Diffusing alpha-emitters radiation therapy in combination with temozolomide or bevacizumab in human glioblastoma multiforme xenografts

Yossi Nishri; Maayan Vatarescu; Ishai Luz; Lior Epstein; Mirta Dumančić; Sara Del Mare; Amit Shai; Michael Schmidt; Lisa Deutsch; Robert B Den; Itzhak Kelson; Yona Keisari; Lior Arazi; Tomer Cooks; Vered Domankevich

doi:10.3389/fonc.2022.888100

Diffusing alpha-emitters radiation therapy in combination with temozolomide or bevacizumab in human glioblastoma multiforme xenografts

Front Oncol. 2022 Sep 27:12:888100. doi: 10.3389/fonc.2022.888100. eCollection 2022.

Authors

Yossi Nishri¹, Maayan Vatarescu^{1

2}, Ishai Luz^{1

2}, Lior Epstein^{3

4

5}, Mirta Dumančić³, Sara Del Mare¹, Amit Shai¹, Michael Schmidt⁶, Lisa Deutsch⁷, Robert B Den^{1

8}, Itzhak Kelson⁹, Yona Keisari¹⁰, Lior Arazi³, Tomer Cooks², Vered Domankevich¹

Affiliations

¹ Translational Research Laboratory, Alpha Tau Medical, Jerusalem, Israel.
² The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.
³ Unit of Nuclear Engineering, Faculty of Engineering Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
⁴ Radiation Protection Department, Soreq Nuclear Research Center, Yavne, Israel.
⁵ Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel.
⁶ Physics Laboratory, Alpha Tau Medical, Jerusalem, Israel.
⁷ Biostatistics Department, BioStats Statistical Consulting Ltd., Maccabim, Israel.
⁸ Department of Radiation Oncology, Urology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, United States.
⁹ School of Physics and Astronomy, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel.
¹⁰ Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Abstract

Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy [e.g., temozolomide (TMZ)], and targeted therapy [e.g., the antiangiogenic agent bevacizumab (BEV)]. Diffusing alpha-emitters radiation therapy (DaRT) is a new modality that employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown to be effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with standard-of-care therapies such as TMZ or BEV was investigated. In a viability assay, the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone in U87 cultured cells. A colony formation assay demonstrated that the surviving fraction of U87 cells treated by TMZ in combination with alpha irradiation was lower than was achieved by alpha- or x-ray irradiation as monotherapies, or by x-ray combined with TMZ. The treatment of U87-bearing mice with DaRT and TMZ delayed tumor development more than the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in large tumors relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of ²²⁴Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care chemotherapy or antiangiogenic therapy are promising approaches, which may improve the treatment of GBM patients.

Keywords: alpha DaRT; alpha particle; antiangiogeic therapy; glioblasoma multiforme; radiotheapy.