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CD133-targeted oncolytic adenovirus demonstrates anti-tumor effect in colorectal cancer.

ABSTRACT: Oncolytic Adenoviruses (OAds) are one of the most promising anti-cancer agents that can induce cancer specific cell death. Recently, we generated infectivity-selective OAd, and the resultant OAd tumor-specific binding shows strong efficacy and mitigates toxicity. In this study, we applied this strategy based on adenovirus library screening system for generation of CD133-targeted OAd, and examined their oncolytic activity against colorectal cancer (CRC) in vitro and in vivo. CD133 (Prominin-1) is an important cell surface marker of cancer stem (like) cells (CSCs) in various cancers, including CRC. Elimination of CSCs has a high likelihood to improve CRC treatment because CSCs population in the tumor contributes to recurrence, metastases, chemotherapy resistance, and poor survival. The OAd with CD133-targeting motif (AdML-TYML) selectively infected CD133+ cultured cells and lysed them efficiently. Treatment with AdML-TYML prior to tumor inoculation inhibited the establishment of tumor of CD133+ CRC cell lines in nude mice. AdML-TYML also showed strong antitumor effect after intratumoral injections in already established CD133+ CRC subcutaneous xenografts. Our results indicate that CD133-targeted OAd selectively infected CD133+ CRC, and exhibited anti-tumorigenicity and therapeutic effect in established tumors. This novel infectivity selective virus could be a potent tool for the prevention of metastases and relapses in CRC.

SUBMITTER: Sato-Dahlman M

PROVIDER: S-EPMC5652684 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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CD133-targeted oncolytic adenovirus demonstrates anti-tumor effect in colorectal cancer.

Sato-Dahlman Mizuho M Miura Yoshiaki Y Huang Jing Li JL Hajeri Praveensingh P Jacobsen Kari K Davydova Julia J Yamamoto Masato M

Oncotarget 20170602 44

Oncolytic Adenoviruses (OAds) are one of the most promising anti-cancer agents that can induce cancer specific cell death. Recently, we generated infectivity-selective OAd, and the resultant OAd tumor-specific binding shows strong efficacy and mitigates toxicity. In this study, we applied this strategy based on adenovirus library screening system for generation of CD133-targeted OAd, and examined their oncolytic activity against colorectal cancer (CRC) <i>in vitro</i> and <i>in vivo</i>. CD133 ( ...[more]

PMID: 29100290

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Project description:Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RTs) are rare pediatric brain tumors affecting mainly infants and young children. However, AT/RTs encompass almost 10% of death caused by pediatric brain tumors, and the 2-year overall survival for these children remains below 20%. For this reason, AT/RT ranks among the deadliest pediatric brain tumors. Therefore, it is clear we need to find out new therapeutic options for these children. Delta-24-RGD is an oncolytic adenovirus that has already demonstrated its efficacy as in Phase I/II clinical trials in adult patients affected by high grade gliomas with no evidence of severe side effects. Of interest for pediatric brain tumors, the safety of Delta-24-RGD is has also been demonstrated in an ongoing Phase I clinical trial for the treatment of DIPGs (NCT03178032). For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT. MATERIAL AND METHODS Our studies have been carried out in three stablished AT/RT cell lines (BT-12, CHLA-06 and CHLA-266). In vitro, AT/RT cultures were infected with Delta-24-RGD-GFP to confirm the infectivity of the virus by flow cytometry. Replication of Delta-24-RGD was ensured by titrating the PFUs generated in AT/RT infected cultures. In regard to cytolytic effect, viability assays (MTS) were conducted in AT/RT cultures infected at increasing MOIs of Delta-24-RGD. In vivo, AT/RT cell lines were engrafted in Rag-2 mice in supratentorial and infratentorial locations, and the animals were treated with Delta-24-RGD at 107 or 108 PFU/animal (intra-tumor administration), or PBS. The therapeutic benefit of Delta-24-RGD was evaluated comparing the overall survival obtained for treated and untreated animals using the Log-rank test. We have also generated models of disseminated disease through intraventricular injection of the tumor cells, thus mimicking the lesions found in patients. AT/RT cell lines were transduced with a luc-expressing lentivirus to facilitate the follow up of these tumors. Mice bearing disseminated AT/RT were treated with Delta-24-RGD at 107 or 108 PFU/animal, or PBS (control). The therapeutic effect was monitored by bioluminescence and by comparison of the survival curves (Log-rank). RESULTS The virus was able to infect and replicate in tumor three different cell culture models of AT/RT, inducing a potent cytotoxic effect that resulting in IC50 values below 1 PFU/cell. Administration of the virus in mice bearing localized AT/RT (supratentorial and infratentorial) extended significantly the survival the animals, leading to up to 20% of long-term survivors. In disseminated AT/RT models, light emission reveals reduction of tumor growth in virus treated animals, resulting in an increased overall survival. CONCLUSION In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic choice for patients affected by AT/RT.

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CD133-targeted oncolytic adenovirus demonstrates anti-tumor effect in colorectal cancer.

Publications

CD133-targeted oncolytic adenovirus demonstrates anti-tumor effect in colorectal cancer.

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