Friday, April 26, 2024
4/26/2024
Project Summary Glioblastoma (GBM) is the most common and aggressive primary malignant brain cancer in the adult population. Current standard of care: tumor resection, ionizing radiation (IR) and (TMZ) produce minimum clinical benefits for most patients due to innate or acquired resistance to treatment. Thus, optimization therapeutic approaches targeting oncogenic pathways in glioblastoma is an urgent need. Genomic alterations lead to dysregulation of Cyclin Dependent Kinase 4/6-Rb pathway in 84% of the 230 GBM cases profiled by The Cancer Genome Atlas. This results in the decoupling E2F from regulatory mechanisms to permit unchecked transcription of genes required for cell division as well as DNA-damage response. This points to CDK4/6 pharmacological inhibitors (CDK4/6i) as a promising strategy to treat GBM. Accordingly, three CDK4/6i (Abemaciclib, Ribociclib and Palbociclib) approved by the FDA for treatment of breast cancer are now in clinical trials for GBM patients. A priori genomics based selection of GBM patients for treatment with CDK4/6i are Rb-competent tumors (wildtype RB1), and CDK4/6 amplification or deletion of CDKN2A, which codes for P16INK4a, an endogenous inhibitor of CDK4/6 enzymatic activity. Studies point to CDK4/6-Rb dysregulation as an early evolutionary event which requires additional alterations to progress to malignancy, and there is insufficient evidence utilizing the incorporation of additional molecular biomarkers in the prediction of durable patient response. This deficiency is exemplified in preclinical studies showing adaptive resistance in patients previously predicted to respond to CDK4/6i.This is corroborated by my preliminary data showing a variability in Abemaciclib treatment response amongst GBM cancer stem cells (CSCs) that cannot be explained by CDK4/6-Rb alterations alone. My hypothesis is that the identification of molecular features driving the malignant phenotype, and co-occurring with CDK4/6-Rb pathway dysregulation, such as alterations in the other oncogenic pathways in p53, receptor tyrosine kinase receptor signaling and MYC, as well as epigenetic and transcriptional adaptation will strengthen our predictive capabilities in determining durable response versus resistance in GBM patients. I will test my hypothesis by measuring the sensitivity of a representative panel of 20 genomically heterogeneous GBM patient-derived CSCs to Abemaciclib and Ribociclib against control treatments. I will incorporate this response with their various somatic genomic alterations co-occurring with CDK4/6-RB axis dysregulation. This will enable the identification of baseline molecular correlates of GBM response with CDK4/6i. I will then interrogate the alterations in CDK4/6 copy number amplifications, present in extrachromosomal DNA elements, global transcriptome and targeted proteomics in response to CDK4/6 inhibition to identify potential escape mechanisms that lead to resistance in GBMs. Finally, to evaluate the translational impact of our studies, I will determine if the phenotypes observed in vitro are reproduced in orthotopic patient- derived xenografts (PDX). I will also determine if CDK4/6i can potentiate the genotoxic effects of TMZ. The results from this research will provide evidence towards interpreting upcoming clinical trials results and identifying GBM patient cohorts that will benefit from treatment with CDK4/6 inhibitors. Thus, the proposed project has significant translational potential, aligning with the mission of the National Cancer Institute to develop evidence-based treatment strategies for cancer patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
