and its association with clinical outcomes

Abstract: PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors. Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial. Blocking antibodies that target PD-1 and PD-L1 have achieved remarkable response rates in cancer patients who have PD-L1-overexpressing tumors. However, using PD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the low accuracy of PD-L1 immunohistochemistry staining. Factors that affect the accuracy of PD-L1 immunohistochemistry staining are as follows. First, antibodies used in different studies have different sensitivity. Second, in different studies, the cut-off value of PD-L1 staining positivity is different. Third, PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining. Therefore, better understanding of tumor microenvironment and use of other biomarkers such as gene marker and combined index are necessary to better identify patients who will benefit from PD-1/PD-L1 checkpoint blockade therapy.

PI3K inhibitors as new cancer therapeutics: implications for clinical trial design

Abstract: The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described.

Quality of life of patients with lung cancer.

Abstract: Lung cancer is the major cause of oncologic-related death worldwide. Due to delayed diagnosis, 5-year survival rate accounts for only 15%. Treatment includes surgery, adjuvant chemotherapy, and radiation therapy; however, it is burdened by many side effects. Progress of the disease, severity of its symptoms, and side effects decrease significantly the quality of life (QoL) in those patients. The level of self-assessed QoL helps in predicting survival, which is especially important among patients receiving palliative care. Patients assess their functioning in five dimensions (physical, psychological, cognitive, social, and life roles), severity of symptoms, financial problems, and overall QoL. The QoL in lung cancer patients is lower than in healthy population and patients suffering from other malignancies. It is affected by the severity and the number of symptoms such as fatigue, loss of appetite, dyspnea, cough, pain, and blood in sputum, which are specific for lung tumors. Fatigue and respiratory problems reduce psychological dimension of QoL, while sleep problems reduce cognitive functioning. Physical dimension (related to growing disability) decreases in most of the patients. Also, most of them are unable to play their family and social roles. The disease is a frequent reason of irritation, distress, and depression. Management of the disease symptoms may improve QoL. Controlling the level of fatigue, pulmonary rehabilitation, and social and spiritual support are recommended. Early introduction of tailored palliative treatment is a strategy of choice for improvement of QoL in lung cancer patients.

Next-generation sequencing: advances and applications in cancer diagnosis.

Abstract: Technological advances have led to the introduction of next-generation sequencing (NGS) platforms in cancer investigation. NGS allows massive parallel sequencing that affords maximal tumor genomic assessment. NGS approaches are different, and concern DNA and RNA analysis. DNA sequencing includes whole-genome, whole-exome, and targeted sequencing, which focuses on a selection of genes of interest for a specific disease. RNA sequencing facilitates the detection of alternative gene-spliced transcripts, posttranscriptional modifications, gene fusion, mutations/single-nucleotide polymorphisms, small and long noncoding RNAs, and changes in gene expression. Most applications are in the cancer research field, but lately NGS technology has been revolutionizing cancer molecular diagnostics, due to the many advantages it offers compared to traditional methods. There is greater knowledge on solid cancer diagnostics, and recent interest has been shown also in the field of hematologic cancer. In this review, we report the latest data on NGS diagnostic/predictive clinical applications in solid and hematologic cancers. Moreover, since the amount of NGS data produced is very large and their interpretation is very complex, we briefly discuss two bioinformatic aspects, variant-calling accuracy and copy-number variation detection, which are gaining a lot of importance in cancer-diagnostic assessment.

Comprehensive profile of differentially expressed circular RNAs reveals that hsa_circ_0000069 is upregulated and promotes cell proliferation, migration, and invasion in colorectal cancer

