Abstract 479: ATM pathway upregulation of combination therapy with radiation and MSC-based IL-12M gene vaccine, Gx-051, in allograft animal model.
Authors: Yeo Jiyoung , Park Eun-Ji , Cho Kwang-Jae , Kim Kyung Min , Sung Young-chul , Park Jun-Ook , Nam In-chul , Kim Chung-su , Kim Min-Sik 
Published: August 2014

PURPOSE: In spite of the powerful therapeutic effects of radiotherapy, the attempts to combined radiotherapy with others have so far kept going on to find better therapeutic protocol for patients in the head and neck cancer. Previously, we announced some part of anticancer effects of combined radiotherapy with Gx-051 named as mesenchymal stem cell (MSC) expressing modified interleukin-12 (MSCs/IL-12M). It is a novel component of human immune system to attack cancer cells by the recruitment of immune cells with a high specificity. Thus, in the present study, we have tried to reveal another therapeutic effect of combined radiation and immunotherapy, compared to the treatment with each single modality in allograft animal model.

METHODS AND MATERIALS: AT-84 cells, one of murine head and neck carcinoma cells, were injected for allograft induction on C3H/HeN mice. All the mice were randomly divided into 4 groups; control (non-treated), radiation only-treated, Gx-051 only-treated, and irradiation with Gx-051-treated. Intra-tumoral injection of Gx-051 (adopted within 24hr after irradiation) as well as 8 Gy-local irradiation was carried out, totally 4 times (twice a week for 2 weeks). To clarify the anti-tumoral effect of radiation with Gx-051 administration, we provided reasonable evidences; tumor volume, levels of IL-12 and IFN-r, and the changes in signaling pathway related-protein expression level.

RESULTS: In the present study, we could confirm that combined treatment with radiation and Gx-051 significantly enhanced the anti-tumor effect. The proliferation of cancer cell was markedly inhibited in all the treated groups compared to non-treated group (p&lt;0.05) as down-regulating of PCNA expression. Also, via mediating the expression of ATM and CDK2, the combined treatment group (radiotherapy with Gx-051) significantly enhanced the activation of ATM pathway-related proteins (p&lt;0.05). The tumor suppress gene, p53, was highly expressed and the one of typical oncogenes, Met, was suppressed in combined treatment group compared to others. In addition, expression of p38-MAPk as one of the cell stress markers was decreased in combined treatment group compared to others.

CONCLUSIONS: We determined the combined radiotherapy with Gx-051 improved the responses to HNSCC by AT-84 via the activation of ATM pathway that influenced cell proliferation, apoptosis, and regulation of tumor suppress gene and oncogene. These results gave us the partial rationale to the further study about the combined therapy of radiation with Gx-051 for the advanced treatment of human HNSCC.

This study was supported by grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare (A091205) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2012-0004140).

Citation Format: Jiyoung Yeo, Eun-Ji Park, Kwang-Jae Cho, Kyung Min Kim, Young-chul Sung, Jun-Ook Park, In-chul Nam, Chung-su Kim, Min-Sik Kim. ATM pathway upregulation of combination therapy with radiation and MSC-based IL-12M gene vaccine, Gx-051, in allograft animal model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 479. doi:10.1158/1538-7445.AM2013-479