Abstract 19: Examination of HJC0152, a putative modulator of glucose and energy metabolism, for mammary cancer prevention
Authors: Kim Hyejin , Liu Xi , Wen Yefei , Zhou Jia , Fernando Romaine , Sei Shizuko , Brown Powel H. , Shen Qiang 
Published: September 2020

Abstract
Breast cancer (BC) is the most common cancer in women in the US. Approximately 30-40% of BC cases are estrogen-receptor (ER)-negative (ENBC); the majority of these are triple-negative (TNBC). No drugs have been shown to effectively prevent ENBC including TNBC. TNBC incidence is higher in young African American and Hispanic/Latina women, thus the need for preventive agents for TNBC is critical. Developing agents targeting non-ER-based oncogenic pathways will therefore offer alternative and potentially more effective approaches for preventing ENBC/TNBC. Glucose metabolism is an essential energy-producing process for normal cells and is aberrant and reprogrammed in cancer cells including BC cells. We recently developed HJC0152, a novel small-molecule glucose metabolism modulator as a potential cancer preventive agent. HJC0152 has been shown to inhibit glycolysis by differentially regulating glycolytic enzyme expression and the function of mitochondrial respiratory complexes in both EPBC and TNBC cells, leading to reduced production of energy molecule adenosine-triphosphate (ATP), induced apoptosis, and decreased proliferation and tumor progression. In this study, we determined the preventive anti-cancer efficacies of long-term and short-term (inhibition of premalignant lesions) HJC0152 administration in mouse models of ENBC and TNBC. HJC0152 was given orally 6 days/wk for 2-10 months in well-established ENBC model, MMTV-erbB2; and TNBC model, C3(1)/TAgSV40. HJC0152 at 50 and 75 mg/Kg doses delayed and partially prevented mammary tumor development in ENBC (MMTV-erbB2) mice (p=0.0034 for all groups). A maximum 6-week delay was achieved for median time to tumor formation (TTF). In the TNBC (C3(1)/TAgSV40) model, HJC0152 significantly delayed mammary tumor development (p=0.0114 for all groups) and achieved 3.3-week delay for median TTF. Up to 21% less mice developed mammary tumors in both models. In addition, TNBC mice developed less number of tumors per mouse than in ENBC mice, and the tumor volume doubling time increased from 6.9 to 9.2 days. In the short-term premalignant lesion study, the number of mammary intraepithelial neoplasia (MIN) lesion (representing human DCIS) was significantly decreased (p=0.034) in the HJC0152-treated MMTV-erbB2 mice. In the HJC0152-treated C3(1)/TAgSV40 mice, the number of hyperplasia and MIN lesions were significantly decreased (p=0.0014 and 0.0203, respectively). These results demonstrate that HJC0152 suppresses mammary tumor development in ENBC and TNBC models via reducing premalignant lesions, even in the most aggressive TNBC model, C3(1)/TAgSV40. There were no significant side effects or toxicity signs observed in both long- and short-term prevention experiments. We conclude that HJC0152 has promising cancer preventive efficacy by targeting non-ER-based signaling pathways such as STAT3 signaling and glucose metabolism. This study was supported by a NIH/NCI PREVENT Program fund. *Current Affiliation: LSUHSC.
Citation Format: Hyejin Kim, Xi Liu, Yefei Wen, Jia Zhou, Romaine Fernando, Shizuko Sei, Powel H. Brown, Qiang Shen. Examination of HJC0152, a putative modulator of glucose and energy metabolism, for mammary cancer prevention [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 19.