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.
Highlights
Several replication-selective oncolytic adenoviral mutants have been developed as potential therapies for the treatment of various cancers including prostate cancer [1,2,3]
We previously demonstrated that the oncolytic mutants AdDCR2 and dl922–947 deleted in the CR2region similar to dl1108, had only slightly attenuated replication and genome amplification in proliferating normal primary NHBE and PrEC cells when compared to wild type virus [16,40]
We show that expression of the small viral E1A12S protein from a replicationdefective virus or plasmid is sufficient to synergistically enhance cell killing in combination with mitoxantrone or docetaxel
Summary
Several replication-selective oncolytic adenoviral mutants have been developed as potential therapies for the treatment of various cancers (virotherapy) including prostate cancer [1,2,3]. In addition to altered AR-activity, prostate cancers frequently present with genetic alterations in cell cycle and cell death pathways including Ras/Raf/MEK/ERK, JAK/STAT and PI3K/AKT or deregulated pRb, p16, p53, PTEN, Bcl and related factors [5,6,7,8]. These alterations have been exploited for development of oncolytic adenoviruses since they complement and support replication of mutants deleted in the genes regulating the same pathways, while replication in normal tissue cannot proceed. Ad5-yCD/ mutTKSR39rep-ADP is currently being evaluated in a phase II/III randomized clinical trial in combination with chemo- and radiotherapies (NCT00583492: www.clinicaltrials.gov) [14]
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