Assessment and development of adenovirus type 11 for cancer therapy

PhDThe efficacy of oncolytic virotherapy is influenced by the interactions between the tumour, virus and host immunity. The first generation of oncolytic adenoviruses, based on serotype 5 (Ad5), has achieved limited success in clinical trials. Its shortcomings include the downregulation and inaccessibility of its receptor, the Coxsackie and adenovirus receptor (CAR) in cancer cells, high prevalence of neutralising antibodies and hepatotoxicity. In contrast, Ad11 binds to CD46 and other receptor(s) but its potential as an oncolytic virus remains to be explored. A panel of human cancer cell lines were found to express higher levels of CD46 than CAR. However, not all cell lines were more sensitive to Ad11-mediated cytotoxicity in vitro compared to Ad5. Treatment of Ad5-insensitive PC-3 human prostate cancer xenografts with Ad11 resulted in significant reduction in tumour growth, but not Ad11-insensitive MIA PaCa-2 human pancreatic cancer xenografts. Virus attachment and nuclear entry of Ad11 were significantly better than Ad5 even in cells that were insensitive to Ad11 killing. In these cells, however, Ad11 E1A mRNA levels were much lower than those of Ad5, producing a negative effect on viral DNA amplification, structural protein synthesis, progeny production and cell killing. Cells that were sensitive to Ad11 cytotoxicity showed higher levels of E1A mRNA. The region upstream of Ad5 E1A demonstrated higher transcription-enhancing activity than the corresponding region of Ad11. Two Ad11 mutants were constructed in which E1A was under the control of the Ad5 E1A promoter and enhancer-promoter, respectively. With the latter virus, improved oncolytic potency was observed. It was superior to Ad11 and also to Ad5 in many cancer cell lines, and was as effective as Ad5 in the MIA PaCa-2 xenograft model. Therefore, Ad11 with the Ad5 E1A enhancerpromoter should be used as a backbone for the future development of potent and tumour-specific oncolytic Ad11 mutants

A Comprehensive Single Institutional Review of 2 Years in a Designated Fast-Track Sarcoma Diagnostic Clinic Linked with a Sarcoma Specialist Advisory Group: Meeting the Target but Failing the Task?

Background. National guidelines prompted the implementation of a designated two-week wait referral pathway to facilitate the early diagnosis of sarcomas, to improve treatment outcomes. Methods. Patients referred to the Cambridge Sarcoma Diagnostic Clinic between January 2013 and December 2014 were identified through the electronic appointments system. Information was retrospectively retrieved about patient characteristics and details of the diagnostic pathway. Results. 17.3% of patients referred (69/397) were diagnosed with a malignancy. Of these, 59.3% (41/69) had primary sarcomas, 17.4% (12/69) had metastatic cancer, and 23.2% (16/69) had a different primary malignancy. 15% of the 41 sarcomas were 10 cm. Sarcomas diagnosed through this clinic represented 13% (41/315) of sarcomas managed at the centre during the same 2 years. Conclusion. While we achieved the target of 10% (41/397) sarcoma diagnosis rate in the rapid access clinic, only 15% of these were <5 cm better prognosis lesions. This calls into question the "real world" impact of such diagnostic clinics on early diagnosis of sarcomas. In order to enhance generic cancer diagnostic skills, training in these diagnostic clinics could be usefully integrated into national training curricula for both surgical and nonsurgical oncologists.This is the final version of the article. It first appeared from the Hindawi Publishing Corporation via http://dx.doi.org/10.1155/2016/603260

Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles

Targeted therapy of cancer using oncolytic viruses has generated much interest over the past few years in the light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. In 2006, the world witnessed the first government-approved oncolytic virus for the treatment of head and neck cancer. It has been known for many years that viruses have the ability to replicate in and lyse cancer cells. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response. This review focuses on discussion of the obstacles that oncolytic virotherapy faces and recent advances made to overcome them, with particular reference to adenoviruses

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)