Abstract: BACKGROUND Nowadays, despite great progress in cancer research, the detailed mechanisms of colorectal cancer (CRC) are still poorly understood. Circular RNAs (circRNAs), a new star of the non-coding RNA network, have been identified as critical regulators in various cancers, including CRC. METHODS AND RESULTS In this study, by using unsupervised hierarchical clustering analysis, a novel dysregulated circRNA, hsa_circ_0000069, was found. The expression of hsa_circ_0000069 was measured in 30 paired CRC tissues and adjacent noncancerous tissues using quantitative polymerase chain reaction. A high expression of hsa_circ_0000069 was observed in CRC tissues and correlated with patients' age and tumor, node, metastasis (TNM) stage (P<0.05). Furthermore, by using specifically designed siRNAs in CRC cells, a functional analysis was performed which revealed that hsa_circ_0000069 knockdown could notably inhibit cell proliferation, migration, and invasion, and induce G0/G1 phase arrest of cell cycle in vitro. CONCLUSION This study's findings are the first to demonstrate that hsa_circ_0000069, an important regulator in cancer progression, could be a promising target in the diagnosis and therapy in colorectal cancer.

Onivyde for the therapy of multiple solid tumors.

Abstract: Drug delivery system based on nanobiotechnology can improve the pharmacokinetics and therapeutic index of chemotherapeutic agents, which has revolutionized tumor therapy. Onivyde, also known as MM-398 or PEP02, is a nanoliposomal formulation of irinotecan which has demonstrated encouraging anticancer activity across a broad range of malignancies, including pancreatic cancer, esophago-gastric cancer, and colorectal cancer. This up-to-date review not only focuses on the structure, pharmacokinetics, and pharmacogenetics of Onivyde but also summarizes clinical trials and recommends Onivyde for patients with advanced solid tumors.

The neutrophil lymphocyte ratio is associated with breast cancer prognosis: an updated systematic review and meta-analysis.

Abstract: Breast cancer (BC) is the most common female malignancy within the spectrum of human cancer. One promising way to reduce the mortality and morbidity of BC is to explore novel diagnostic markers for early diagnosis and prognostication. The neutrophil lymphocyte ratio (NLR) is a good reflection of inflammation, which plays an important role in tumor progression and metastasis. However, the association between NLR and BC prognosis remains unclear. The aim of this meta-analysis is to explore the prognostic value of NLR in BC. Among the screened references in the database, 12 eligible studies were identified in this study. Patients with a higher NLR had a shorter disease-free survival (hazard ratio =1.46, 95% confidence interval: 1.12-1.90, P=0.044) and overall survival (hazard ratio =2.03, 95% confidence interval: 1.41-2.93, P<0.001). In the subgroup analysis of NLR and disease-free survival, the studies from Eastern countries had a positive result with perfect homogeneity (I (2)=0); however, this homogeneity has not been achieved in studies from Western countries. In the subgroup analysis of the NLR and overall survival, the results of the univariate and multivariate analyses were completely different, with different heterogeneity. In the luminal A and luminal B subtypes, we found that there was no association between the NLR and overall survival in the BC patients. Positive results were obtained in the analyses of the human epidermal growth factor receptor 2 (HER2)-positive and triple-negative BC subtypes. In conclusion, this meta-analysis suggests that NLR is a good prognostic marker for BC, and patients with a higher NLR have poorer prognoses. Future studies should perform more detailed investigations to decrease heterogeneity and determine the appropriate cut-off values for different races.

Verteporfin, a suppressor of YAP-TEAD complex, presents promising antitumor properties on ovarian cancer.

Abstract: Yes-associated protein (YAP) is a key transcriptional coactivator of Hippo pathway and has been shown to be an oncoprotein in ovarian cancer (OC). Verteporfin (VP), clinically used in photodynamic therapy for neovascular macular degeneration, has been recently proven to be a suppressor of YAP–TEAD complex and has shown potential in anticancer treatment. In this study, we aimed to explore the potential effect of VP in the treatment of OC. Our results showed that VP led to inhibition of proliferation in a time- and dose-dependent manner and to the suppression of migratory and invasive capacities of OC cells. Western blot and real-time polymerase chain reaction demonstrated that VP induced YAP cytoplasmic retention and deregulated inducible YAP and CCNs in OC cells. In vivo, VP exerted a significant effect on tumor growth in OVCAR8 xenograft mice, resulting in tumor nodules with lower average weight and reduced volume of gross ascites. In addition, VP treatment remarkably upregulated cytoplasmic YAP and phosphorylation YAP and downregulated CCN1 and CCN2, but exerted little effect on YAP-upstream components in Hippo pathway. In conclusion, our results suggested that VP may be a promising agent for OC, acting by suppressing YAP–TEAD complex.

