Selective Activator Protein-1 Inhibitor T-5224 Prevents Lymph Node Metastasis in an Oral Cancer Model

Summary

Activator protein-1 (AP-1) is a transcriptional factor that regulates the expression of various genes associated with tumor invasion and migration. The purpose of our study was to assess the therapeutic effects of a novel selective AP-1 inhibitor–T-5224–in preventing lymph-node metastasis in head and neck squamous-cell carcinoma (HNSCC) in an orthotopic mouse model. We assessed the effect of T-5224 on HNSCC cell invasion, migration, proliferation, and matrix-metalloproteinase activity by performing an in vitro study using an invasion assay, scratch assay, WST-8 assay, and gelatin zymography. We also observed morphological changes in HNSCC cells by time-lapse microscopy. Furthermore, cervical lymph-node metastasis was assessed using an orthotopic tumor model of human oral squamous-cell carcinoma cells (HSC-3-M3) injected in the tongue of a BALB/c nude mouse. T-5224 (150 mg/kg) or vehicle was administered orally every day for 4 weeks. Animals were sacrificed and assessed for lymph-node metastasis by hematoxylin-eosin staining of resected lymph nodes. T-5224 significantly inhibited the invasion, migration, and matrix-metalloproteinase activity of HNSCC cells in a dose-dependent manner; there was no significant influence on cell proliferation. The anti-metastatic effect of T-5224 was also confirmed in our animal study. The rate of cervical lymph-node metastasis in the model was 40.0% in the T-5224-treated group (n = 30) versus 74.1% in the vehicle-treated group (n = 27; P < 0.05). In conclusion, T-5224 inhibited the invasion and migration of HNSCC cells in vitro, and prevented lymph-node metastasis in head and neck cancer in an animal model.

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The Effect of Food on the Pharmacokinetics of TAS-102 and its Efficacy and Safety in Patients with Advanced Solid Tumors

Summary

TAS-102, a novel oral antitumor agent, consists of trifluridine and tipiracil hydrochloride (molar ratio, 1:0.5). We investigated the effects of food on trifluridine and tipiracil hydrochloride. The efficacy and safety of TAS-102 were evaluated in patients with advanced solid tumors. We analyzed drug pharmacokinetics using a randomized, single-dose, two-treatment (fed versus fasting), two-period, two-sequence crossover design, followed by repeated administration. Patients were administered single doses of TAS-102 (35 mg/m²) in the pharmacokinetic phase and received twice-daily doses of TAS-102 in 28-day cycles in the repeated administration phase for evaluating efficacy and safety. Food showed no effect on the area under the curve from 0–12 h or 0 h–infinity values of trifluridine following administration of TAS-102 under fasting and fed conditions, whereas those of tipiracil hydrochloride decreased by approximately 40%. Maximum concentrations of both drugs decreased by approximately 40%, indicating that food influenced the absorption and bioavailability of trifluridine and tipiracil hydrochloride, respectively. During the repeated administration, stable disease was observed in nine patients with rectal, small-cell lung, breast, thymic, duodenal, and prostate cancers. Major adverse events were neutropenia, leukopenia, anemia, and nausea. Postprandial administration was optimal for TAS-102 because trifluridine's area under the curve was not changed by food, indicating that its clinical efficacy would not be affected. Additionally, postprandial administration was reasonable because the maximum concentration of trifluridine decreased in neutrophils, which correlated with previous studies. These results suggest that TAS-102 would be an effective treatment for small-cell lung, thymic, and colorectal cancers

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The role of hyaluronan in pancreatic cancer biology and therapy: Once again in the spotlight

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains the most deadly disease worldwide, with the lowest survival rate among all cancer types. Recent evidence suggests hyaluronan (HA), a major component of extracellular matrix, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma (PDAC) is characterized typically by a dense desmoplastic stroma containing a large amount of HA. Accumulation of HA promotes tumor growth in mice and correlates with poor prognosis in patients with PDAC. Because HA is involved in various malignant behaviors of cancer (such as increased cell proliferation, migration, invasion, angiogenesis, and chemoresistance), inhibiting HA synthesis/signaling or depleting HA in tumor stroma could represent a promising therapeutic strategy against PDAC. In this review article, we summarize our current understanding of the role of HA in the progression of PDAC and discuss possible therapeutic approaches targeting HA.

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Dietary acrylamide and the risk of endometrial cancer: An Italian case-control study.

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Dietary acrylamide and the risk of endometrial cancer: An Italian case-control study.

