Abstract 3961: Effectiveness of the combined treatment with hsp90 inhibitor and heavy ion irradiation

Abstract

Abstract Hsp90 inhibitors have been studied as effective sensitizers for radiation therapy. Some encouraging results have been observed and the mechanism of radio-sensitization has also been investigated mostly with X-or gamma-rays. There has not been any study for Hsp90 inhibitors with heavy ion radiation. In this report we show the data with the combined effect with hsp90 inhibitors including 17AAG and PU-H71 with high linear energy transfer (LET) heavy ion radiation. As in proton radiation treatment, heavy ions can be targeted to tumor tissues due to its physical properties, while significantly lower radiation doses are delivered in surrounding normal tissues. In addition, with heavy ions higher biological effectiveness, i.e, more tumor cell killing, can be attained than with proton or conventional photon radiation. We are finding that if tumor cells were pre-treated with an hsp90 inhibitor and then exposed to heavy ion (carbon) radiation, very effective cell killing were observed using SQ5 human lung tumor cells. Another interesting feature of hsp90 inhibitors is that normal cells are not much influenced by the drug. Our in vivo mouse xenograft studies using nude mice also indicate a better tumor control with the combination of hsp90 inhibitor and local carbon irradiation as compared with carbon irradiation alone. Further studies show that the mechanism behind this radio-sensitization may be attributed to inhibition of DNA double strand breaks (DSBs) by hsp90 inhibitors; particularly homologous recombination pathway of DSB repair might be affected. Our flow cytometry study also reveals some new aspect of tumor cell killing by this combination therapy. Our data suggest that hsp 90 inhibitors are good candidates for the combined cancer therapy using heavy ion irradiation. Citation Format: Ryuichi Okayasu, Aya Masaoka, Hirokazu Hirakawa, Hiroshi Fujisawa, Shigeaki Sunada, Ryoichi Hirayama, Miho Noguchi, Huizi Li, Akira Fujimori. Effectiveness of the combined treatment with hsp90 inhibitor and heavy ion irradiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3961. doi:10.1158/1538-7445.AM2014-3961