Cell-free DNA as a diagnostic marker for cancer: current insights.

Abstract: The increasing knowledge of the molecular pathogenesis of cancer and the rapid development of new molecular techniques are promoting the study of early molecular alterations involved in cancer development in body fluids. Specific genetic and epigenetic alterations could be found in plasma, serum, and urine cell-free DNA (cfDNA) and could potentially be used as diagnostic biomarkers for several types of cancers. This review focuses on the role of cfDNA in diagnosis: a PubMed search was performed by selecting papers according to journal impact factor and robustness of statistical analysis. A comprehensive evaluation of "liquid biopsy", including cfDNA analysis, will be one of the critical challenges to better understand the early mechanisms of cancer development.

Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations.

Abstract: Identifying activating EGFR mutations is a useful predictive strategy that helps select a population of advanced non-small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors (TKIs). Patients with sensitizing EGFR mutations (predominantly an in-frame deletion in exon 19 and an L858R substitution) are highly responsive to first-generation EGFR TKIs, such as gefitinib and erlotinib, and show improved progression-free survival without serious side effects. However, all patients with activating EGFR mutations who are initially responsive to EGFR TKIs eventually develop acquired resistance after a median progression-free survival of 10–16 months, followed by disease progression. Moreover, ~20%–30% of NSCLC patients have no objective tumor regression on initial EGFR TKI treatment, although they harbor an activating EGFR mutation. These patients represent an NSCLC subgroup that is defined as having intrinsic or primary resistance to EGFR TKIs. Different mechanisms of acquired EGFR TKI resistance have been identified, and several novel compounds have been developed to reverse acquired resistance, but little is known about EGFR TKI intrinsic resistance. In this review, we summarize the latest findings involving mechanisms of intrinsic resistance to EGFR TKIs in advanced NSCLC with activating EGFR mutations and present possible therapeutic strategies to overcome this resistance.

Irreversible electroporation: state of the art

Abstract: The field of focal ablative therapy for the treatment of cancer is characterized by abundance of thermal ablative techniques that provide a minimally invasive treatment option in selected tumors. However, the unselective destruction inflicted by thermal ablation modalities can result in damage to vital structures in the vicinity of the tumor. Furthermore, the efficacy of thermal ablation intensity can be impaired due to thermal sink caused by large blood vessels in the proximity of the tumor. Irreversible electroporation (IRE) is a novel ablation modality based on the principle of electroporation or electropermeabilization, in which electric pulses are used to create nanoscale defects in the cell membrane. In theory, IRE has the potential of overcoming the aforementioned limitations of thermal ablation techniques. This review provides a description of the principle of IRE, combined with an overview of in vivo research performed to date in the liver, pancreas, kidney, and prostate.

Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the Phase III OPTiM trial

Abstract: Objectives: Talimogene laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial (NCT00769704), talimogene laherparepvec significantly improved durable response rate (DRR) versus granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 patients with unresectable stage IIIB-IVM1c melanoma. The median overall survival (OS) was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB-IVM1a). Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB-IVM1a disease. Patients and methods: The patients were randomized (2:1 ratio) to intralesional talimogene laherparepvec or subcutaneous GM-CSF and were evaluated for DRR, overall response rate (ORR), OS, safety, benefit-risk and numbers needed to treat. Descriptive statistics were used for subgroup comparisons. Results: Among 249 evaluated patients with stage IIIB-IVM1a melanoma, DRR was higher with talimogene laherparepvec compared with GM-CSF (25.2% versus 1.2%; P < 0.0001). ORR was also higher in the talimogene laherparepvec arm (40.5% versus 2.3%; P < 0.0001), and 27 patients in the talimogene laherparepvec arm had a complete response, compared with none in GM-CSF-treated patients. The incidence rates of exposure-adjusted adverse events (AE) and serious AEs were similar with both treatments. Conclusion: The subgroup of patients with stage IIIB, IIIC and IVM1a melanoma (57.1% of the OPTiM intent-to-treat population) derived greater benefit in DRR and ORR from talimogene laherparepvec compared with GM-CSF. Talimogene laherparepvec was well tolerated.

