Speaker
Dr
Yasuhiro Ohshima
(National Institutes for Quantum and Radiological Science and Technology)
Description
**Purpose:** Targeted α-particle therapy is a promising option for patients with malignant pheochromocytoma. Recent observations of *meta*-211At-astato-benzylguanidine (211At-MABG) in a pheochromocytoma mouse model showed a strong anti-tumor effect, but its molecular mechanism remains elusive (Y. Ohshima et al., 2018). Here, we showed the first comprehensive RNA-sequencing (RNA-seq) data of pheochromocytoma cells from *in vitro* 211At-MABG administration experiments, and screened key genes and pathways in the tumor α-particle radiation response, in order to obtain novel molecular imaging and therapeutic targets.
**Methods:** We evaluated genome-wide transcriptional alterations of rat pheochromocytoma cell line (PC12) at 3, 6, 12 h after 211At-MABG treatment. In order to highlight 211At-MABG specific gene expression, we carried out the control experiment of 60Co $\gamma$
-rays irradiation. Ten-percent and eighty-percent iso-survival dose (0.8 and 0.1 kBq/ml for 211At-MABG, 10 and 1 Gy for 60Co $\gamma$-rays) were used for the comparison of both treatments.
**Results:** Enrichment analysis of the differentially expressed genes (DEGs) and analysis of the gene expression profiles of the cell cycle checkpoints showed similar modes of cell death via p53-p21 signaling pathway following 211At-MABG treatment and $\gamma$-ray irradiation. Ten percent iso-survival dose of $\gamma$-ray irradiation and 211At-MABG showed cell cycle arrest at G2/M phase. Representative DEGs of 211At-MABG-treated cells between 80\% and 10\% survival showed the expression of key genes not only on the decrease in the survival, but also on the anti-therapeutic effects such as DNA repair, invasion, and metastasis. Furthermore, representative DEGs between γ-ray irradiation and 211At-MABG demonstrated that the expression of four potential genes including Otub1 related to ubiquitin mediated proteolysis was remarkably elevated only after treatment with 211At-MABG. Western blot analysis indicated the increase of translocator protein 18 kDa (TSPO) expression in 211At-MABG treated cells, suggesting the potential PET imaging probe.
**Conclusion:** Comprehensive RNA-seq revealed contrasting cellular responses to $\gamma$γ-ray irradiation and targeted α-particle therapy leading to the identification of four novel potential genes (Mien1, Otub1, Vdac1 and Vegfa) for molecular imaging and therapeutic targets of 211At-MABG therapy. Moreover, our results suggest possible mechanism of the anti-tumor effect of 211At-MABG in pheochromocytoma.
**Reference:** Y. Ohshima, H. Sudo, S. Watanabe, K. Nagatsu, A.B. Tsuji, T. Sakashita, Y.M. Ito, K. Yoshinaga, T. Higashi, N.S. Ishioka, Antitumor effects of radionuclide treatment using α-emitting *meta*-211At-astato-benzylguanidine in a PC12 pheochromocytoma model, *Eur. J. Nucl. Med. Mol. Imaging*, **45**, 999-1010. (2018)
**Acknowledgement:** The authors thank Yuki Takai for technical assistance in sequencing, and the staff of Takasaki ion accelerators for advanced radiation application and food irradiation facilities of QST for their operation.
| Funding Agency | The Yamagata Prefectural Government and Tsuruoka City, Japan. |
|---|---|
| Email Address | ohshima.yasuhiro@qst.go.jp |
| Presentation Type | Poster |
Primary author
Dr
Yasuhiro Ohshima
(National Institutes for Quantum and Radiological Science and Technology)
Co-authors
Mr
Ichiro SASAKI
(National Institutes for Quantum and Radiological Science and Technology)
Dr
Kazuharu ARAKAWA
(Keio University)
Dr
Nobuaki KONO
(Keio University)
Dr
Noriko ISHIOKA
(National Institutes for Quantum and Radiological Science and Technology)
Dr
Shigeki WATANABE
(National Institutes for Quantum and Radiological Science and Technology)
Dr
Tetsuya SAKASHITA
(National Institutes for Quantum and Radiological Science and Technology)
Dr
Yuichiro YOKOTA
(National Institutes for Quantum and Radiological Science and Technology)
