A new era in cancer therapeutics?

Highlights from the 14th EORTC-NCI-AACR Symposium Molecular Targets and Cancer Therapeutics, 19-22 November 2002, in Frankfurt, Germany.     

Can cancer centres in New Zealand help the cancer registry generate survival data? A pilot study in prostate cancer

AIMS: One of the current limitations of reports issued by the New Zealand Cancer Registry (NZCR) is that the only measure of the success of treatment is provided by the mortality ratio. A pilot study was therefore carried out to see if collaboration between cancer centres and the NZCR might allow the generation of more meaningful survival data that could be used for the audit of treatment outcome. METHODS: Clinical details of patients seen at the Wellington Cancer Centre (WCC), in whom a diagnosis of prostate cancer was made in 1997, were provided to the NZCR. These details were matched with registration and mortality data held by the NZCR. RESULTS: WCC records identified 82 patients who were diagnosed with prostate cancer in 1997. Of these, the NZCR registered 60 (73%) in 1997, 3 (4%) prior to 1997, and 14 (17%) after 1997. Five patients (6%) were not registered at all. In the cohort of 82 patients, 17 (21%) had subsequently died. Of these, 11 (65%) had been treated with palliative intent, and six (35%) with radical intent. Of those patients treated radically, three had died of prostate cancer and three of other causes. CONCLUSIONS: Cooperation between Cancer Centres and the NZCR would allow the NZCR to generate useful survival data. This could help evaluate the impact on survival of specific treatments and interventions, such as screening programs. Regional variations in outcome could be detected. The exercise is feasible, without compromising patient confidentiality.     

HBXIP blocks myosin-ⅡA assembly by phosphorylating and interacting with NMHC-ⅡA in breast cancer metastasis

Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton.As a key component of actomyosin filaments,non-muscle myosin-ⅡA disassembly contributes to tumor cell spreading and migration.However,its regulatory mechanism in tumor migration and invasion is poorly understood.Here,we found that oncoprotein hepatitis B X-interacting protein(HBXIP) blocked the myosin-ⅡA assemble state promoting breast cancer cell migration.Mechanistically,mass spectrometry analysis,co-immunoprecipita...     

Do nonsteroidal anti-inflammatory drugs affect the risk of developing ovarian cancer? A meta-analysis

AIM: The relationship between the use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, and the risk of ovarian cancer has been controversial. This study examines the strength of this association by conducting a detailed meta-analysis of the studies published in peer-reviewed literature on the subject. METHODS: A comprehensive search for articles published up to April 2004 was performed, reviews of each study were conducted and data were abstracted. Prior to meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk estimates (RR) and 95% confidence intervals (CIs) were calculated. RESULTS: Ten reports (six case-control and four cohort studies), published between 1998 and 2004, were identified. There was no evidence of an association between aspirin use and ovarian cancer risk either assuming a random-effects model (RR = 0.92, 95% CI 0.80, 1.06), or a fixed-effects model (RR = 0.93, 95% CI 0.81, 1.06). Similarly, we did not find evidence of an association between non-aspirin NSAID use and ovarian cancer, both on the basis of a random-effects model (RR = 0.86, 95% CI 0.68, 1.08), and on the basis of a fixed-effects model (RR = 0.88, 95% CI 0.76, 1.01). When the analyses were stratified into subgroups, there was no evidence that study design substantially influenced the estimate of effects. Furthermore, our analysis did not show decreasing risks with increasing frequency or duration of use, features often associated with causal relationships. CONCLUSIONS: Our meta-analysis findings do not support that NSAID use plays a role in the chemoprevention of ovarian cancer. Future research should examine potential relationships between specific NSAIDs and ovarian cancer, taking into account the possible biases that may have affected this meta-analysis.     