Monitoring the effects of doxorubicin on 3D-spheroid tumor cells in real-time.

Abstract: Recently, increasing numbers of cell culture experiments with 3D spheroids presented better correlating results in vivo than traditional 2D cell culture systems. 3D spheroids could offer a simple and highly reproducible model that would exhibit many characteristics of natural tissue, such as the production of extracellular matrix. In this paper numerous cell lines were screened and selected depending on their ability to form and maintain a spherical shape. The effects of increasing concentrations of doxorubicin (DXR) on the integrity and viability of the selected spheroids were then measured at regular intervals and in real-time. In total 12 cell lines, adenocarcinomic alveolar basal epithelial (A549), muscle (C2C12), prostate (DU145), testis (F9), pituitary epithelial-like (GH3), cervical cancer (HeLa), HeLa contaminant (HEp2), embryo (NIH3T3), embryo (PA317), neuroblastoma (SH-SY5Y), osteosarcoma U2OS, and embryonic kidney cells (293T), were screened. Out of the 12, 8 cell lines, NIH3T3, C2C12, 293T, SH-SY5Y, A549, HeLa, PA317, and U2OS formed regular spheroids and the effects of DXR on these structures were measured at regular intervals. Finally, 5 cell lines, A549, HeLa, SH-SY5Y, U2OS, and 293T, were selected for real-time monitoring and the effects of DXR treatment on their behavior were continuously recorded for 5 days. A potential correlation regarding the effects of DXR on spheroid viability and ATP production was measured on days 1, 3, and 5. Cytotoxicity of DXR seemed to occur after endocytosis, since the cellular activities and ATP productions were still viable after 1 day of the treatment in all spheroids, except SH-SY5Y. Both cellular activity and ATP production were halted 3 and 5 days from the start of the treatment in all spheroids. All cell lines maintained their spheroid shape, except SHSY-5, which behaved in an unpredictable manner when exposed to toxic concentrations of DXR. Cytotoxic effects of DXR towards SH-SY5Y seemed to cause degradation of the extracellular matrix, since all cells were dismantled from the spheroid upon cell death. On the other hand, 293T spheroids revealed retarded cellular activity and ATP productions upon DXR treatment throughout the experiment. Since 293T was the embryonic kidney cells, the fast clearance or neutralizations could have made them resistant towards DXR. In conclusion, the same degree of sensitivity from the 2D system did not translate to a 3D culture system, resulting in higher IC50 values than the 2D system. The varying sensitivities and tolerances to drugs could be better understood with a 3D cell culture system.

Effects of exercise intervention in breast cancer survivors: a meta-analysis of 33 randomized controlled trails

Abstract: Background Exercise is associated with favorable outcomes in cancer survivors. The purpose of this meta-analysis is to comprehensively summarize the effects of exercise intervention in breast cancer survivors.

Expression profile analysis of long noncoding RNA in HER-2-enriched subtype breast cancer by next-generation sequencing and bioinformatics.

