Kenichiro Naito

Increased phosphorylation of Akt in triple-negative breast cancers

Cells from breast cancers lacking hormone receptors (estrogen receptor [ER], progesterone receptor [PgR]) and human epidermal growth factor receptor (HER) 2 strongly express the cell proliferation marker Ki‐67. However, the mechanisms of and stimulus signals involved in cell proliferation of this type of breast cancer are not well understood. The aim of the present study was to examine the characteristics of signal transduction in triple‐negative (ER‐, PgR‐, and HER2‐negative) breast cancers. For 44 tumor samples, western blotting analysis was conducted to examine the phosphorylation of HER2, external signal‐regulated kinase (ERK)1 and ‐2 and Akt, and the immunohistochemical phenotypes of the samples with respect to ER and HER2 were also assessed. Phosphorylation of HER2 was detected in 4 of 15 immunohistochemically HER2‐positive tumor samples (26.7%). ERK1/2 was more highly phosphorylated in triple‐negative breast cancers. Phosphorylation of Akt kinase was significantly higher in triple‐negative breast cancers. Triple‐negative breast cancers are characterized by increased phosphorylation of Akt kinase. In the present study, we found for the first time that there is a population with a significantly activated Akt pathway in this type of breast cancer. (Cancer Sci 2007; 98: 1889–1892)

Novel HER2 selective tyrosine kinase inhibitor, TAK‐165, inhibits bladder, kidney and androgen‐independent prostate cancer in vitro and in vivo

Purpose:  TAK‐165 is a new potent inhibitor of human epidermal growth factor receptor 2 (HER2) tyrosine kinase. Several reports suggest HER2 expression in bladder cancer, renal cell carcinoma (RCC) and androgen‐independent prostate cancer. We therefore investigated the antitumor effect of TAK‐165 on these urological cancer cells.

Abstract 1368: Preclinical evaluation of NC-6201, an antibody/drug-conjugated micelle incorporating novel hemiasterlin analogue E7974

Background: Antibody-drug conjugates (ADCs) have been recognized as a promising anticancer agent. There have been a lot of registered clinical trials for ADCs. However, not all ADC compounds were successful. To overcome the difficulties and drive the next generation of ADCs, we have recently developed Antibody/Drug-Conjugated Micelle (ADCM) system. ADCM is composed of polyethylene glycol-poly (amino acid derivative) polymers, which can form a micellar nanoparticle spontaneously in aqueous media with a diameter of 20-100 nm. Antibodies are attached to the surface of the nanoparticle, while payloads are incorporated in the inner core at a payload-to-antibody molecular ratio of 100-200. In this study, anti-EGFR monoclonal antibody NCAB001 and novel hemiasterlin analogue E7974 were used as a targeting sensor and a payload of the ADCM (NC-6201), respectively. Here we report the results of in vitro evaluation and in vivo efficacy and toxicity studies. Methods: NC-6201 was prepared as described previously (Japan Patent No.4538666) with slight modification. The antigen affinity and the cytotoxicity of NC-6201 were evaluated using a Biacore system and Cell Counting Kit-8, respectively. NC-6201 was administered intravenously to BALB/c-nu/nu mice xenografted with various human tumor cell lines. Tumor volumes and animal body weights were monitored 2 or 3 times a week. Also, the dose- and schedule-dependency of the antitumor effect were evaluated. Single-dosed toxicological studies of NC-6201 in SD rats and cynomolgus monkeys were performed. Results: NC-6201 showed similar antigen affinity to the unconjugated NCAB001 and had a broad range of in vitro cytotoxicity against a panel of tumor cells. NC-6201 potently suppressed tumor growth in nude mice bearing subcutaneous human tumor xenografts expressing EGFR, such as BxPC-3 (pancreas) and MDA-MB-231 (triple-negative breast) tumor models. The efficacious NC-6201 dose schedules were achieved at one tenth or two fifth of its MTD. In an EGFR-null tumor model, NC-6201 and untargeted micelle incorporating E7974 showed comparable tumor growth inhibition. Overall, NC-6201 at efficacious doses was well tolerated without significant body weight loss, indicating that NC-6201 has an excellent therapeutic window. Relative to E7974, NC-6201 showed an unaltered toxicity profile in rats and monkeys, and the potential for reduced toxicity and an improved therapeutic window. Conclusion: Based on these promising results, NC-6201 is advanced in our project pipeline as a clinical candidate for cancer therapy. Citation Format: Mitsunori Harada, Masami Tsuchiya, Ryusuke Miyazaki, Tadashi Inoue, Ryosuke Tanaka, Yuuki Yanagisawa, Masayoshi Ito, Yu Ito, Kenichiro Naito. Preclinical evaluation of NC-6201, an antibody/drug-conjugated micelle incorporating novel hemiasterlin analogue E7974. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1368.