Abstract 1238: Treating estrogen receptor (ER)-negative and triple-negative breast cancer by targeting STAT3 signaling with putative STAT3 inhibitors

Abstract

Abstract Approximately 20% to a quarter of breast cancer cases are estrogen receptor (ER)-negative breast cancer (ENBC), including the most aggressive subtype, triple-negative breast cancer (TNBC), which spreads early and shows poor prognosis. ENBCs do not respond to selective ER modulators such as tamoxifen. Therefore, there is an urgent need for non-ER-based therapies for ENBC. Recently, STAT3 was found to play an important role in maintaining cancer stem cells in vitro and in mouse models of human cancers. In addition, during mammary carcinogenesis, STAT3 is highly activated in mammary epithelial cells involving in mammary epithelial cell transformation, tumor initiation, progression, and metastasis. STAT3 has been traditionally considered as non-targetable or undruggable, and there is currently a lack of FDA-approved STAT3 inhibitors for clinical use. We recently developed a putative STAT3 inhibitor, HJC0152, and a series of HJC0152-based analogues as orally bioavailable STAT3 inhibitors. These small molecules have been evaluated and a number of them showed low micro-molar potency in inhibiting the proliferation of a panel of breast cancer cell lines. Compound JMX0804 showed improved anti-proliferative effects against the highly aggressive TNBC cell line MDA-MB-231 and other ER+ and ER- breast cancer cell lines in comparison to HJC0152. JMX0804 inhibited STAT3 phosphorylation at the Tyr705 residue and induced apoptosis in MDA-MB-231 cells. In vivo, mice treated with JMX0804 at a 10 mg/kg dose via i.p. showed reduced growth of xenograft tumors arisen from MDA-MB-231 cells, with minimal impact on general health and body weight. Our current research supports the notion that JMX0804 suppresses breast cancer growth by inhibiting breast cancer cell proliferation and inducing apoptosis via mediating STAT3 signaling. JMX0804 is currently undergoing further characterization for breast cancer metastasis and mechanisms of action as well as optimization to improve drug properties including potency and safety profile. This work is supported by NIH/NCI grant R01 CA231150. Citation Format: Hyejin Kim, Doerte R. Fricke, Jimin Xu, Haiying Chen, Jia Zhou, Qiang Shen. Treating estrogen receptor (ER)-negative and triple-negative breast cancer by targeting STAT3 signaling with putative STAT3 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1238.