Targeting CDK9 for the Treatment of Glioblastoma

Abstract

Glioblastoma is the most common and aggressive primary malignant brain tumor, and more than two-thirds of patients with glioblastoma die within two years of diagnosis. The challenges of treating this disease mainly include genetic and microenvironmental features that often render the tumor resistant to treatments. Despite extensive research efforts, only a small number of drugs tested in clinical trials have become therapies for patients. Targeting cyclin-dependent kinase 9 (CDK9) is an emerging therapeutic approach that has the potential to overcome the challenges in glioblastoma management. Here, we discuss how CDK9 inhibition can impact transcription, metabolism, DNA damage repair, epigenetics, and the immune response to facilitate an anti-tumor response. Moreover, we discuss small-molecule inhibitors of CDK9 in clinical trials and future perspectives on the use of CDK9 inhibitors in treating patients with glioblastoma.

CDK9 inhibitors in cancer research

“…ZK 304709 failed in phase I studies for patients with advanced solid tumors due to doselimited absorption and high inter-patient variability. 21 Roniciclib (BAY 1000394, Fig. 4A) was derived from further lead optimization of ZK 304709.…”

“…18 The dysregulation of transcriptional programs has been observed in various human cancers, which makes CDK9 a prioritized target for cancer therapy across a range of tumor types. [19][20][21] The importance of CDK9 has led to an intensive search for CDK9 inhibitors for therapeutic purposes. In this review, we provide an overview of CDK9 inhibitors in cancer research and therapy.…”

Glioblastomas

“… On the left, an illustration of the different cell populations composing glioblastoma and its microenvironment, as well as associated blood-brain barrier disruption. On the right, a summary of the different areas covered by the articles in this Special Issue: GBM cells, stem cells, and preclinical studies [ 2 , 3 , 4 , 5 , 6 ], clinical studies [ 7 , 8 ], immunotherapy and new treatments [ 9 , 10 , 11 , 12 ]. Created with BioRender.com.…”

“…Eleven papers are included in this issue [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ], and they range from in vitro and preclinical studies to clinical studies, and to immunotherapy and new potential treatments for glioblastomas ( Figure 1 ).…”

“…Finally, Ranjan et al discussed targeting cyclin-dependent kinase 9 (CDK9), one of the CDKs that regulate transcription by RNA Polymerase II (RNA Pol II), as an emerging therapeutic approach that has the potential to overcome challenges in GBM management [ 12 ]. Specifically, they discussed how CDK9 inhibition can impact transcription, metabolism, DNA damage repair, epigenetics, and the immune response and therefore facilitate anti-GBM responses.…”