Inhibition of BMI1, a Therapeutic Approach in Endometrial Cancer

Abstract

With rising incidence rates, endometrial cancer is one of the most common gynecologic malignancies in the United States. Although surgery provides significant survival benefit to early-stage patients, those with advanced or recurrent metastatic disease have a dismal prognosis. Limited treatment options include chemotherapy and radiotherapy. Hence, there is a compelling need for developing molecularly targeted therapy. Here, we show that the polycomb ring finger protein BMI1, also known as a stem cell factor, is significantly overexpressed in endometrial cancer cell lines, endometrial cancer patient tissues as well as in nonendometrioid histologies and associated with poor overall survival. PTC-028, a second-generation inhibitor of BMI1 function, decreases invasion of endometrial cancer cells and potentiates caspase-dependent apoptosis, while normal cells with minimal expression of BMI1 remain unaffected. In an aggressive uterine carcinosarcoma xenograft model, single-agent PTC-028 significantly delayed tumor growth and increased tumor doubling time compared with the standard carboplatin/paclitaxel therapy. Therefore, anti-BMI1 strategies may represent a promising targeted approach in patients with advanced or recurrent endometrial cancer, a population where treatment options are limited. .

Epigenetic regulator BMI1 promotes fusion-positive rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

“…As previously described, treatments began when tumors were equal to or greater than 100 mm 3 . 28,29 The mice were tagged and randomly separated into 2 groups: vehicle (n = 10) and PTC-028 (n = 10). Mice received vehicle (0.5% HPMC, 1% Tween-80) or 15 mg/kg PTC-028 twice weekly by oral gavage.…”

“…Mice received vehicle (0.5% HPMC, 1% Tween-80) or 15 mg/kg PTC-028 twice weekly by oral gavage. 28,29 Weights and tumor sizes were measured three times weekly. Tumor volumes were calculated by using an ellipsoid volume formula: π / 6 x L x W x H. 30 In accordance with the IACUC protocol, mice were sacrificed when tumors reached a volume greater than or equal to 1500 mm 3 .…”

“…To provide the initial foundation for targeting BMI1 in FP-RMS, we employed PTC-028, which is orally bioavailable. 28,29 Nude mice bearing Rh30 xenografts were treated with vehicle or PTC-028 (15 mg/kg by oral gavage) daily, a dosing scheme guided by previous studies 28,29 . As shown in Fig.…”

Bmi-1 Immunohistochemical Expression in Endometrial Carcinoma is Correlated with Prognostic Activity

“…Several reports have identified Bmi-1 overexpression in endometrial carcinoma. Bmi-1 levels are significantly elevated in both type I and type II models of endometrial cancer cell lines [18]. Furthermore, Bmi-1 expression is strongly associated with the enhanced invasive activity of endometrial carcinoma cell lines [19].…”

“…In endometrial carcinoma, a second-generation inhibitor of Bmi-1 (PTC-028) decreased the invasion of endometrial cancer cells and potentiated caspase-dependent apoptosis. Therefore, anti-Bmi-1 strategies may represent a promising targeted approach in patients with advanced or recurrent endometrial cancer, a population where treatment is very challenging [18]. However, to date, there has been limited research into the role of Bmi-1 in endometrial cancer.…”