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OS8.6 Sensitivity of human meningioma cells to the cyclin-dependent kinase inhibitor, TG02
Abstract
BACKGROUND
Standards of care for meningioma include surgical resection, which may be curative, and radiotherapy as required. Pharmacotherapy plays only a minor role in this disease; however, novel systemic approaches are urgently needed for patients who are no longer candidates for local therapy.
MATERIAL AND METHODS
We generated primary cultures from surgically removed meningiomas to explore the activity of a novel cyclin-dependent kinase inhibitor, TG02, in meningioma cell cultures. Tumor and cell cultures were characterized by mutation profiling and DNA methylation profiling. DNA methylation data were used to allot each sample to one out of six previously established meningioma methylation classes: benign (ben)-1, 2, 3, intermediate (int)-A, B, and malignant (mal). The activity of TG02 was assessed by standard cell culture assays.
RESULTS
Cell cultures were derived from nine meningiomas. Four tumors assigned to the methylation class ben-2 showed the same class in the cell culture whereas cell cultures from five non-ben-2 tumors showed a different class, a more malignant class in four of five patients. Cell cultures were uniformly sensitive to the growth inhibitory effects of TG02 in the nanomolar range. Assignment of the cell cultures to a more malignant methylation classifier appeared to be more closely associated with TG02 sensitivity than assignment to a higher WHO grade of the primary tumors.
CONCLUSION
Primary cell cultures from meningioma facilitate the investigation of the anti-meningioma activity of novel agents. TG02, an orally available cyclin-dependent kinase inhibitor, warrants further exploration in this disease.
... 87 Zotiraciclib also inhibited the growth of meningioma primary cell cultures in the nanomolar range. 88 In CLL cells, zotiraciclib-induced cell apoptosis and blocked Bcell receptor signaling and the survival of CLL. 86 This compound has completed phase I/II clinical trials for second-line use in combination with temozolomide in adults with recurrent anaplastic astrocytoma and glioblastoma and showed promising results in cancer treatment (NCT02942264) ( Table 2). ...
Cancer is a worldwide leading cause of cancer‐related death due to a lack of efficient disease control by drugs. With the increasing unmet needs in cancer treatment, developing novel effective cancer drugs is in great demand. Macrocyclic molecules represent a group of drug molecules with a cyclic skeleton which endows them with unique drug properties such as improved bioavailability, enhanced metabolic stability, increased binding affinity, and favorable pharmacokinetics parameters. The Food and Drug Administration (FDA) has approved a bunch of macrocyclic drugs to treat cancer patients. However, the importance of such molecules in cancer drug development remains underestimated. Recent studies support that macrocyclic molecules can also serve as an effective strategy to overcome drug resistance in cancer treatment, but is a lack of review. The purpose of this manuscript was to provide shreds of evidence on the applications of macrocyclic molecules for cancer therapy: (1) act as cancer drugs to target different proteins critical for cancer development; (2) act as cancer drugs to target resistant mutants of oncogenes to overcome drug resistance in targeted therapy. This review will help to attract more interest in developing macrocyclic drugs for cancer therapy and potentially provide more novel strategies to benefit cancer patients and society.
Cell division, differentiation, and controlled cell death are all regulated by phosphorylation, a key biological function. This mechanism is controlled by a variety of enzymes, with cyclin-dependent kinases (CDKs) being particularly important in phosphorylating proteins at serine and threonine sites. CDKs, which contain 20 unique components, serve an important role in regulating vital physiological functions such as cell cycle progression and gene transcription. Methodologically, an extensive literature search was performed using reputable databases such as PubMed, Google Scholar, Scopus, and Web of Science. Keywords encompassed "cyclin kinase," "cyclin dependent kinase inhibitors," "CDK inhibitors," "natural products," and "cancer therapy." The inclusion criteria, fo-cused on relevance, publication date, and language, ensured a thorough representation of the most recent research in the field, encompassing articles published from January 2015 to September 2023. Categorization of CDKs into those regulating transcription and those orchestrating cell cycle phases provides a comprehensive understanding of their diverse functions. Ongoing clinical trials featuring CDK inhibitors, notably CDK7 and CDK4/ 6 inhibitors, illuminate their promising potential in various cancer treatments. This review undertakes a thorough investigation of CDK inhibitors derived from natural (marine, terrestrial, and peptide) sources. The aim of this study is to provide a comprehensive comprehension of the chemical classifications, origins, target CDKs, associated cancer types, and therapeutic applications.
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