Abstract: Background Human epidermal growth factor receptor 2 (HER-2)-enriched subtype breast cancer is associated with a more aggressive phenotype and shorter survival time. Long non-coding RNAs (LncRNAs) have essential roles in tumorigenesis and occupy a central place in cancer progression. Notably, few studies have focused on the dysregulation of LncRNAs in the HER-2-enriched subtype breast cancer. In this study, we analyzed the expression profile of LncRNAs and mRNAs in this particular subtype of breast cancer. Methods Seven pairs of HER-2-enriched subtype breast cancer and normal tissue were sequenced. We screened out differently expressed genes and measured the correlation of the expression levels of dysregulated LncRNAs and HER-2 by Pearson's correlation coefficient analysis. Gene ontology analysis and pathway analysis were used to understand the biological roles of these differently expressed genes. Pathway act network and coexpression network were constructed. Results More than 1,300 LncRNAs and 2,800 mRNAs, which were significantly differently expressed, were identified. Among these LncRNAs, AFAP1-AS1 was the most dysregulated LncRNA, while ORM2 was the most dysregulated mRNA. LOC100288637 had the highest positive correlation coefficient of 0.93 with HER-2, while RPL13P5 had the highest negative correlation coefficient of -0.87. The pathway act network showed that MAPK signaling pathway, PI3K-Akt signaling pathway, metabolic pathways, cell cycle, and regulation of actin cytoskeleton were highly related with HER-2-enriched subtype breast cancer. Coexpression network recognized LINC00636, LINC01405, ADARB2-AS1, ST8SIA6-AS1, LINC00511, and DPP10-AS1 as core genes. Conclusion These results analyze the functions of LncRNAs and provide useful information for exploring candidate therapeutic targets and new molecular biomarkers for HER-2-enriched subtype breast cancer.

Overexpression of BUB1B contributes to progression of prostate cancer and predicts poor outcome in patients with prostate cancer.

Abstract: BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) is a member of the spindle assembly checkpoint protein family, which has been proven to be associated with many kinds of cancers. The aim of this study was to investigate whether BUB1B was correlated with progression and prognosis in patients with prostate cancer (PCa) and how BUB1B regulated the proliferation, migration, and invasion of PCa cell lines. Compared to benign prostate cells and tissues, both messenger RNA and protein expressions of BUB1B were statistically increased in PCa cell lines and tumor tissues. In vitro studies revealed that BUB1B overexpression enhanced the proliferation, migration, and invasion ability of PCa cell lines, whereas depletion of BUB1B did not affect the cell functions. Microarray analysis showed the positive staining of BUB1B was upregulated in the higher Gleason score group, which also correlated with advanced clinicopathological stage, higher serum prostate-specific antigen, metastasis, overall survival, and prostate-specific antigen failure. Furthermore, the survival analysis indicated that high expression of BUB1B was an independent predictor for shorter biochemical recurrence-free survival, which had no effect on overall survival. BUB1B plays an important role in tumor growth and progression, which can lead to its use as a potential biomarker for the diagnosis and prognosis of PCa.

Increased expression of the long noncoding RNA CRNDE-h indicates a poor prognosis in colorectal cancer, and is positively correlated with IRX5 mRNA expression.

Abstract: Background The long noncoding RNA (lncRNA) colorectal neoplasia differentially expressed – h (CRNDE-h) plays important roles in the early stages of human development and cancer progression. We investigated the expression and clinical significance of lncRNA CRNDE-h in colorectal cancer (CRC).

Different levels of serum microRNAs in prostate cancer and benign prostatic hyperplasia: evaluation of potential diagnostic and prognostic role

Abstract: Introduction Diagnosis of prostate cancer (PCa) is based on prostate biopsy that is performed when prostate specific antigen (PSA) is persistently altered over time and/or abnormal digital rectal examination is found. Serum PSA levels increase in both PCa and benign prostatic hyperplasia, leading to an increased number of unnecessary biopsies. There is an urgent need to unravel PCa-specific molecular signatures. Patients and methods This study aimed at characterizing a panel of circulating micro RNAs (miRNAs) that could distinguish PCa from benign prostatic hyperplasia in a population of age-matched patients with increased PSA levels. Both miRNAs targeting genes involved in PCa onset and miRNAs whose role in PCa has been highlighted in other studies were included. For this purpose, let-7c, let-7e, let-7i, miR-26a-5p, miR-26b-5p, miR-24-3p, miR-23b-3p, miR-27-b-3p, miR-106a-5p, miR-20b-5p, miR-18b-5p, miR-19b-2-5p, miR-363-3p, miR-497, miR-195, miR-25-3p, miR-30c-5p, miR-622, miR-874-3p, miR-346 and miR-940 were assayed through real-time PCR in 64 patients with PCa and compared with 60 patients with benign prostatic hyperplasia. The ability of miRNAs to predict the stage of disease was also analyzed. Results Let-7c, let-7e, let-7i, miR-26a-5p, miR-26b-5p, miR-18b-5p and miR-25-3p were able to discriminate patients with PCa from those harboring benign prostatic hyperplasia, both presenting altered PSA levels (>3 ng/mL). MiR-25-3p and miR-18b-5p showed the highest sensitivity and specificity to predict PCa, respectively. The combination of these two miRNAs improved the overall sensitivity. A correlation between pathological Gleason score and miRNA expression levels was reported; miR-363-3p, miR-26a-5p, miR-26b-5p, miR-106a-5p, miR-18b-5p, miR-25-3p and let-7i decreased in expression concomitantly with an increase in malignancy. Conclusion This study confirms serum miRNAs to be reliable candidates for the development of minimally invasive biomarkers for the diagnosis and prognosis of PCa, particularly in those cases where PSA acts as a flawed marker.

