NOVEL AGENT TO RESTORE SENSITIVITY TO ANTI-ESTROGEN THERAPY

芳香化酶抑制剂（AI）是绝经后女性雌激素受体阳性乳腺癌（BC）的首选激素治疗，在美国每年用于治疗约140，000例患者。然而，约40%的患者将对AI产生耐药性。如果能够在已经耐药的患者中重新建立对AI的敏感性，这将是治疗ER+ BC患者的重大进展。PI已经表征了生长因子GP88，并证明了其在癌细胞的发育、增殖和存活中的关键作用。重要的是，PI已经使用体外研究证明，GP88是控制癌细胞对AI（如来曲唑）耐药性的驱动因素。PI已开发出一种中和性单克隆抗GP88抗体，在体外显示可恢复BC细胞对先前AI耐药细胞系中AI的敏感性。本申请试图通过使用异种移植研究来证明抗GP88在体内有效恢复先前抗性肿瘤中的AI敏感性。如果成功，抗GP88联合AI治疗AI耐药患者将是治疗目前全身化疗作为唯一选择的BC患者的重大进展，并可改善整体BC生存率。

Aromatase Inhibitors (AI) are the preferred hormonal treatment for estrogen receptor positive Breast Cancer (BC) in postmenopausal women and are used to treat approximately 140,000 patients annually in the US. However, ~40% of patients will be, or become resistant to AIs. If sensitivity to AI can be re-established in patients that have become resistant, this would be a major step forward in treating ER+ BC patients. The PI has characterized a growth factor, GP88, and demonstrated its critical role in the development, proliferation and survival of cancer cells. Importantly, the PI has demonstrated using in vitro studies that GP88 is a driver in controlling cancer cell resistance to AIs such as Letrozole. The PI has developed a neutralizing monoclonal anti-GP88 antibody, shown in vitro to return BC cell sensitivity to AIs in previously AI resistant cell lines. This application seeks to prove through the use of xenograft studies that anti-GP88 is effective in vivo in restoring AI sensitivity in previously resistant tumors. If successful, anti-GP88 in conjunction with AI therapy in AI resistant patients would be a major advancement in treating BC patients that currently have systemic chemotherapy as their only option and could improve overall BC survival.