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）的首选激素治疗方法，在美国每年用于治疗约14万例患者。然而，约40%的患者会对ai产生或产生耐药性。如果耐药患者能够重新建立对AI的敏感性，这将是治疗ER+ BC患者的重要一步。PI表征了一种生长因子GP88，并证明其在癌细胞的发育、增殖和存活中起着关键作用。重要的是，PI已经通过体外研究证明，GP88是控制癌细胞对来曲唑等ai的耐药性的驱动因素。PI已经开发了一种中和性单克隆抗gp88抗体，在体外显示，在先前的AI耐药细胞系中，BC细胞对AI的敏感性恢复。该应用旨在通过异种移植研究证明抗gp88在体内有效地恢复先前耐药肿瘤的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以全身化疗为唯一选择的BC患者的重大进展，并可能提高BC的总生存率。

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.