Oncolytic viruses as immunotherapy: progress and remaining challenges

Abstract: Oncolytic viruses (OVs) comprise an emerging cancer therapeutic modality whose activity involves both direct tumor cell lysis and the induction of immunogenic cell death (ICD). Cellular proteins released from the OV-lysed tumor cells, known as damage-associated molecular patterns and tumor-associated antigens, activate dendritic cells and elicit adaptive antitumor immunity. Interaction with the innate immune system and the development of long-lasting immune memory also contribute to OV-induced cell death. The degree to which the ICD component contributes to the clinical efficacy of OV therapy is still unclear. Modulation of a range of immune interactions may be beneficial or detrimental in nature and the interactions depend on the specific tumor, the site and extent of the disease, the immunosuppressive tumor microenvironment, the OV platform, the dose, time, and delivery conditions, as well as individual patient responses. To enhance the contribution of ICD, OVs have been engineered to express immunostimulatory genes and strategies have been developed to combine OV therapy with chemo- and immune-based therapeutic regimens. However, these approaches carry the risk that they may also be tolerogenic depending on their levels and the presence of other cytokines, their direct antiviral effects, and the timing and conditions of their expression. The contribution of autophagy to adaptive immunity, the ability of the OVs to kill cancer stem cells, and the patient's baseline immune status are additional considerations. This review focuses on the complex and as yet poorly understood balancing act that dictates the outcome of OV therapy. We summarize current understanding of the OVs' function in eliciting antitumor immunity and its relationship to therapeutic efficacy. Also discussed are the criteria involved in restraining antiviral immune responses and minimizing pathology while promoting antitumor immunity to override immune tolerance.

Mesoporous silica nanoparticles functionalized with folic acid/methionine for active targeted delivery of docetaxel.

Abstract: Mesoporous silica nanoparticles (MSNs) are known as carriers with high loading capacity and large functionalizable surface area for target-directed delivery. In this study, a series of docetaxel-loaded folic acid- or methionine-functionalized mesoporous silica nanoparticles (DTX/MSN-FA or DTX/MSN-Met) with large pores and amine groups at inner pore surface properties were prepared. The results showed that the MSNs were successfully synthesized, having good pay load and pH-sensitive drug release kinetics. The cellular investigation on MCF-7 cells showed better performance of cytotoxicity and cell apoptosis and an increase in cellular uptake of targeted nanoparticles. In vivo fluorescent imaging on healthy BALB/c mice proved that bare MSN-NH2 are mostly accumulated in the liver but MSN-FA or MSN-Met are more concentrated in the kidney. Importantly, ex vivo fluorescent images of tumor-induced BALB/c mice organs revealed the ability of MSN-FA to reach the tumor tissues. In conclusion, DTX/MSNs exhibited a good anticancer activity and enhanced the possibility of targeted drug delivery for breast cancer.

Long noncoding RNA AK126698 inhibits proliferation and migration of non-small cell lung cancer cells by targeting Frizzled-8 and suppressing Wnt/β-catenin signaling pathway.

