Off-campus WSU users: To download campus access dissertations, please use the following link to log into our proxy server with your WSU access ID and password, then click the "Off-campus Download" button below.
Non-WSU users: Please talk to your librarian about requesting this dissertation through interlibrary loan.
Access Type
WSU Access
Date of Award
January 2023
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Pharmacology
First Advisor
Ana C. deCarvalho
Second Advisor
Sokol Todi
Abstract
Glioblastoma, a grade IV astrocytoma, is the most aggressive primary malignant brain tumor. Its genomic heterogeneity and diverse oncogenic alterations often lead to aberrant regulation of the cell cycle, making it an appealing target for therapy. Among the pivotal regulators of the G1 phase of the cell cycle is the Cyclin-Dependent Kinase 4/6 (CDK4/6) - Retinoblastoma (Rb) signaling axis, which is deregulated in 82% of GBMs, according to the TCGA. Pharmacological inhibition of CDK4/6, demonstrated by FDA-approved small molecule inhibitors including abemaciclib, ribociclib, and palbociclib, initially approved for breast cancer, shows promise in Glioblastoma treatment. However, a poor GBM clinical trial track necessitates the identification of predictive markers to enhance treatment outcomes. Two CDK4/6 inhibitors, abemaciclib, and ribociclib, were employed to assess response to CDK4/6 inhibitors in a panel of GBM cohorts. We show that MYC amplification co-occurring with deregulation of growth factor signaling including amplifications in EGFR or PIK3CA is indicative of a refractory phenotype to CDK4/6 inhibitors (CDK4/6i) in GBM patients. Our findings also challenge the efficacy of current monogenic biomarkers, including CDK4 amplification and CDKN2A deep deletion, in effectively stratifying CDK4/6i responsiveness among GBM cohorts. To comprehensively interrogate resistance to G1 blockade, the study explored the potential of CDK2/4/6 inhibition using ebvaciclib and combination therapy of an EGFR inhibitor (dacomatinib) with ribociclib. Combination therapy was decidedly more efficacious in inducing an anti-proliferative phenotype across all CSC lines, even in the recovery period post-treatment; however, ebvaciclib demonstrated high anti-proliferative efficacy in select CSC models. Furthermore, transcriptomic analysis implicated MYC and mTOR signaling as critical drivers of CDK4/6i refractory phenotype in GBMs. Additionally, deregulation of ribosomal processes and activation of non-canonical translation mechanisms emerged as contributors to resistance. Finally, we combined CDK4/6i with ionizing radiation in a large-scale in vitro pharmaco-radiogenomic study. We found that CDK4/6 inhibitors antagonize the cytotoxic effects of ionizing radiation in GBM CSCs. While the utilization of CDK4/6i remains promising in GBMs, our findings have important implications for developing more precise therapeutic strategies, offering new avenues for enhancing the stratification and efficacy of CDK4/6i treatments in GBM.
Recommended Citation
Nuga, Oluwademilade, "Cdk4/6 As A Therapeutic Target In The Treatment Of Glioblastomas" (2023). Wayne State University Dissertations. 3961.
https://digitalcommons.wayne.edu/oa_dissertations/3961