Bevacizumab IncreasesViral Distribution in Human Anaplastic Thyroid Carcinoma Xenografts and Enhances the Effects of E1A-DefectiveAdenovirus dl 922-947 Silvana Libertini, 1 IrmaIacuzzo, 1 GiuseppePerruolo, 1 Stefania Scala, 3 CaterinaIerano' , 3 Renato Franco, 4 Gunnel Hallden, 5 andGiuseppePortella 1,2 Abstract Purpose: Anaplastic thyroid carcinoma is a prime target for innovative therapy because it repre- sents one of the most lethal human neoplasms and is refractory to conventional treatments such aschemotherapyandradiotherapy.Wehaveevaluatedanoveltherapeuticapproachbasedonthe oncolytic replication-selective adenovirus dl 922-947. Experimental Design: The antitumor efficacies of the E1ADCR2 ( dl 922-947) and DE1B55K ( dl1520) mutants were compared in human thyroid anaplastic carcinoma cells in culture and in xenografts in vivo.To enhance the effects of dl 922-947, anaplastic thyroid carcinoma tumorxen- ografts were treated with dl 922-947 in combination withbevacizumab. Results: We showed that the efficacy of dl 922-947 exceeded that of dl1520 in all tested ana- plasticthyroidcarcinomacells in vitro and in vivo.Furthermore,bevacizumabincombinationwith dl 922-947significantlyreducedtumorgrowthcomparedwithsingletreatmentsalone.Bevacizu- mab treatment significantly improved viraldistributioninneoplastic tissues. Conclusions: Our data showed that dl 922-947 had a higher oncolytic activity compared with dl1520 in anaplastic thyroid carcinoma cell lines and might represent a better option for virother- apy of anaplastic thyroid carcinoma. Moreover, bevacizumab increased the oncolytic effects of dl 922-947 by enhancing viral distribution in tumors.The results described herein encourage the use of the dl 922-947 virus in combination withbevacizumab. Thyroid neoplasia comprises tumors with different molecular and clinical features, including well-differentiated follicular and papillary carcinomas and poorly differentiated and undifferen- tiated anaplastic carcinomas (1). Anaplastic thyroid carcinoma constitutes 1% to 7% of all thyroid cancer cases. It arises from thyroid follicular cells with morphologic features of malignant undifferentiated neoplasms without features of thyroid differentiation (2). At odds with papillary and follicular carcinomas, which have a long-term favorable prognosis (3) with a high survival rate (>95%), patients affected by anaplastic thyroid carcinoma have a survival time of 2 to 6 months following diagnosis (4). The major impediment to successful control of the disease is the absence of active therapies (4); therefore, novel therapeutic approaches are required. Selectively replicating oncolytic viruses represent a novel therapeutic approach. Several viruses, including adenoviruses, have been engineered for selective targeting of neoplastic cells. The most common approach is the deletion of a viral gene whose product is necessary for its replication in normal cells but expendable in cancer cells (5). The first engineered replication-competent adenoviral mutant was dl 1520 (Onyx- 015), with a deletion of the E1B-55K gene, making this mutant unable to inhibit p53 and apoptosis. Consequently, dl 1520 could replicate in cancer cells lacking the functional p53 pathway but not in normal cells (6). The dl 1520 mutant was predicted to replicate in most human cancers because the p53 pathway is nonfunctional in most human neoplasias. However, E1B-55K also mediates late viral RNA nuclear export, and the absence of this gene restricts viral replication to tumor cells able to complement the viral RNA export function (7). Despite these limitations, promising antitumor activity of dl 1520 in combination with chemotherapy was shown in several clinical trials (8). Recently, results from a phase III clinical trial confirmed the ability of a similar oncolytic mutant (H101), with the E1B-55kD gene deleted, to Cancer Therapy: Preclinical Authors’Affiliations: 1 DipartimentodiBiologiaePatologiaCellulareeMolecolare; 2 Cattedra di Patologia Clinica Universita' Federico II; 3 Clinical Immunology and 4 Pathology, National Cancer Institute, Fondazione ‘‘G. Pascale,’’ Naples, Italy; and 5 Cancer Research UK Molecular Oncology Unit, Barts and the London School of Medicine and Dentistry, London, United Kingdom Received1/24/08;revised4/21/08;accepted4/30/08. Grant support: AssociazioneItalianaperlaRicercasulCancro;theItalianMinistry of Instruction, University and Research; and a grant from Fondazione Italiana per la Ricerca sul Cancro (S. Libertini). Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.This article must therefore be hereby marked advertisement in accordance with18U.S.C.Section1734solely toindicatethisfact. Note: S. Libertini and I. Iacuzzo contributed equally to this work. Presented in part atthe31stAnnualMeetingofEuropeanThyroidAssociation,September2-6,2006, Naples, Italy [Iacuzzo I, Libertini S, Fiorillo M, Pacelli R, Hallden G, Portella G.‘‘An E1A mutant adenovirus ( dl 922-947)enhancestheeffectsofpaclitaxel,doxorubicin and radiationinhumananaplastic thyroid carcinoma celllines’’]. Requests for reprints: Giuseppe Portella, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facolta' di Medicina e Chirurgia, Universita' di Napoli Federico II,Via S. Pansini 5, 80131Naples, Italy. Phone: 39-81-746-3056; Fax: 39-81-746-3037;E-mail:portella@unina.it. F 2008AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-08-0200 www.aacrjournals.org Clin Cancer Res 2008;14(20) October15, 2008 6505 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/14/20/6505/1977035/6505.pdf by guest on 19 June 2022