Cyclin-dependent kinase inhibitors in brain cancer: current state and future directions

Juric, Viktorija; Murphy, Brona M.

doi:10.20517/cdr.2019.105

Cited by 28 publications

(30 citation statements)

References 126 publications

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“…Furthermore, we found decreased proliferation and cell cycle arrest of ZNF554-transfected cells, which might be due to the downregulation of several cyclin-dependent kinases (CDK2, CDK9, CDK10, CDK13, CDK17), and five (CCNC, CCND3, CCNE2, CCNG1, CCNG2) out of six cyclin genes. This is in strong concordance with recent studies, one showing the anti-glioma effect of CDK inhibitors already in preclinical/clinical use [45], the other finding several CDKs and cyclin genes amongst top hub nodes in glioma network analysis [46].…”

Section: Znf554 As a Potential Tumor Suppressor In Gliomassupporting

confidence: 91%

Decreased Expression of ZNF554 in Gliomas is Associated with the Activation of Tumor Pathways and Shorter Patient Survival

Balogh

Reiniger

Hetey

et al. 2020

IJMS

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Zinc finger protein 554 (ZNF554), a member of the Krüppel-associated box domain zinc finger protein subfamily, is predominantly expressed in the brain and placenta in humans. Recently, we unveiled that ZNF554 regulates trophoblast invasion during placentation and its decreased expression leads to the early pathogenesis of preeclampsia. Since ZNF proteins are immensely implicated in the development of several tumors including malignant tumors of the brain, here we explored the pathological role of ZNF554 in gliomas. We examined the expression of ZNF554 at mRNA and protein levels in normal brain and gliomas, and then we searched for genome-wide transcriptomic changes in U87 glioblastoma cells transiently overexpressing ZNF554. Immunohistochemistry of brain tissues in our cohort (n = 62) and analysis of large TCGA RNA-Seq data (n = 687) of control, oligodendroglioma, and astrocytoma tissues both revealed decreased expression of ZNF554 towards higher glioma grades. Furthermore, low ZNF554 expression was associated with shorter survival of grade III and IV astrocytoma patients. Overexpression of ZNF554 in U87 cells resulted in differential expression, mostly downregulation of 899 genes. The “PI3K-Akt signaling pathway”, known to be activated during glioma development, was the most impacted among 116 dysregulated pathways. Most affected pathways were cancer-related and/or immune-related. Congruently, cell proliferation was decreased and cell cycle was arrested in ZNF554-transfected glioma cells. These data collectively suggest that ZNF554 is a potential tumor suppressor and its decreased expression may lead to the loss of oncogene suppression, activation of tumor pathways, and shorter survival of patients with malignant glioma.

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Section: Znf554 As a Potential Tumor Suppressor In Gliomassupporting

confidence: 91%

Decreased Expression of ZNF554 in Gliomas is Associated with the Activation of Tumor Pathways and Shorter Patient Survival

Balogh

Reiniger

Hetey

et al. 2020

IJMS

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“…Thus, identification of novel molecular targets is critical for the development of successful therapies for this highly aggressive and deadly type of brain tumour. In the last decade CKIs have been studied as a potential novel treatment in many cancers including GBM [ 18 ]. The CDK2, 7 and 9 genes are frequently upregulated in GBM patients compared to non-tumour tissue [ 27 ] and thus establishes a therapeutic rationale for targeting these CDKs specifically, using transcriptional CDK inhibitors, CYC065 (CDK2/9i) and THZ1 (CDK7i).…”

Section: Discussionmentioning

confidence: 99%

“…CDKs are critical regulatory enzymes that drive all cell cycle transitions [ 17 ]. CDK1, -2, -4 and -6, directly promote cell cycle progression, while CDKs, such as CDK7, -8 and -9 regulate transcription [ 18 ]. As one of the most fundamental traits of cancer cells involves their ability to sustain chronic proliferation, it is unsurprising that virtually all cancers, including GBM, harbour genomic alterations that lead to the constitutive activation of CDKs, resulting in unchecked cancer cell growth and division.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional CDK Inhibitors CYC065 and THZ1 Induce Apoptosis in Glioma Stem Cells Derived from Recurrent GBM

Juric

Düßmann

Lamfers

et al. 2021

Cells

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Glioma stem cells (GSCs) are tumour initiating cells which contribute to treatment resistance, temozolomide (TMZ) chemotherapy and radiotherapy, in glioblastoma (GBM), the most aggressive adult brain tumour. A major contributor to the uncontrolled tumour cell proliferation in GBM is the hyper activation of cyclin-dependent kinases (CDKs). Due to resistance to standard of care, GBMs relapse in almost all patients. Targeting GSCs using transcriptional CDK inhibitors, CYC065 and THZ1 is a potential novel treatment to prevent relapse of the tumour. TCGA-GBM data analysis has shown that the GSC markers, CD133 and CD44 were significantly upregulated in GBM patient tumours compared to non-tumour tissue. CD133 and CD44 stem cell markers were also expressed in gliomaspheres derived from recurrent GBM tumours. Light Sheet Florescence Microscopy (LSFM) further revealed heterogeneous expression of these GSC markers in gliomaspheres. Gliomaspheres from recurrent tumours were highly sensitive to transcriptional CDK inhibitors, CYC065 and THZ1 and underwent apoptosis while being resistant to TMZ. Apoptotic cell death in GSC subpopulations and non-stem tumour cells resulted in sphere disruption. Collectively, our study highlights the potential of these novel CKIs to induce cell death in GSCs from recurrent tumours, warranting further clinical investigation.

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“…The blood-brain barrier (BBB) consists of specialized endothelial cells with tight junctions and transport proteins that serve to restrict brain uptake of drugs, including systemic chemotherapies [89]. Hence, effective BBB permeability is a prerequisite for the successful application of therapeutic drugs in patients with brain cancer or brain metastases.…”

Section: Blood-brain Barrier Penetration Of Cdk Inhibitorsmentioning

confidence: 99%

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

Riess

Irmscher

Salewski

et al. 2020

Cancer Metastasis Rev

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Cyclin-dependent kinases (CDK) control the cell cycle and play a crucial role in oncogenesis. Pharmacologic inhibition of CDK has contributed to the recent clinical approval of dual CDK4/6 inhibitors for the treatment of breast and small cell lung cancer. While the anticancer cell effects of CDK inhibitors are well-established, preclinical and early clinical studies describe additional mechanisms of action such as chemo- and radiosensitization or immune stimulation. The latter offers great potential to incorporate CDK inhibitors in immune-based treatments. However, dosing schedules and accurate timing of each combination partner need to be respected to prevent immune escape and resistance. In this review, we provide a detailed summary of CDK inhibitors in the two solid cancer types head and neck cancer and glioblastoma multiforme; it describes the molecular mechanisms of response vs. resistance and covers strategies to avoid resistance by the combination of immunotherapy or targeted therapy.

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Cyclin-dependent kinase inhibitors in brain cancer: current state and future directions

Cited by 28 publications

References 126 publications

Decreased Expression of ZNF554 in Gliomas is Associated with the Activation of Tumor Pathways and Shorter Patient Survival

Decreased Expression of ZNF554 in Gliomas is Associated with the Activation of Tumor Pathways and Shorter Patient Survival

Transcriptional CDK Inhibitors CYC065 and THZ1 Induce Apoptosis in Glioma Stem Cells Derived from Recurrent GBM

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

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