Abstract: Background Recent studies indicate that long noncoding RNAs (lncRNAs) play a key role in the control of cellular processes such as proliferation, metastasis, and differentiation. The lncRNA dysregulation has been identified in all types of cancer. We previously found that lncRNA {"type":"entrez-nucleotide","attrs":{"text":"AK126698","term_id":"34533276","term_text":"AK126698"}}AK126698 suppresses cisplatin resistance in A549 cells through the Wnt/β-catenin signaling pathway. However, the clinical significance of lncRNA {"type":"entrez-nucleotide","attrs":{"text":"AK126698","term_id":"34533276","term_text":"AK126698"}}AK126698 and the molecular mechanisms through which it regulates cancer cell proliferation and migration are largely unknown.

Mechanism-based management for mucositis: option for treating side effects without compromising the efficacy of cancer therapy

Abstract: Mucositis is a major side effect induced by chemotherapy and radiotherapy. Although mucositis is a leading cause of morbidity and mortality in cancer patients, management is largely limited to controlling symptoms, and few therapeutic agents are available for treatment. Since mucositis could be inhibited by the modulation of radiotherapy- or chemotherapy-induced pathways independently of cancer treatment, there is an opportunity for the development of more targeted therapies and interventions. This article examined potential therapeutic agents that have been investigated for the prevention and/or inhibition of mucositis induced by conventional chemotherapy and radiotherapy. They can be classified according to their mechanisms of action: scavenging reactive oxygen species, inhibition of specific cytokine production or inflammation, and inhibition of apoptosis. These early events may be good target pathways for preventing the pathogenesis of mucositis. Considering that both cancer therapy and therapeutic agents for mucositis act on both normal and cancer cells, agents that inhibit mucositis should act through mechanisms that selectively protect normal cells without compromising cancer treatment. Therefore, mechanism-based guidance for the treatment of mucositis is critical to prevent risky treatments for cancer patients and to relieve detrimental side effects effectively from cancer therapy.

Cancer: fundamentals behind pH targeting and the double-edged approach

Abstract: The highly regulated pH of cells and the less-regulated pH of the surrounding extracellular matrix (ECM) is the result of a delicate balance between metabolic processes and proton production, proton transportation, chemical buffering, and vascular removal of waste products. Malignant cells show a pronounced increase in metabolic processes where the 10- to 15-fold rise in glucose consumption is only the tip of the iceberg. Aerobic glycolysis (Warburg effect) is one of the hallmarks of cancer metabolism that implies excessive production of protons, which if stayed inside the cells would result in fatal intracellular acidosis (maintaining a strict acid-base balance is essential for the survival of eukaryotic cells). Malignant cells solve this problem by increasing mechanisms of proton transportation which expel the excess acidity. This allows cancer cells to keep a normal intracellular pH, or even overshooting this mechanism permits a slightly alkaline intracellular tendency. The proton excess expelled from malignant cells accumulates in the ECM, where chronic hypoxia and relative lack of enough blood vessels impede adequate proton clearance, thus creating an acidic microenvironment. This microenvironment is quite heterogeneous due to the tumor's metabolic heterogeneity and variable degrees of hypoxia inside the tumor mass. The acidic environment (plus other necessary cellular modifications) stimulates migration and invasion and finally intravasation of malignant cells which eventually may result in metastasis. Targeting tumor pH may go in two directions: 1) increasing extracellular pH which should result in less migration, invasion, and metastasis; and 2) decreasing intracellular pH which may result in acidic stress and apoptosis. Both objectives seem achievable at the present state of the art with repurposed drugs. This hypothesis analyzes the altered pH of tumors and its implications for progression and metastasis and also possible repurposed drug combinations targeting this vulnerable side of cancer development. It also analyzes the double-edged approach, which consists in pharmacologically increasing intracellular proton production and simultaneously decreasing proton extrusion creating intracellular acidity, acid stress, and eventual apoptosis.

Overexpression of long noncoding RNA HOTTIP promotes tumor invasion and predicts poor prognosis in gastric cancer

Abstract: Purpose Long noncoding RNAs have been proved to play important roles in the tumorigenesis and development of human gastric cancer (GC). Our study aims to investigate the expression and function of Homeobox A transcript at the distal tip (HOTTIP) in GC.

