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

Cyclin-dependent kinases (CDKs) are important regulatory enzymes in the normal physiological processes that drive cell-cycle transitions and regulate transcription. Virtually all cancers harbour genomic alterations that lead to the constitutive activation of CDKs, resulting in the proliferation of cancer cells. CDK inhibitors (CKIs) are currently in clinical use for the treatment of breast cancer, combined with endocrine therapy. In this review, we describe the potential of CKIs for the treatment of cancer with specific focus on glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. Despite intense effort to combat GBM with surgery, radiation and temozolomide chemotherapy, the median survival for patients is 15 months and the majority of patients experience disease recurrence within 6-8 months of treatment onset. Novel therapeutic approaches are urgently needed for both newly diagnosed and recurrent GBM patients. In this review, we summarise the current preclinical and clinical findings emphasising that CKIs could represent an exciting novel approach for GBM treatment.</p

Modulators of neuronal cell death in epilepsy

Experimental and human data have shown that certain seizures cause damage to brain. Such neuronal loss may result in cognitive impairments and perhaps contribute to the development or phenotype of emergent epilepsy. Recent work using genetically modified mice, Tat protein transduction, and viral vectors has shown functional effects of manipulating Bcl-2 and Bcl-w, heat shock proteins, caspases, and their regulators and endonucleases on neuronal death in models of status epilepticus. Ancillary effects on seizure induction and excitability thresholds have emerged for several genes suggesting additional properties of therapeutic potential. Differing hippocampal expression of certain Bcl-2 family genes, elevated endoplasmic reticulum stress chaperones, and death receptor pathway modulation in epilepsy patients support clinical relevance of this focus. These findings may yield potentially valuable adjunctive neuroprotective or anti-epileptogenic strategies

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

Cyclin-dependent kinases (CDKs) are important regulatory enzymes in the normal physiological processes that drive cell-cycle transitions and regulate transcription. Virtually all cancers harbour genomic alterations that lead to the constitutive activation of CDKs, resulting in the proliferation of cancer cells. CDK inhibitors (CKIs) are currently in clinical use for the treatment of breast cancer, combined with endocrine therapy. In this review, we describe the potential of CKIs for the treatment of cancer with specific focus on glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. Despite intense effort to combat GBM with surgery, radiation and temozolomide chemotherapy, the median survival for patients is 15 months and the majority of patients experience disease recurrence within 6-8 months of treatment onset. Novel therapeutic approaches are urgently needed for both newly diagnosed and recurrent GBM patients. In this review, we summarise the current preclinical and clinical findings emphasising that CKIs could represent an exciting novel approach for GBM treatment.</p

Targeting the apoptosis pathway to treat tumours of the paediatric nervous system

New, more effective therapeutics are required for the treatment of paediatric cancers. Current treatment protocols of cytotoxic treatments including chemotherapy trigger cancer-cell death by engaging the apoptosis pathway, and chemotherapy efficacy is frequently impeded by apoptosis dysregulation. Apoptosis dysregulation, through genetic or epigenetic mechanisms, is a feature of many cancer types, and contributes to reduced treatment response, disease progression and ultimately treatment resistance. Novel approaches are required to overcome dysregulated apoptosis signalling, increase the efficacy of cancer treatment and improve patient outcomes. Here, we provide an insight into current knowledge of how the apoptosis pathway is dysregulated in paediatric nervous system tumours, with a focus on TRAIL receptors, the BCL-2 proteins and the IAP family, and highlight preclinical evidence demonstrating that pharmacological manipulation of the apoptosis pathway can restore apoptosis signalling and sensitise cancer cells to treatment. Finally, we discuss the potential clinical implications of these findings

Targeting the apoptosis pathway to treat tumours of the paediatric nervous system

