BMI-1 is a potential therapeutic target in diffuse intrinsic pontine glioma

Kumar, Shiva Senthil; Sengupta, Satarupa; Lee, Kyung-Woo; Hura, Nanki; Fuller, Christine; DeWire, Mariko; Stevenson, Charles B.; Fouladi, Maryam; Drissi, Rachid

doi:10.18632/oncotarget.18002

Cited by 48 publications

(52 citation statements)

References 46 publications

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“…S1). We and others previously reported that under serum-free culture conditions, HGG-, DIPG-, and medulloblastoma neurospheres expressed neural stem cell markers such as nestin, CD133, and olig2, and were capable of self-renewal and differentiation in the presence of serum (22,23). These cancer stem-like cells are thought to be responsible for tumor recurrence (30).…”

Section: -Thio-dg Selectively Inhibits Cell Growth Of Telomerase-posmentioning

confidence: 91%

“…Primary patient-derived neurospheres high-risk group-3 medulloblastoma (MB004; refs. 19,20), GBM (R0315-GBM), and DIPG [SU-DIPG-VI (21) and CCHMC-DIPG-1 (22)] were cultured in neurosphere stem cell media as described elsewhere (22,23). Patient-derived medulloblastoma cell lines collected from the same patient at diagnosis D-425, and at recurrence D-458 (24,25), were cultured in RPMI1640 (Gibco) supplemented with 15% FBS.…”

Section: Cell Lines and Primary Tumor Cell Culturementioning

confidence: 99%

“…Western blot analysis was performed as described previously (22). Antibodies used were against ATM-S1981P (R&D Systems); ATM (SIGMA); ATR-T1989P (GeneTex); and ATR, CHK1-S345P, CHK1, CHK2-T68P, CHK2, cleaved caspase-3, and b-actin (Cell Signaling Technology).…”

Section: Western Blot Analysismentioning

confidence: 99%

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Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors

Sengupta

Sobo

Lee

et al. 2018

Molecular Cancer Therapeutics

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Brain tumors remain the leading cause of cancer-related deaths in children and often are associated with long-term sequelae among survivors of current therapies. Hence, there is an urgent need to identify actionable targets and to develop more effective therapies. Telomerase and telomeres play important roles in cancer, representing attractive therapeutic targets to treat children with poor-prognosis brain tumors such as diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), and high-risk medulloblastoma. We have previously shown that DIPG, HGG, and medulloblastoma frequently express telomerase activity. Here, we show that the telomerase-dependent incorporation of 6-thio-2'deoxyguanosine (6-thio-dG), a telomerase substrate precursor analogue, into telomeres leads to telomere dysfunction-induced foci (TIF) along with extensive genomic DNA damage, cell growth inhibition, and cell death of primary stem-like cells derived from patients with DIPG, HGG, and medulloblastoma. Importantly, the effect of 6-thio-dG is persistent even after drug withdrawal. Treatment with 6-thio-dG elicits a sequential activation of ATR and ATM pathways and induces G-M arrest. treatment of mice bearing medulloblastoma xenografts with 6-thio-dG delays tumor growth and increases in-tumor TIFs and apoptosis. Furthermore, 6-thio-dG crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Together, our findings suggest that 6-thio-dG is a promising novel approach to treat therapy-resistant telomerase-positive pediatric brain tumors..

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Section: -Thio-dg Selectively Inhibits Cell Growth Of Telomerase-posmentioning

confidence: 91%

Section: Cell Lines and Primary Tumor Cell Culturementioning

confidence: 99%

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Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors

Sengupta

Sobo

Lee

et al. 2018

Molecular Cancer Therapeutics

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“…BMI‐1 (B cell‐specific Moloney murine leukaemia virus integration site 1) is a polycomb ring finger oncogene which plays a crucial role in cell growth, metastasis and stem cell self‐renewal . It has been reported that BMI‐1 is a potential therapeutic target for glioma . Clinical studies revealed that BMI‐1 expression was negatively correlated with survival of patient with colon cancer .…”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10][11][12][13] It has been reported that BMI-1 is a potential therapeutic target for glioma. 14 Clinical studies revealed that BMI-1 expression was negatively correlated with survival of patient with colon cancer. 15 It has recently reported that CBX4 is an important upstream regulator of BMI-1, controlling the sumoylation status of BMI-1 and regulating BMI-1 recruitment to sites of DNA damage in mammalian cells.…”

