Abstract LB-299: Glucose metabolism modulator HJC0152 differentially regulates glycolytic enzymes to suppress breast carcinogenesis
Authors: Jiabin Dong, Dengfeng Li, Hyejin Kim, Hong Wang, Zhi Zheng, Ziwei Zhang, Na Ye, Haiying Chen, Jia Zhou, Qiang Shen
Journal: Cancer Research (2017)

Abstract Currently available preventive therapies for breast cancer (BC) are primarily based on selective estrogen receptor (ER) modulators (SERMs) to target ER signaling. However, these drugs only partially prevent ER-positive BCs (EPBCs) but not ER-negative BCs (ENBCs), rendering approximately 60% of BCs unpreventable. About half of established EPBCs respond to SERMs and aromatase inhibitors (AIs), whereas ENBCs, most of which are triple-negative BCs (TNBCs), do not respond to SERMs or AIs. To date, there is no other targeted therapy for ENBCs or nonresponsive/resistant EPBCs, presenting a pressing need of non-ER-based targets and the agents that can effectively target such targets. Dysregulated glucose and energy metabolism is critically involved in the development and progression of various cancers, however, such a role in BC development remains largely unknown, thus representing a key knowledge gap and a potential avenue for non-ER-based targeted prevention and treatment of BC. Several metabolic and biogenetic anticancer therapies have been developed, but none has progressed to clinical use owing to their limited potency or specificity and/or their undesirable drug properties, such as toxicity and poor bioavailability. We recently developed a new class of anticancer agents, including HJC0152, that target glucose and energy metabolism and thus may have promise for the prevention and treatment of BCs, particularly ENBCs and resistant EPBCs. In this study, orally active HJC0152 differentially modulates glycolytic enzymes in BC cells. HJC0152 also regulates the transcription of genes involved in glucose and mitochondrial energy metabolism, including the subunits of mitochondrial respiratory chain complexes. HJC0152 also significantly inhibits Complexes IV but increases Complex V (ATP synthase) function, while Complexes I and II function is minimally affected. Migration and invasion of MDA-MB-231 cells are significantly inhibited by HJC0152 exposure. In vivo, HJC0152 significantly blocked mammary tumor development in mouse ENBC and TNBC models via inhibiting premalignant lesions. HJC0152 also dramatically blocked the development of experimental lung macro- and micro-metastasis in mice. These results suggest that HJC0152 can reprogram/restore the dysregulated glucose metabolism by inducing specific glycolytic enzyme expression and mitochondrial respiratory chain function, likely via targeting one or more upstream signal molecule(s) that regulates glucose and energy metabolism, thereby suppressing BC development and progression. To elucidate the mechanisms and discover the oncogenic drivers that promote BC development and progression, we are employing several strategies including in silico HJC0152 function-modelling and structure-modelling analysis, Unique Polymer Technology, and HJC0152-derived tool compounds to identify the HJC0152-interacting target(s). An initial in silico analysis has resulted in 12 potential targets, including the known JAK/STAT pathway molecules and proteins important for glucose/energy metabolism for further validation studies. This work was supported by Grants P50 CA097007, and P30DA028821(JZ) from NIH, CPRIT (JZ), John Sealy Memorial Endowment Fund (JZ), DFI Seed Grants from MDACC (QS), the Prevent Cancer Foundation (QS), and the PREVENT Program from NIH/NCI (QS). Citation Format: Jiabin Dong, Dengfeng Li, Hyejin Kim, Hong Wang, Zhi Zheng, Ziwei Zhang, Na Ye, Haiying Chen, Jia Zhou, Qiang Shen. Glucose metabolism modulator HJC0152 differentially regulates glycolytic enzymes to suppress breast carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-299. doi:10.1158/1538-7445.AM2017-LB-299