The development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years. Resistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients. The oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to ‘molecular chess’. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results.

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Molecular chess? Hallmarks of anti-cancer drug resistance

Data on cell viability have long been obtained from in vitro cytotoxicity assays Today, there is a focus on markers of cell death, and the MTT cell survival assay is widely used for measuring cytotoxic potential of a compound However, a comprehensive evaluation of cytotoxicity requires additional assays which -measure short and long-term cytotoxicity Assays which measure the cytostatic effects of compounds are not less important, particularly for newer anticancer agents This overview discusses the advantages and disadvantages of different non-clonogenic assays for measuring short and medium-term cytotoxicity It also discusses clonogenic assays, which accurately measure long-term cytostatic effects of drugs and toxic agents For certain compounds and cell types, the advent of high throughput, multiparameter, cytotoxicity assays, and gene expression assays have made it possible to predict cytotoxic potency in vivo

Cellular chemosensitivity assays: an overview.

An enduring challenge in personalized medicine is to select right drug for individual patients. Testing drugs on patients in large clinical trials is one way to assess their efficacy and toxicity, but it is impractical to test hundreds of drugs currently under development. Therefore the preclinical prediction model is highly expected as it enables prediction of drug response to hundreds of cell lines in parallel. Recently, two large-scale pharmacogenomic studies screened multiple anticancer drugs on over 1000 cell lines in an effort to elucidate the response mechanism of anticancer drugs. To this aim, we here used gene expression features and drug sensitivity data in Cancer Cell Line Encyclopedia (CCLE) to build a predictor based on Support Vector Machine (SVM) and a recursive feature selection tool. Robustness of our model was validated by cross-validation and an independent dataset, the Cancer Genome Project (CGP). Our model achieved good cross validation performance for most drugs in the Cancer Cell Line Encyclopedia (≥80 % accuracy for 10 drugs, ≥ 75 % accuracy for 19 drugs). Independent tests on eleven common drugs between CCLE and CGP achieved satisfactory performance for three of them, i.e., AZD6244, Erlotinib and PD-0325901, using expression levels of only twelve, six and seven genes, respectively. These results suggest that drug response could be effectively predicted from genomic features. Our model could be applied to predict drug response for some certain drugs and potentially play a complementary role in personalized medicine.

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Anticancer drug sensitivity prediction in cell lines from baseline gene expression through recursive feature selection.

Efficacy of anti-cancer agents in cell lines versus human primary tumour tissue.

BACKGROUND: Metastatic prostate cancer (PCa) has no curative treatment options. Some forms of PCa are indolent and slow growing, while others metastasise quickly and may prove fatal within a very short time. The basis of this variable prognosis is poorly understood, despite considerable research. The aim of this study was to identify markers associated with the progression of PCa. METHODS: Artificial neuronal network analysis combined with data from literature and previous work produced a panel of putative PCa progression markers, which were used in a transcriptomic analysis of 29 radical prostatectomy samples and correlated with clinical outcome. RESULTS: Statistical analysis yielded seven putative markers of PCa progression, ANPEP, ABL1, PSCA, EFNA1, HSPB1, INMT and TRIP13. Two data transformation methods were utilised with only markers that were significant in both selected for further analysis. ANPEP and EFNA1 were significantly correlated with Gleason score. Models of progression co-utilising markers ANPEP and ABL1 or ANPEP and PSCA had the ability to correctly predict indolent or aggressive disease, based on Gleason score, in 89.7% and 86.2% of cases, respectively. Another model of TRIP13 expression in combination with preoperative PSA level and Gleason score was able to correctly predict recurrence in 85.7% of cases. CONCLUSION: This proof of principle study demonstrates a novel association of carcinogenic and tumourigenic gene expression with PCa stage and prognosis.

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Identification of markers of prostate cancer progression using candidate gene expression.

Dissecting intramural haematoma of the oesophagus (DIHO) is a rare condition, which has an excellent prognosis when managed conservatively. Awareness of this condition is vital to guide subsequent investigations and avoid inappropriate treatment or unnecessary surgical intervention. We describe an unusual case of massive DIHO causing left atrial compression presenting with pericarditic electrocardiographic changes and document the utility of endoscopic ultrasound/computed tomography to make the diagnosis.

Dissecting intramural haematoma of the oesophagus

Background: NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. Methods: The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue. Results: There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. Conclusion: Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.

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Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)

The incidence of 'accidental' splenectomy during oesophagectomy varies from 4 to 42% and leads to an increase in sepsis, anastomotic leakage and mortality. Therefore, preservation of the spleen should be the aim of treatment whenever splenic injury occurs. We describe the use of fibrin glue delivered as a thin film by a spray applicator for rapid and definitive haemostasis of grades 1 and 2 splenic injuries in patients undergoing oesophagectomy.

Paul Modi

Papers

Dissecting intramural haematoma of the oesophagus

Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)

Fibrin sealant treatment of splenic injuries during oesophagectomy.