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confidence: 99%

CBX4 promotes the proliferation and metastasis via regulating BMI‐1 in lung cancer

Zhang

Tang

et al. 2019

J Cellular Molecular Medi

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Proliferation and metastasis are significantly malignant characteristics of human lung cancer, but the underlying molecular mechanisms are poorly understood. Chromobox 4 (CBX4), a member of the Polycomb group (PcG) family of epigenetic regulatory factors, enhances cellular proliferation and promotes cancer cell migration. However, the effect of CBX4 in the progression of lung cancer is not fully understood. We found that CBX4 is highly expressed in lung tumours compared with adjacent normal tissues. Overexpression of CBX4 significantly promotes cell proliferation and migration in human lung cancer cell lines. The knockdown of CBX4 obviously suppresses the cell growth and migration of human lung cancer cells in vitro. Also, the proliferation and metastasis in vivo are blocked by CBX4 knockdown. Furthermore, CBX4 knockdown effectively arrests cell cycle at the G0/G1 phase through suppressing the expression of CDK2 and Cyclin E and decreases the formation of filopodia through suppressing MMP2, MMP9 and CXCR4. Additionally, CBX4 promotes proliferation and metastasis via regulating the expression of BMI‐1 which is a significant regulator of proliferation and migration in lung cancer cells. Taken together, these data suggest that CBX4 is not only a novel prognostic marker but also may be a potential therapeutic target in lung cancer.

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Pharmacokinetics and Safety of PTC596, a Novel Tubulin‐Binding Agent, in Subjects With Advanced Solid Tumors

Shapiro

O’Mara

Laskin

et al. 2021

Clinical Pharm in Drug Dev

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PTC596 is a novel, orally bioavailable, small-molecule tubulin-binding agent that reduces B-cell-specific Moloney murine leukemia virus insertion site 1 activity and is being developed for the treatment of solid tumors. A phase 1, open-label, multiple-ascending-dose study was conducted to evaluate the pharmacokinetics and safety of the drug in subjects with advanced solid tumors. PTC596 was administered orally biweekly based on body weight. Dose escalation followed a modified 3 + 3 scheme using doses of 0.65, 1.3, 2.6, 5.2, 7.0, and 10.4 mg/kg. Following oral administration, PTC596 was rapidly absorbed, and between 0.65 and 7.0 mg/kg reached a maximum plasma concentration 2 to 4 hours after dosing. Area under the plasma concentration-time curve increased proportionally with body weight-adjusted doses. Maximum plasma concentration increased with dose, although the increase was less than dose proportional at dose levels >2.6 mg/kg. No accumulation occurred after multiple administrations up to 7.0 mg/kg. PTC596 had a terminal half-life ranging 12 to 15 hours at all doses except for the highest dose of 10.4 mg/kg, where the half-life was approximately 20 hours. Overall, PTC596 was well tolerated. The most frequently reported PTC596-related treatment-emergent adverse events were mild to moderate gastrointestinal symptoms, including diarrhea (54.8%), nausea (45.2%), vomiting (35.5%), and fatigue (35.5%). Only 1 patient treated with 10.4 mg/kg experienced dose-limiting toxicity of neutropenia and thrombocytopenia, both of which were reversible. Stable disease as best overall response was observed among 7 patients, with 2 patients receiving the study drug up to 16 weeks. These results support the further development of PTC596 for the treatment of solid tumors.

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BMI-1 is a potential therapeutic target in diffuse intrinsic pontine glioma

Cited by 48 publications

References 46 publications

Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors

Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors

CBX4 promotes the proliferation and metastasis via regulating BMI‐1 in lung cancer

Pharmacokinetics and Safety of PTC596, a Novel Tubulin‐Binding Agent, in Subjects With Advanced Solid Tumors

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