Oncotarget

Research Papers:

IL13RA2 targeted alpha particle therapy against glioblastomas

Anirudh Sattiraju, Kiran Kumar Solingapuram Sai, Ang Xuan, Darpan N. Pandya, Frankis G. Almaguel, Thaddeus J. Wadas, Denise M. Herpai, Waldemar Debinski and Akiva Mintz _

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Oncotarget. 2017; 8:42997-43007. https://doi.org/10.18632/oncotarget.17792

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Abstract

Anirudh Sattiraju1,2,*, Kiran Kumar Solingapuram Sai1,2,*, Ang Xuan4,*, Darpan N. Pandya2, Frankis G. Almaguel1, Thaddeus J. Wadas1,3, Denise M. Herpai2,3, Waldemar Debinski2,3 and Akiva Mintz1,2

1Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA

2Brain Tumor Center of Excellence, Wake Forest University Comprehensive Cancer Center, Winston-Salem, NC 27157, USA

3Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA

4Department of Nuclear Medicine and Radiology, The People’s Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China

*These authors contributed equally to this work

Correspondence to:

Akiva Mintz, email: amintz@wakehealth.edu

Keywords: glioblastoma, IL13RA2, alpha particle therapy, Actinium-225, Copper-64

Received: January 10, 2017     Accepted: April 15, 2017     Published: May 11, 2017

ABSTRACT

Glioblastoma (GBM) is the most aggressive primary malignant brain cancer that invariably results in a dismal prognosis. Chemotherapy and radiotherapy have not been completely effective as standard treatment options for patients due to recurrent disease. We and others have therefore developed molecular strategies to specifically target interleukin 13 receptor alpha 2 (IL13RA2), a GBM restricted receptor expressed abundantly on over 75% of GBM patients. In this work, we evaluated the potential of Pep-1L, a novel IL13RA2 targeted peptide, as a platform to deliver targeted lethal therapies to GBM. To demonstrate GBM-specificity, we radiolabeled Pep-1L with Copper-64 and performed in vitro cell binding studies, which demonstrated specific binding that was blocked by unlabeled Pep-1L. Furthermore, we demonstrated real-time GBM localization of [64Cu]Pep-1L to orthotopic GBMs using small animal PET imaging. Based on these targeting data, we performed an initial in vivo safety and therapeutic study using Pep-1L conjugated to Actinium-225, an alpha particle emitter that has been shown to potently and irreversibly kill targeted cells. We infused [225Ac]Pep-1L into orthotopic GBMs using convection-enhanced delivery and found no significant adverse events at injected doses. Furthermore, our initial data also demonstrated significantly greater overall, median and mean survival in treated mice when compared to those in control groups (p < 0.05). GBM tissue extracted from mice treated with [225Ac]Pep-1L showed double stranded DNA breaks, lower Ki67 expression and greater propidium iodide internalization, indicating anti-GBM therapeutic effects of [225Ac]Pep-1L. Based on our results, Pep-1L warrants further investigation as a potential targeted platform to deliver anti-cancer agents.


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