Nutr Cancer. 2016 Feb 23;:1-6

Authors: Pelucchi C, Galeone C, Negri E, Bosetti C, Serraino D, Montella M, Talamini R, La Vecchia C

Abstract
The role of dietary acrylamide on the risk of hormone-related, and specifically endometrial, cancers is debated. Epidemiological data are scanty. Thus, we examined the relation between acrylamide intake and endometrial cancer risk in a case-control study conducted between 1992 and 2006 in 3 Italian areas. Cases were 454 women with incident, histologically confirmed endometrial cancer. Controls were 908 age-matched women admitted to the same network of hospitals of cases for acute, non-neoplastic conditions. We calculated multivariate odds ratios (OR) and 95% confidence intervals (CI) using logistic regression models. The OR of endometrial cancer for increasing quintiles of dietary acrylamide, as compared to the lowest one, were 1.02 (95% CI: 0.67-1.54), 1.20 (95% CI: 0.80-1.80), 1.00 (95% CI: 0.65-1.54) and 1.17 (95% CI: 0.73-1.85). The OR for an increase of 10 μg/day of dietary acrylamide was 1.00 (95% CI: 0.91-1.10). In subgroup analyses, the ORs for high vs. low acrylamide intake were 1.28 (95% CI: 0.73-2.25) in never smokers and 1.14 (95% CI: 0.45-2.90) in ever smokers. Our data do not support an association between dietary acrylamide intake and endometrial cancer.

PMID: 26905095 [PubMed - as supplied by publisher]

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Vitamin D receptor polymorphisms relate to risk of adenomatous polyps in a sex-specific manner.

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Vitamin D receptor polymorphisms relate to risk of adenomatous polyps in a sex-specific manner.

Nutr Cancer. 2016 Feb 23;:1-8

Authors: Beckett EL, Gras KL, Martin C, Boyd L, Ng X, Duesing K, Yates Z, Veysey M, Lucock M

Abstract
Vitamin D receptor (VDR) gene polymorphisms may influence risk for adenomatous polyps (AP), a benign precursor to colon cancer, via modulation of vitamin D sensitive pathways, including cell proliferation and differentiation. However, results have been mixed and any association remains contentious. Failure to clinically exclude the presence of (AP in control cohorts may contribute to the lack of consensus. Therefore, we assessed the role of the FokI, BsmI, ApaI, and TaqI VDR polymorphisms in modifying risk for AP, adjusting for a range of dietary and lifestyle variables. Blood was collected from colonoscopy patients (n = 258) and VDR polymorphisms assessed by restriction fragment length polymorphism. Dietary habits were estimated from food frequency questionnaires. Odds ratios for AP were calculated by genotype, stratified by sex, and adjusted for age, lifestyle, and dietary factors. FokI was associated with modified risk for AP in males, whereas the BsmI/ApaI/TaqI haplotype was associated with modified risk in females. No interaction was found between VDR variants and vitamin D intake. This study offers novel insight into the potential for VDR genetics to contribute to risk for AP and is the first to demonstrate a sex-specific relationship between these polymorphisms and risk for AP.

PMID: 26904920 [PubMed - as supplied by publisher]

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Issue Information

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Report on the use of non-clinical studies in the regulatory evaluation of oncology drugs

Non-clinical studies are necessary at each stage of the development of oncology drugs. Many experimental cancer models have been developed to investigate carcinogenesis, cancer progression, metastasis, and other aspects in cancer biology and these models turned out to be useful in the efficacy evaluation and the safety prediction of oncology drugs. While the diversity and the degree of engagement in genetic changes in the initiation of cancer cell growth and progression are widely accepted, it has become increasingly clear that the roles of host cells, tissue microenvironment, and the immune system also play important roles in cancer. Therefore, the methods used to develop oncology drugs should continuously be revised based on the advances in our understanding of cancer. In this review, we extensively summarize the effective use of those models, their advantages and disadvantages, ranges to be evaluated and limitations of the models currently used for the development and for the evaluation of oncology drugs.

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In This Issue

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Co-localization of Ki67, CD44v adn deltaNp63 in the invasive front of lung squamous cell carcinoma

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Expression levels of microRNA-145 and microRNA-10b are associated with metastasis in non-small cell lung cancer.

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Expression levels of microRNA-145 and microRNA-10b are associated with metastasis in non-small cell lung cancer.

Cancer Biol Ther. 2016 Jan 30;:1-8

Authors: Li Y, Li Y, Liu J, Fan Y, Li X, Dong M, Liu H, Chen J

Abstract
Although metastasis remains the overwhelming cause of death for patients with non-small cell lung cancer (NSCLC), the underlying mechanisms of metastasis remain unknown. Accumulating evidence suggests that microRNAs (miRNAs) are key players in the regulation of tumor cell invasion and metastasis. Expression of miR-9, miR-10b, miR-145, and miR-155, 4 miRNAs previously shown to play roles in metastasis in other tumor types, was compared in lymph node (LN)-positive NSCLC versus LN-negative NSCLC. Expression of miR-145 was significantly lower in LN-positive NSCLC (P < 0.05), while expression of miR-10b was significantly higher (P < 0.05). Expression of both miR-145 and miR-10b was correlated with lymph node metastasis in NSCLC (both Ps < 0.001). In addition, miR-10b facilitated the migration and invasion of lung cancer cell line A549, while miR-145 suppressed the migration and invasion capacity of A549 in vitro. These results suggest that miR-10b and miR-145 may act as an oncogene or tumor suppressor gene, respectively, in NSCLC metastasis.

PMID: 26909466 [PubMed - as supplied by publisher]

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Expression levels of microRNA-145 and microRNA-10b are associated with metastasis in non-small cell lung cancer.