Biomarkers in pancreatic adenocarcinoma: current perspectives

Abstract: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 7.7%. Most patients are diagnosed at an advanced stage not amenable to potentially curative resection. A substantial portion of this review is dedicated to reviewing the current literature on carbohydrate antigen (CA 19-9), which is currently the only guideline-recommended biomarker for PDAC. It provides valuable prognostic information, can predict resectability, and is useful in decision making about neoadjuvant therapy. We also discuss carcinoembryonic antigen (CEA), CA 125, serum biomarker panels, circulating tumor cells, and cell-free nucleic acids. Although many biomarkers have now been studied in relation to PDAC, significant work still needs to be done to validate their usefulness in the early detection of PDAC and management of patients with PDAC.

Integrin and gene network analysis reveals that ITGA5 and ITGB1 are prognostic in non-small-cell lung cancer

Abstract: Background Integrin expression has been identified as a prognostic factor in non-small-cell lung cancer (NSCLC). This study was aimed at determining the predictive ability of integrins and associated genes identified within the molecular network.

Downregulation of ALDOB is associated with poor prognosis of patients with gastric cancer

Abstract: Objectives To examine the expression of ALDOB in gastric cancer (GC) tissue and to reveal its potential clinicopathological and prognostic significance.

A dried blood spot mass spectrometry metabolomic approach for rapid breast cancer detection.

Abstract: Objective Breast cancer (BC) is still a lethal threat to women worldwide. An accurate screening and diagnosis strategy performed in an easy-to-operate manner is highly warranted in clinical perspective. Besides the routinely focused protein markers, blood is full of small molecular metabolites with diverse structures and properties. This study aimed to screen metabolite markers with BC diagnosis potentials.

Sunitinib: the antiangiogenic effects and beyond.

Abstract: As a multitargeted kinase inhibitor, sunitinib has carved its way into demonstrating itself as a most effective tyrosine kinase inhibitor in the treatment of metastatic renal cell carcinoma. Mechanistically, sunitinib inhibits multiple receptor tyrosine kinases, especially those involved in angiogenesis, that is, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and proto-oncogene cKIT. Sunitinib has also been implicated in enhancing cancer invasiveness and metastasis. Mechanisms of resistance are poorly understood, but both intrinsic and acquired mechanisms are thought to be involved. While the side effects are manageable, sunitinib, like many other tyrosine kinase inhibitors, can be associated with serious toxicities that require careful management including frequent dose reductions. Although still in the early stage, emerging evidence points to an immunomodulatory role for sunitinib. It is also likely to contribute to the overall outcomes, especially those seen in metastatic renal cell carcinoma, and such effects are thought to be mediated by the proto-oncogene cKIT receptor. Combination with other modalities such as stereotactic body radiation therapy, therapeutic vaccines, and checkpoint inhibitors is being pursued for improved efficacy.

Tremelimumab: research and clinical development.

Abstract: The immune checkpoint therapy is a relatively recent strategy that aims to tweak the immune system to effectively attack cancer cells. The understanding of the immune responses and their regulation at the intracellular level and the development of fully humanized monoclonal antibodies are the pillars of an approach that could elicit durable clinical responses and even remission in some patients with cancer. Most of the immune checkpoints that regulate the T-cell responses (activation and inhibition) operate through proteins present on the cytoplasmic membrane of the immune cells. Therefore, specific antibodies capable of blocking the inhibitory signals should lead to unrestrained immune responses that supersede the inhibitory mechanisms, which are naturally present in the tumor microenviroment. The best-known and most successful targets for immune checkpoint therapy are the cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 coreceptors. Tremelimumab (CP-675,206) is a fully humanized monoclonal antibody specific for cytotoxic T-lymphocyte antigen-4, which has been successfully used to treat patients with metastatic melanoma and some other cancers. Although still a work in progress, the use of tremelimumab as an immune checkpoint therapeutic agent is a promising approach alone or in combination with other anticancer drugs. Here, we review the use of this antibody in a number of clinical trials against solid tumors.