title: Efficacy of oncolytic mutants targeting pRb and p53 pathways is synergistically enhanced when combined with cytotoxic drugs in prostate cancer cells and tumor xenografts.
abstract: Replication-selective oncolytic adenoviruses have proven safety records with promising clinical outcomes. However, strategies to improve efficacy are still required. Here we report greatly improved antitumor efficacy for both attenuated (dl1520) and highly potent (dl922–947) oncolytic mutants in combination with the current standard of care for late-stage hormone-independent prostate cancers, mitoxantrone or docetaxel. In agreement with previous reports, dl922–947 had superior potency compared with dl1520 both as a single agent and in combination with cytotoxic drugs. The dl922–947 mutant caused significant synergistic cell killing in both drug-insensitive and -sensitive prostate cancer cell lines, PC3 and DU145, respectively, when combined with docetaxel or mitoxantrone. The magnitude of the synergistic response was greatest for dl1520 whereas overall efficacy was greatest for dl922–947, and the latter was also more efficacious in vivo in prostate cancer models. In DU145 and PC3 cells increased viral uptake (up to 9- and 8-fold, respectively), E1A expression, and altered cell cycle progression contributed to the synergistic cell killing. A similar trend was also detected in LNCaP cells. Potent E1A expression was essential for the response. In murine xenograft models (DU145 and PC3) tumor growth inhibition was improved when suboptimal doses of docetaxel and viral mutants were combined. These findings demonstrate that the efficacy of highly potent oncolytic mutants such as dl922–947 that target the retinoblastoma protein (pRb) pathway could be further enhanced even with low drug doses, and support the deletion of the E1ACR2 region in future candidate adenoviruses for treatment of hormone-independent prostate cancers.
authors.affiliation: Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Suresh
authors.initials: S
authors.lastname: Radhakrishnan
authors.forename: Enrique
authors.initials: E
authors.lastname: Miranda
authors.forename: Maria
authors.initials: M
authors.lastname: Ekblad
authors.forename: Alan
authors.initials: A
authors.lastname: Holford
authors.forename: Maria Tome
authors.initials: MT
authors.lastname: Pizarro
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Lemoine
authors.forename: Gunnel
authors.initials: G
authors.lastname: Halldén
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D017501:Adenovirus E1B Proteins / Q000235:genetics; D000260:Adenoviruses, Human / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D000077143:Docetaxel; D005434:Flow Cytometry; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008942:Mitoxantrone / Q000494:pharmacology / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D000970:Antineoplastic Agents; D016160:Retinoblastoma Protein; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000077143:Docetaxel; D008942:Mitoxantrone