A network-based predictive gene expression signature for recurrence risks in stage Ⅱ colorectal cancer

OBJECTIVE To explore novel gene signature to predict recurrence risksand reveal underlying mechanisms in stage Ⅱ colorectal cancer( Ⅱ CRC).METHODS In this study, we performed bioinformatical analyses based on high throughput RNA sequencing of CRC from The Cancer Genome Atlas(TCGA) database to gain a panoramic view of expression patterns between recurrence and non-recurrence patients in stageⅡ CRC.Furthermore, Differentially Expressed Genes(DEGs)were used to establish a model for predict the recurrence risk by random forest sequencing, and the diagnostic effectiveness was showed by receiver operating characteristic(ROC). Then used another gene expression profiling date which were extracted from GEO(GSE12032) for further validate the robust diagnostic effectiveness of therecurrent model. In addition, gene ontology(GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, Protein Protein Interaction(PPI) network analysis and hub genesselection were adopted to jointly analyze the underlying mechanism of recurrence. And the clinical values of the recurrent model and the hub genes were further explored at the same time. RESULTS First, 124 patients gene-expression profiles dataset of stageⅡ CRC from the TCGA database were obtained to screen DEGs. 202 DEGs including 128 up-regulated and 74 down-regulated were identified in recurrence group(n=24) compared to nonrecurrence group(n=100). Furthermore, the top five(ZNF561, WFS1, SLC2 A1, MFI2, PTGR1) DEGs were identified by random forest variable hunting, and four(ZNF561, WFS1, SLC2 A1, PTGR1) of them were selected to create a four-gene recurrent model(GRM) with the area under the curve(AUC) 0.882 by ROC, and the robust diagnostic effectiveness of GRM were further validated by another gene expression profiling date from GEO(GSE12032) with the AUC of 0.943. The diagnostic effectivenessof GRM about recurrence was confirmed associated with poor disease-free survival(DFS) to all stage CRC. In addition, GO functional annotation and KEGG pathway enrichment analysissuggested 18 functions and6 pathways were enrichment. Four genes as ABCG2,CACNA1 F, CYP19 A1, TF were identified as hub genes by PPI network, which further validated they were correlated with poor pathologic stage and overall survival(OS)in all stage CRC. CONCLUSION The GRM can effectively classify stageⅡCRC into groups at high and low risks of recurrence, thereby making up for the prognostic value of the traditional clinicopathological risk factors defined by the NCCN guidelines. And the hub genes may be the useful therapeutic targets for recurrence. Thus, the GRM and hub genes potentially offer clinical values in directing individualized and precision therapeutic regimen for stageⅡ CRC.     

Upregulation of human DNA binding protein A （dbpA） in gastric cancer cells

Aim： To determine the effect of human DNA binding protein （dbpA） on the biology of gastric cancer cells. Methods： DbpA expression was analyzed by Western blot analysis and immunofluorescence staining in gastric cancer tissues and cell lines. A dbpA-specific small interference （si） RNA was designed and synthesized. Suppressive effect of siRNA on dbpA expression was assessed by real-time RT-PCR. Transwell migration and colony formation assays were used to assess the inhibitory effects of dbpA siRNA on cell invasion and tumorigenesis in vitro. Drug-sensitivity was evaluated using a conventional 3-（4,5-dJmethylthiazol-2-yl）-2,5- diphenyl tetrazolium bromide （MTT） assay. Results： The expression of dbpA was upregulated in gastric cancer tissues and cell lines as compared to adjacent normal tissues or gastric epithelial cells, siRNA treatment successfully silenced dbpA expression. Silencing of dbpA increased expression of E-cadherin, decreased expression of adenomatous polyposis coil （APC）, β-catenin and cyclin D1, but had no effect on expression of NF-KB. Silenc- ing of dbpA also suppressed cell invasion and colony formation of SGC7901 cells, and enhanced their chemosensitivity to 5-fluoroura- cil. Conclusion： DbpA plays an important role in the pathogenesis and development of gastric cancer, and the process involves E-cadherin, APC, β-catenin and cyclin D1. Silencing of dbpA might be a novel therapeutic strategy for increasing chemosensitivity to 5-fluorouracil in gastric cancer.     