Related Articles

Expression levels of microRNA-145 and microRNA-10b are associated with metastasis in non-small cell lung cancer.

Cancer Biol Ther. 2016 Jan 30;:1-8

Authors: Li Y, Li Y, Liu J, Fan Y, Li X, Dong M, Liu H, Chen J

Abstract
Although metastasis remains the overwhelming cause of death for patients with non-small cell lung cancer (NSCLC), the underlying mechanisms of metastasis remain unknown. Accumulating evidence suggests that microRNAs (miRNAs) are key players in the regulation of tumor cell invasion and metastasis. Expression of miR-9, miR-10b, miR-145, and miR-155, 4 miRNAs previously shown to play roles in metastasis in other tumor types, was compared in lymph node (LN)-positive NSCLC versus LN-negative NSCLC. Expression of miR-145 was significantly lower in LN-positive NSCLC (P < 0.05), while expression of miR-10b was significantly higher (P < 0.05). Expression of both miR-145 and miR-10b was correlated with lymph node metastasis in NSCLC (both Ps < 0.001). In addition, miR-10b facilitated the migration and invasion of lung cancer cell line A549, while miR-145 suppressed the migration and invasion capacity of A549 in vitro. These results suggest that miR-10b and miR-145 may act as an oncogene or tumor suppressor gene, respectively, in NSCLC metastasis.

PMID: 26909466 [PubMed - as supplied by publisher]

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Cancers, Vol. 8, Pages 27: Targeted Therapy in Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (LA-R/M HNSCC)

Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemoradiotherapy is an alternative for patients with locally advanced disease. In recurrent/metastatic disease and after progression to platin-based regimens, no standard treatments other than best supportive care are currently available. Most SCCHN tumours overexpress the epidermal growth factor receptor (EGFR). This receptor is a tyrosine-kinase membrane receptor that has been implicated in angiogenesis, tumour progression and resistance to different cancer treatments. In this review, we analysed the different drugs and pathways under development to treat SCCHN, especially recurrent/metastatic disease. Until now, the EGFR signalling pathway has been considered the most important target with respect to new drugs; however, new drugs, such as immunotherapies, are currently under study. As new treatments for SCCHN are developed, the influence of therapies with respect to overall survival, progression free survival and quality of life in patients with this disease is changing.

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Cancers, Vol. 8, Pages 29: Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells

The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources. Eugenia jambolana (Java plum) is a tropical medicinal fruit rich in anthocyanins, however, its anti-colon cancer properties are not well characterized. Furthermore, recent evidence suggests that colon cancer stem cells (colon CSCs) promote resistance to chemotherapy, relapse of tumors and contribute to poor prognosis. The objectives of this study were to 1) characterize the anthocyanin profile of Java plum using HPLC-MS; and 2) determine the anti-proliferative (cell counting and MTT) and pro-apoptotic (TUNEL and caspase 3/7 glo assay) properties of Java plum fruit extract (JPE) using HCT-116 colon cancer cell line and colon CSCs (positive for CD 44, CD 133 and ALDH1b1 markers). HPLC-MS analysis showed that JPE contains a variety of anthocyanins including glucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin. JPE anthocyanins suppressed (p < 0.05) proliferation in HCT-116 cells and elevated (p < 0.05) apoptosis in both HCT-116 cells and colon CSCs. JPE also suppressed the stemness in colon CSCs as evaluated using colony formation assay. These results warrant further assessment of the anti-cancer activity of JPE, and its molecular mechanisms using pre-clinical models of colon cancer.

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A longitudinal exploration of the psychological resources influencing depression and anxiety in newly diagnosed Asian persons with cancer

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Psychological variables associated with quality of life following primary treatment for head and neck cancer: a systematic review of the literature from 2004 to 2015

Abstract

Objective

There has been a recent proliferation of research on quality of life (QoL) in head and neck cancer (HNC). The objective of this review was to systematically examine the evidence on psychological factors associated with QoL outcomes for HNC survivors in the post-treatment period published during 2004–2015.

Methods

Five databases were searched for studies investigating psychological factors associated with QoL in HNC survivors. Empirical studies published between January 2004 and June 2015 were included if they measured QoL as an outcome following treatment using a reliable and valid measure, examined its association with at least one psychological factor and included at least 50 HNC survivors.

Results

Twenty-four publications describing 19 studies (9 cross-sectional, 10 prospective) involving 2,263 HNC survivors were included. There was considerable heterogeneity in study design and diversity in measurement and analysis. Distress-related variables (depression, anxiety, distress) were most frequently investigated, and mostly reported negative associations with QoL outcomes. Associations were also observed between other psychological factors (e.g., coping, neuroticism and fear of recurrence) and QoL.

Conclusions

Several psychological factors predict QoL among HNC survivors who have completed treatment. Routine screening and early interventions that target distress could improve HNC survivors' QoL following treatment. Longitudinal and population-based studies incorporating more systematic and standardised measurement approaches are needed to better understand relationships between psychological factors and QoL and to inform the development of intervention and supportive care strategies. Copyright © 2016 John Wiley & Sons, Ltd.

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