Abstract A62: Combination of BXL-0124, a vitamin D analog and LG100268 for the prevention of ER-negative breast cancer
Authors: Mazumdar Abhijit , Zhang Yun , Hill Jamal , Suh Nanjoo , Brown Powel 
Published: January 2014

Abstract
Background: ER-positive Breast cancer prevention is now possible using antiestrogen drugs; however, this treatment is ineffective against estrogen receptor (ER)-negative breast cancers. Current treatments for ER-negative tumors include chemotherapy, or for those ER-negative cancers that overexpress HER2, the anti-HER2 antibody herceptin. Targeted therapy for ER-negative tumors, particularly those that do not express HER2 (triple-negative breast cancer) is urgently needed. Epidemiological evidence from several case control and cohort studies support an inverse relationship between vitamin D intake and breast cancer incidence. Vitamin D deficiency was also linked to poor outcomes in patients with early breast cancer. Using a transgenic mouse model of ER-negative breast cancer, our laboratory previously demonstrated that rexinoid LG100268 reduced mammary tumor development in these mice. We hypothesized that the combination of a rexinoid and a vitamin D analog (BXL-0124) would more effectively prevent the development of ER-negative breast cancer. To test the hypothesis, we used MMTV-erbB2 mouse tumors that do not express ER, to determine whether LG100268 and BXL-0124 combination is more effective than either treatment alone in preventing ER-negative mammary tumors.
Methods: Virgin female MMTV-erbB2 mice (Jackson Lab) were housed in the institutional animal facilities and fed a purified diet (AIN-76A; Harlan Teklad). Mice were separated into 4 treatment groups: 1) sesame oil and DMSO control 2) Rexinoid (25 mg/kg) plus DMSO 3) BXL-0124 (3ug) plus sesame oil. 4) LG100268 (25mg/kg) plus BXL-0124 (3ug). All treatments were given by oral gavage, five days a week from 3 months of age. Mice were observed daily for tumor formation, toxicity and the percentage of tumor free mice were recorded. Tumor incidence and time to tumor formation was visualized using Kaplan Meier curves and analyzed using the generalized Wilcoxon test.
Results: Rexinoid LG100268 reduced tumor incidence and was associated with an increase in median survival time from 242 days to 365 days. BXL-0124 also reduced tumor incidence with an increase in median survival time from 242 days to 288 days. The combination of LG 100268 and BXL-0124 had additive effect in preventing ER-negative mammary tumor development with a median survival time increase from 242 days to 422. days. We are investigating blood and tissue biomarkers currently and that results are forthcoming.
Conclusion: Rexinoid LG100268 and vitamin D analog BX-0124 reduced tumor incidence in MMTV-erbB2 mice. The combination treatment of LG100268 and BXL0124 was more effective in preventing mammary tumor development compare to either agent alone. Based on our results, more combinatorial studies of LG100268 and BXL-0124 in other ER-negative models are warranted. In future clinical trials of the combination of BXL-0124 and LG100268 should be considered for the prevention of breast cancer in high-risk patients. (Supported by NIH R01 CA078480 (PB) and MDACC CCSG P30 CA 016672)
Citation Format: Abhijit Mazumdar, Yun Zhang, Jamal Hill, Nanjoo Suh, Powel Brown. Combination of BXL-0124, a vitamin D analog, and LG100268 for the prevention of ER-negative breast cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A62.