Andrographolide down-regulates hypoxia-inducible factor-1α in human non-small cell lung cancer A549 cells

Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess multiple pharmacological activities. In our previous study, Andro had been shown to inhibit non-small cell lung cancer (NSCLC) A549 cell migration and invasion via down-regulation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Here we demonstrated that Andro inhibited the expression of hypoxia-inducible factor-1α (HIF-1α) in A549 cells. HIF-1α plays an important role in tumor growth, angiogenesis and lymph node metastasis of NSCLC. The Andro-induced decrease of cellular protein level of HIF-1α was correlated with a rapid ubiquitin-dependent degradation of HIF-1α, and was accompanied by increased expressions of hydroxyl-HIF-1α and prolyl hydroxylase (PHD2), and a later decrease of vascular endothelial growth factor (VEGF) upon the treatment of Andro. The Andro-inhibited VEGF expression appeared to be a consequence of HIF-1α inactivation, because its DNA binding activity was suppressed by Andro. Molecular data showed that all these effects of Andro might be mediated via TGFβ1/PHD2/HIF-1α pathway, as demonstrated by the transfection of TGFβ1 overexpression vector and PHD2 siRNA, and the usage of a pharmacological MG132 inhibitor. Furthermore, we elucidated the involvement of Andro in HIF-1α transduced VEGF expression in A549 cells and other NSCLC cell lines. In conclusion, these results highlighted the potential effects of Andro, which may be developed as a chemotherapeutic or an anti-angiogenesis agent for NSCLC in the future.     

A case of human polyomavirus Bk infection in a patient affected by late stage prostate cancer: could viral infection be correlated with cancer progression?

The basic molecular mechanisms regulating prostate cancer (PCA) development and progression are very poorly understood. Different tumor suppressor genes are implicated in PCA. In particular, since the mutation rate of the p53 gene is also low, researchers have speculated that an infectious agent might play an important role in PCA. Polyomaviruses are candidates for this agent. We selected a patient with a diagnosis of PCA and underwent radical prostatectomy, to investigate the presence of polyomavirus BK (BKV) sequences (urine and neoplastic tissues) and the mutation pattern of p53 gene. The results obtained showed the presence of BKV DNA and of p53 gene mutations in exons 6, 8 and 9. We speculate that BKV might contribute to cellular transformation process, triggered possibly by p53 gene mutations.     

TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy?

The Food and Drug Administration (FDA) has approved label changes for two anticancer drugs, 6-mercaptopurine (6-MP) and irinotecan, to include pharmacogenetic testing as a potential means to reduce the rate of severe toxic events. Comprehensive evaluation of the clinical benefit and cost effectiveness of screening strategies with these tests has not been completed. However, the FDA decided that evidence indicates sufficient benefit to warrant informing prescribers, pharmacists and patients of the availability of pharmacogenetic tests and their possible role in the selection and dosing of these anticancer agents. Reviewing the gene-drug-phenotype relationships of 6-MP, irinotecan and 5-fluorouracil reveals properties of these relationships that lead to a clinically useful pharmacogenetic test. Research in the near future should clarify the role of pharmacogenetic testing in reducing the risk of severe toxicity and determine how these same tests might identify a subset of patients who should safely receive higher doses of treatment to derive the same benefit as the rest of the patient population.     

4β-hydroxycholesterol as an endogenous CYP3A marker in cancer patients treated with taxanes

Aim

Taxanes are anti-cancer agents used to treat several types of solid tumours. They are metabolized by cytochrome P450 (CYP) 3A, displaying a large pharmacokinetic (PK) variability. In this study, we evaluated the endogenous CYP3A4 marker 4β-hydroxycholesterol (4β-OHC) as a potential individual taxane PK predictor.

Methods

Serum 4β-OHC and cholesterol concentrations were determined in 291 paclitaxel and 151 docetaxel-treated patients, and were subsequently correlated with taxane clearance.

Results

In the patients treated with paclitaxel, no clinically relevant correlations between the 4β-OHC or 4β-OHC : cholesterol ratio and paclitaxel clearance were found. In the patients treated with docetaxel, 4β-OHC concentration was weakly correlated with docetaxel clearance in males (r = 0.35 P = 0.01, 95% CI 0.08, 0.58). Of the 10% patients with taxane outlier clearance values, 4β-OHC did correlate with docetaxel clearance in males (r = 0.76, P = 0.03, 95% CI 0.12, 0.95).

Conclusion

There was no clinical correlation between paclitaxel clearance and the CYP3A4 activity markers 4β-OHC or the 4β-OHC : cholesterol ratio. A weak correlation was observed between 4β-OHC and docetaxel clearance, but only in males. This endogenous CYP3A4 marker has limited predictive value for taxane clearance in patients.     

