Abstract 4172: Oral administration of novel compound targeting triple negative breast cancer (TNBC) through the inhibition of SERCA2

Abstract

Abstract Background: Cancer survival is dependent on the increase of protein synthesis for cell migration, proliferation and metastasis. Cancer adaptive mechanisms include upregulation of endoplasmic reticulum (ER) activities to accommodate increases in misfolded proteins. Sarcoendoplasmic reticulum calcium ATPase (SERCA) are important regulators of calcium found in the endoplasmic reticulum, where inhibition can lead to protein misfolding. Since breast cancer cells express higher level of SERCA2, its overexpression maybe a target for drug development. Method: Using an in vitro screening method to guide our development, we have developed a pharmacophore and made structural changes to enhance anti-cancer activity while reducing of COX-2 inhibition. In this effort, we have identified C1, a coxib analogue with improved antitumor activities with minimal COX-2 inhibitory properties. We have further tested C1 in nu/nu athymic mice xenograft with human breast cancer cell line (MDA MB 231). Tumor volume and animal weights were measured three times a week for 28 days. At the end of the study, tumor volume was correlated with molecular markers using RT-PCR and IHC staining. Results: Our screening identified C1 as a promising anti-cancer compound in vitro and affirmed in xenograft triple negative breast cancer (TNBC) animal model. C1 has EC50 of <20 µM which was more potent than Di-methyl Celecoxib (DMC) and Celecoxib (CBX) with EC50 of ~30 µM and ~40 µM, respectively. Molecular dissection using western blot showed that C1 inhibited SERCA2 in both a time- and exposure-dependent manner. SERCA2 inhibition correlated with blocking the maturation of Notch 1. In vivo studies using oral administration of C1 showed optimal antitumor activity between 25-50 mg/kg/day, which resulted in >85% tumor reduction when compared to vehicle after 28 days of treatment. The safety of C1 was assessed for 48 days at 100 mg/kg/day, where no detectable biochemical, hematologic or histological toxicities were detected. RT-PCR analysis of residual tumor correlated with cell death indicated through the activation of CHOP and DR5 marker. Finally, C1 treatment also decreased angiogenesis markers VEGF-α and IL-8, corresponding to reduction in microvessel formation. Conclusion: C1 is a bioavailable coxib analogue with minimal COX-2 inhibition while possessing broad spectrum antitumor activity, including TNBC. Treatment with C1 leads to dosage dependent antitumor properties as a consequence of specific SERCA2 inhibition. In dosage escalation studies up to 100 mg/kg/day, no detectable biochemical and histological toxicities were detected. With these properties, C1 may be an effective component in the treatment of TNBCs, where effective therapy(ies) is much needed. Citation Format: Tracey J. Lin1, Julie Yoo2, Priyal Dave, Andrew Mead, Kabir Ahluwalia, Tiange Dong, Eugene Zhou, Hua Pei, Isaac Asante, Nicos Petasis, Stan Louie Citation Format: Tracey Lin, Julie Yoo, Priyal Dave, Andrew Mead, Kabir Ahluwalia, Tiange Dong, Eugene Zhou, Hua Pei, Isaac Asante, Nicos Petasis, Stan Louie. Oral administration of novel compound targeting triple negative breast cancer (TNBC) through the inhibition of SERCA2 [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 4172.