Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer

Dey, Anindya; Xiong, Xunhao; Crim, Aleia; Dwivedi, Shailendra Kumar Dhar; Mustafi, Soumyajit Banerjee; Mukherjee, Priyabrata; Cao, Liangxian; Sydorenko, Nadiya; Baiazitov, Ramil; Moon, Yaejin; Dumble, Melissa; Davis, Thomas W.; Bhattacharya, Resham

doi:10.1158/1535-7163.mct-17-0574

Cited by 41 publications

(58 citation statements)

References 34 publications

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“…Here, we demonstrate that BMI1 levels were significantly elevated in endometrial cancer cell lines as well as in endometrial cancer patient tumors. PTC-028 (15), a secondgeneration inhibitor of BMI1 function with optimized pharmaceutical properties, depleted BMI1 levels that led to decreased cellular invasion and reduced cellular viability by potentiating caspase-dependent apoptosis. In a mouse model of endometrial cancer, treatment with PTC-028 significantly increased the tumor doubling time (DT) and delayed tumor growth compared with the standard-of-care carboplatin and paclitaxel.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of BMI1, a Therapeutic Approach in Endometrial Cancer

Buechel

Dey

Dwivedi

et al. 2018

Molecular Cancer Therapeutics

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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. .

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Section: Introductionmentioning

confidence: 99%

Inhibition of BMI1, a Therapeutic Approach in Endometrial Cancer

Buechel

Dey

Dwivedi

et al. 2018

Molecular Cancer Therapeutics

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“…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.…”

Section: In Vivo Xenograft Modelmentioning

confidence: 99%

“…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 .…”

Section: In Vivo Xenograft Modelmentioning

confidence: 99%

“…PTC-028 inhibits BMI1 by a different method than PTC-209, resulting in hyperphosphorylation of BMI1 and disrupting its function. 28 It is also orally bioavailable, allowing for preliminary investigation of BMI1 disruption in the in vivo setting; for these reasons, in subsequent studies we employed PTC-028. Treatment with PTC-028 similarly decreases cell proliferation ( Fig.…”

Section: Pharmacologic Inhibition Of Bmi1 Decreases Cell Proliferatiomentioning

confidence: 99%

“…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.…”

Section: Single Agent Ptc-028 Treatment Causes Tumor Growth Delay In mentioning

confidence: 99%

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

Shields

Potlapalli

Cuya-Smith

et al. 2020

Preprint

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Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma that continues to present significant challenges to pediatric oncology. There are two major subtypes of pediatric rhabdomyosarcoma, alveolar and embryonal. Alveolar rhabdomyosarcomas are characterized by the presence of a PAX-FOXO1 fusion protein and termed fusion-positive (FP-RMS); embryonal rhabdomyosarcomas (ERMS) lack these fusions and are termed fusion-negative (FN-RMS). Fusion-positive rhabdomyosarcoma (FP-RMS) harbors PAX-FOXO1 fusion proteinsand has a worse overall outcome compared to FN-RMS, underscoring the critical need to identify novel targets for this disease. While fusion proteins remain challenging therapeutic targets, recent studies have begun to reveal the key intersection of PAX-FOXO1 fusion proteins with the malignant epigenome, suggesting that epigenetic proteins may serve as novel targets in FP-RMS. Here, we investigate the contribution of the epigenetic regulator BMI1 to FP-RMS.We examined RNA-seq tumor datasets and determined that BMI1 is robustly expressed in FP-RMS tumors, patient derived xenografts (PDXs), and cell lines. We depleted BMI1 using RNA interference and find that this leads to a marked decrease in cell growth.Next, we used two BMI1 inhibitors, PTC-209 and PTC-028, and showed that BMI1 inhibition decreases cell cycle progression and increases apoptosis in FP-RMS cell lines. In the in vivo setting, targeting BMI1 leads to decreased tumor growth.Mechanistically, we observe that BMI1 inhibition activates the tumor suppressive Hippo pathway. Collectively, these results identify BMI1 as a novel therapeutic vulnerability in

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Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

et al. 2021

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Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS typically encompasses fusion-positive rhabdomyosarcoma, which expresses either PAX3-FOXO1 or PAX7-FOXO1 fusion proteins. There are no targeted therapies for ARMS; however, recent studies have begun to illustrate the cooperation between epigenetic proteins and the PAX3-FOXO1 fusion, indicating that epigenetic proteins may serve as targets in ARMS. Here, we investigate the contribution of BMI1, given the established role of this epigenetic regulator in sustaining aggression in cancer. We determined that BMI1 is expressed across ARMS tumors, patient-derived xenografts, and cell lines. We depleted BMI1 using RNAi and inhibitors (PTC-209 and PTC-028) and found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas.

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Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer

Cited by 41 publications

References 34 publications

Inhibition of BMI1, a Therapeutic Approach in Endometrial Cancer

Inhibition of BMI1, a Therapeutic Approach in Endometrial Cancer

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

Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

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