β-Elemene induces apoptosis as well as protective autophagy in human non-small-cell lung cancer A549 cells

Objectives β‐Elemene, a novel traditional Chinese medicine, has been shown to be effective against a wide range of tumours. In this study, the antitumour effect of β‐elemene on human non‐small‐cell lung cancer (NSCLC) A549 cells and the mechanism involved have been investigated. Methods Cell viability and apoptosis were measured by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. Protein expression was assayed by Western blotting. Autophagy was evaluated under fluorescence microscopy and transmission electron microscopy. Key findings β‐Elemene inhibited the viability of A549 cells in a dose‐dependent manner. This suppression of cell viability was due to the induction of apoptosis. Further study showed that β‐elemene inhibited the activity of the PI3K/Akt/mTOR/p70S6K1 signalling pathway, and at the same time it triggered a robust autophagy. The autophagy was characterized by the accumulation of punctate LC3 dots in the cytoplasm, morphological changes, and the increased levels of LC3‐II as well as Atg5‐Atg12 conjugated proteins. Inhibition of autophagy with chlorochine significantly enhanced the antitumour effect of β‐elemene. Conclusions Our data indicated that β‐elemene inhibited the activity of the PI3K/Akt/mTOR/p70S6K1 signalling pathway in human NSCLC A549 cells, which resulted in apoptosis as well as protective autophagy. A combination of β‐elemene with autophagy inhibitor might be an effective therapeutic option for advanced NSCLC.     

Chemokines and breast cancer: a gateway to revolutionary targeted cancer treatments?

Breast cancer is an example of a solid tumour which is well treated in the early stages of disease by surgical excision, but once metastatic spread has occurred, medical therapies (chemotherapy and radiotherapy) are highly toxic, expensive and palliative. It is known that certain tumours exhibit specific patterns of metastasis, chemokines may provide a molecular answer to this mystery. Chemokines and their receptors play important roles in the various stages of tumour development and metastasis. Chemokines interact with their specific receptors as well as interacting with the glycosaminoglycan (GAG) component of proteoglycan. We discuss the basic metastatic process and the involvement of chemokines in breast cancer biology. Finally, we summarize potential therapeutic applications of chemokines and chemokine/glycosaminoglycan interactions including chemokine agonists, antagonists, anti-sense therapy, immunotherapy and soluble GAGs, as well as future perspectives in this field.     

Genetic polymorphism of CYP2A6 is one of the potential factors determining tobacco-related cancer risk

WhilewestudiedpharmacokineticsofSM12502whichwasunderdevelopmentasananti PAFagent,we foundthreesubjectsshowingaslowmetabolicphenotypeinitspharmacokinetics.AnalyzingthegenesforCYP2A6fromthethreesubjects,wediscoveredthatthethreesubjectspossessedthewholeCYP2A6genedeletion(CYP2A64C),anovelgeneticpolymorphismoftheCYP2A6gene.GeneticallyengineeredSalmonellaYG7108cellsexpressinghumanCYP2A6orCYP2E1togetherwiththeNADPH CYPreductasewereestablishedinourlabo ratorytocomparethemutagen produci…     

Cyclosporin A suppresses prostate cancer cell growth through CaMKKβ/AMPK-mediated inhibition of mTORC1 signaling

Cyclosporin A (CsA) has antitumor effects on various cancers including prostate cancer. However, its antitumor mechanism is poorly understood. In this study, we showed that AMP-activated protein kinase (AMPK) mediates the antitumor effect of CsA on prostate cancer cells. CsA attenuated cell growth by inducing a G1 arrest through the inhibition of mTOR complex 1 (mTORC1) signaling. In this context, Akt was paradoxically activated downstream of the EGF receptor (EGFR)-mediated increase in phosphatidylinositol 3,4,5-trisphosphate (PIP₃) production. However, CsA also caused a Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ)-dependent activation of AMPK, which inhibits mTORC1 signaling; this led to ineffective Akt signaling. An EGFR or Akt inhibitor increased the growth suppressive activity of CsA, whereas the combination of an AMPK inhibitor and CsA markedly rescued cells from the G1 arrest and increased cell growth. These results provide novel insights into the molecular mechanisms of CsA on cancer signaling pathways.