Abstract 4691: KRAS mutation specific alkylating pyrrole-imidazole polyamide (KR12) suppresses mutant KRAS expression and inhibits tumor growth by showing accumulation in KRAS mutant xenografts

Abstract

Abstract Constitutive active mutations of KRAS are detected in 35-40% of human colon cancers, and almost all of them are the constitutive active missense mutations at codon 12 (80%) or codon 13 (20%). Consistent with these observations, the presence of KRAS mutations has been shown to be associated with malignant properties of tumors as well as a poor clinical outcome of the patients bearing these tumors. Unfortunately, yet no effective anti-cancer drug(s) specifically targeting KRAS mutations have been developed. Hence, we synthesized an alkylating agent conjugated with the Pyrrole-Imidazole polyamide (KR12: PI-polyamide-seco-CBI), which recognized KRAS G12D or G12V mutations at codon12. We have previously found that KR12 has anti-tumor effects in vitro and in vivo. However, it still remains elusive whether KR12 exerts its selective toxicity towards colon cancer cells by penetrating into the tumor tissues and inhibiting the expression of mutant KRAS gene in mouse model of human cancer. To address this issue, we decided to examine the distribution of KR12 using FITC labeled PI polyamide. In vivo imaging of tumor-bearing mice after single intravenous administration demonstrated that the highest fluorescence intensity was seen in the tumor sites 24 hours after injection with showing nuclear localization. Quantitative RT-PCR revealed that KR12 decreased the mutated KRAS expression in tumor tissues obtained from KRAS-heterozygous-mutated-LS180-xenografted mice (G12D heterozygous mutation). Since KR12 showed long lasting accumulation in xenografts we compared the effect of single and multiple administration of KR12. Once a week injection for five to eight weeks resulted in significant suppression of tumor growth in homozygous mutant SW480 (G12V homozygous mutation) xenografts. Surprisingly, both single and multiple treatments of KR12 induced massive tumor volume reduction without affecting body weight gain. These data suggest that KR12 accumulation in colon xenograft tumor tissues may emphasize drug local effect and minimize systemic adverse effect. Citation Format: Takahiro Inoue, Kiriko Hiraoka, Yusei Suzuki, Hiroyuki Yoda, Takayoshi Watanabe, Atsushi Takatori, Nobuko Koshikawa, Toshinori Ozaki, Hiroki Nagase. KRAS mutation specific alkylating pyrrole-imidazole polyamide (KR12) suppresses mutant KRAS expression and inhibits tumor growth by showing accumulation in KRAS mutant xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4691. doi:10.1158/1538-7445.AM2015-4691