1753 - Ex vivo cytotoxicity and in vivo antitumor activity of a novel highly selective STAT3 inhibitor YHO-1701 for ovarian and endometrial cancer

Background

The signal transducer and activator of transcription (STAT) 3 plays a critical role in the regulation of cell growth, metastasis, and survival. STAT3 signaling is constitutively activated in various cancers including gynecological cancers. We evaluated the efficacy of a novel selective STAT3 inhibitor, YHO-1701, ex vivo and in vivo for ovarian and endometrial cancer.

Methods

An expression profile of YHO-1701 treated cells was compared with that of other STAT3 inhibitors or its upstream Janus kinase inhibitor by RNA sequencing. The downstream signaling of YHO-1701 was investigated by western blot. Patients derived primary cancer cells (PDCs) were isolated from surgical specimens or ascites cells from ovarian or endometrial cancer patients, and the growth inhibitory effect of YHO-1701 on PDCs was evaluated by standard colorimetric assays. Antitumor activity of YHO-1701 was assessed using an SKOV3 abdominal dissemination xenograft model.

Results

We investigated the specificity of YHO-1701 by pathway analysis using RNA sequencing results of the cells treated with or without each inhibitor and found YHO-1701 regulated STAT3 signaling more tightly than others did. We confirmed decreased levels of pSTAT3 S727, Survivin, and c-Myc in the cells treated with YHO-1701. A total of 41 PDCs were treated with YHO-1701 and showed a remarkable growth inhibition compared with the control group (P < 0.0007 and P < 0.0001 for ovarian and endometrial cancer cells, respectively). We tested the potential antitumor activity of orally administrated YHO-1701 in a mouse intraperitoneal dissemination model of ovarian cancer using SKOV3. We observed decreased numbers of peritoneal metastasis in mice treated with YHO-1701 compared with those treated with vehicle control (P < 0.05).

Conclusions

Our results demonstrated the efficacy of YHO-1701 for ovarian and endometrial cancer both ex vivo and in vivo through STAT3 signaling.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Yakult Honsha.

Disclosure

K. Hasegawa: Research grant / Funding (self): Yakult. K. Taniguchi: Full / Part-time employment: Yakult. A. Yoshinaga: Full / Part-time employment: Yakult. M. Tsugane: Full / Part-time employment: Yakut. All other authors have declared no conflicts of interest.