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    ABSTRACT: Although prostate cancer is the most common malignancy to affect men in the Western world, the molecular mechanisms underlying its development and progression remain poorly understood. Like all cancers, prostate cancer is a genetic disease that is characterized by multiple genomic alterations, including point mutations, microsatellite variations, and chromosomal alterations such as translocations, insertions, duplications, and deletions. In prostate cancer, but not other carcinomas, these chromosome alterations result in a high frequency of gene fusion events. The development and application of novel high-resolution technologies has significantly accelerated the detection of genomic alterations, revealing the complex nature and heterogeneity of the disease. The clinical heterogeneity of prostate cancer can be partly explained by this underlying genetic heterogeneity, which has been observed between patients from different geographical and ethnic populations, different individuals within these populations, different tumour foci within the same patient, and different cells within the same tumour focus. The highly heterogeneous nature of prostate cancer provides a real challenge for clinical disease management and a detailed understanding of the genetic alterations in all cells, including small subpopulations, would be highly advantageous.
    No preview · Article · Nov 2012 · Nature Reviews Urology
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    ABSTRACT: Oncolytic adenoviruses have shown promising efficacy in clinical trials targeting prostate cancers that frequently develop resistance to all current therapies. The replication-selective mutants AdΔΔ and dl922-947, defective in pRb-binding, have been demonstrated to synergise with the current standard of care, mitoxantrone and docetaxel, in prostate cancer models. While expression of the early viral E1A gene is essential for the enhanced cell killing, the specific E1A-regions required for the effects are unknown. Here, we demonstrate that replicating mutants deleted in small E1A-domains, binding pRb (dl1108), p300/CBP (dl1104) and p400/TRRAP or p21 (dl1102) sensitize human prostate cancer cells (PC-3, DU145, 22Rv1) to mitoxantrone and docetaxel. Through generation of non-replicating mutants, we demonstrate that the small E1A12S protein is sufficient to potently sensitize all prostate cancer cells to the drugs even in the absence of viral replication and the E1A transactivating domain, conserved region (CR) 3. Furthermore, the p300/CBP-binding domain in E1ACR1 is essential for drug-sensitisation in the absence (AdE1A1104) but not in the presence of the E1ACR3 (dl1104) domain. AdE1A1104 also failed to increase apoptosis and accumulation of cells in G2/M. All E1AΔCR2 mutants (AdE1A1108, dl922-947) and AdE1A1102 or dl1102 enhance cell killing to the same degree as wild type virus. In PC-3 xenografts in vivo the dl1102 mutant significantly prolongs time to tumor progression that is further enhanced in combination with docetaxel. Neither dl1102 nor dl1104 replicates in normal human epithelial cells (NHBE). These findings suggest that additional E1A-deletions might be included when developing more potent replication-selective oncolytic viruses, such as the AdΔCR2-mutants, to further enhance potency through synergistic cell killing in combination with current chemotherapeutics.
    Full-text · Article · Oct 2012 · PLoS ONE
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    ABSTRACT: Introduction: Numerous oncolytic viral mutants derived from a variety of strains have antitumor efficacy with limited or no toxicity to normal tissue. While all modes of administration were determined to be safe in patients with solid cancers refractory to current standard of care, this therapeutic approach requires further improvements to achieve definite efficacy. Areas covered: We review the most promising clinical developments with several oncolytic viruses. The focus is on preclinical and clinical findings with replication-selective adenoviral mutants including ONYX-015, H101 and Ad5ΔCR mutants that, to date, are the most studied oncolytic viruses. Cellular pathways reported to play a role in virus-induced cell killing are reviewed as potential targets for the development of more effective combinatorial therapies. Expert opinion: The most promising clinical outcomes for metastatic cancers have been reported for oncolytic vaccinia and herpes virus mutants expressing the cytokine GMCSF. However, highly efficacious and selective adenoviral mutants have been developed that interact synergistically with cytotoxic drugs in model systems. We anticipate that by delineating the cellular targets for synergistic cancer cell killing in response to adenoviral mutants and drugs such as apoptosis and autophagy signaling, greatly improved anticancer therapies will result in the near future.
    No preview · Article · Aug 2012 · Expert Opinion on Therapeutic Targets
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