New, more effective therapeutics are required for the treatment of paediatric cancers. Current treatment protocols of cytotoxic treatments including chemotherapy trigger cancer-cell death by engaging the apoptosis pathway, and chemotherapy efficacy is frequently impeded by apoptosis dysregulation. Apoptosis dysregulation, through genetic or epigenetic mechanisms, is a feature of many cancer types, and contributes to reduced treatment response, disease progression and ultimately treatment resistance. Novel approaches are required to overcome dysregulated apoptosis signalling, increase the efficacy of cancer treatment and improve patient outcomes. Here, we provide an insight into current knowledge of how the apoptosis pathway is dysregulated in paediatric nervous system tumours, with a focus on TRAIL receptors, the BCL-2 proteins and the IAP family, and highlight preclinical evidence demonstrating that pharmacological manipulation of the apoptosis pathway can restore apoptosis signalling and sensitise cancer cells to treatment. Finally, we discuss the potential clinical implications of these findings

Platinum(iv) oxaliplatin-peptide conjugates targeting memHsp70+ phenotype in colorectal cancer cells.

Novel Pt(iv) tumour penetrating peptide (TPP) conjugates are reported. They are the first example of metallodrugs to target a membrane bound heat shock protein 70 positive (memHSP70+) phenotype in cancer cells. The conjugates exhibit superior cytotoxicity as compared to oxaliplatin alone in Pt resistant colorectal cancer cells with relatively high memHSP70+ expression. Substitution of TPP in Pt(iv) peptide conjugates with scrambled peptide (ScP) essentially abolishes the observed cytotoxicity.</p

Synthesis and characterisation of a novel mono functionalisable Pt(IV) oxaliplatin-type complex and its peptide conjugate

The synthesis and characterisation of a novel Pt(IV) monocarboxy precursor complex c,c,t-[Pt(DACH)(Ox)(OEt)(Suc)], which can be employed to synthesise mono functionalised Pt(IV) oxaliplatin-based complexes is reported. Reaction of c,c,t-[Pt(DACH)(Ox)(OEt)(Suc)] with a tumour penetrating peptide, TPP, afforded the corresponding novel monofunctionalised Pt(IV) peptide conjugate c,c,t-[Pt(DACH)(Ox)(OEt)(SucTPP)] in high purity. Conjugation of TPP to c,c,t-[Pt(DACH)(Ox)(OEt)(Suc)] was demonstrated to ameliorate its inherent cytotoxicity fifteen fold in the Pt sensitive HCT116 colorectal cancer cell line and two fold in the relatively resistant HT29 colorectal cancer cell line

Synthesis and characterisation of a novel mono functionalisable Pt(IV) oxaliplatin-type complex and its peptide conjugate

The synthesis and characterisation of a novel Pt(IV) monocarboxy precursor complex c,c,t-[Pt(DACH)(Ox)(OEt)(Suc)], which can be employed to synthesise mono functionalised Pt(IV) oxaliplatin-based complexes is reported. Reaction of c,c,t-[Pt(DACH)(Ox)(OEt)(Suc)] with a tumour penetrating peptide, TPP, afforded the corresponding novel monofunctionalised Pt(IV) peptide conjugate c,c,t-[Pt(DACH)(Ox)(OEt)(SucTPP)] in high purity. Conjugation of TPP to c,c,t-[Pt(DACH)(Ox)(OEt)(Suc)] was demonstrated to ameliorate its inherent cytotoxicity fifteen fold in the Pt sensitive HCT116 colorectal cancer cell line and two fold in the relatively resistant HT29 colorectal cancer cell line

Transcriptional CDK inhibitors CYC065 and THZ1 induce apoptosis in glioma stem cells derived from recurrent GBM

Glioma stem cells (GSCs) are tumour initiating cells which contribute to treatment re-sistance, 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 glio-maspheres. 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. Collec-tively, our study highlights the potential of these novel CKIs to induce cell death in GSCs from recurrent tumours, warranting further clinical investigation

Transcriptional CDK inhibitors CYC065 and THZ1 induce apoptosis in glioma stem cells derived from recurrent GBM

Glioma stem cells (GSCs) are tumour initiating cells which contribute to treatment re-sistance, 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 glio-maspheres. 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. Collec-tively, our study highlights the potential of these novel CKIs to induce cell death in GSCs from recurrent tumours, warranting further clinical investigation