Cellular Plasticity and equilibrium in GBM Progression

PROJECT SUMMARY
To advance our understanding of therapeutic resistance in Glioblastoma (GBM), it is essential to characterize
the individual cell during therapy those fuel tumor recurrence in GBM. However, it is challenging to study the
GBM during conventional radio- and chemotherapy due to limited accessibility to patient samples during this
time period. Our lab performed a single-cell RNA sequencing screen in the patient-derived xenograft model of
GBM during temozolomide (TMZ) therapy. Our analysis revealed that the Ribonucleotide Reductase Regulatory
Subunit 2 (RRM2) mediates deoxynucleoside triphosphates (dNTPs) production necessary for proper DNA
replication stable cell growth, promotes metabolic adaptation to TMZ therapy, and initiate recurrence. We have
identified a novel mechanism where RRM2-mediated dCTP and dGTP can enhance the DNA repair in response
to TMZ and promotes resistance to therapy. Based on this, we hypothesize that RRM2-mediated RNR activity
is critical for chemoresistance in GBM. To investigate this hypothesis, we intend to elucidate the RNR-mediated
chemoresistance in GBM (Aim 1). Next, we will evaluate a blood-brain permeable RRM2 inhibitor to prevent
RNR-mediated chemoresistance in GBM (Aim 2). We established collaboration with Nanopharmaceutic, which
holds the patent for producing clinical-grade 3-AP and will provide us with clinical-grade 3-AP to test its efficacy
further and advance our understanding of the mechanism of action by which it can be used to treat GBM patients.
Finally, we intend to investigate the mechanism of therapeutic resistance by specific nucleotides produced by
the RRM2-mediated de novo pathway (Aim 3). Collectively, our studies will provide novel insights regarding
changes in dNTP synthesis that are associated with GBM adaptation and resistance during chemotherapy. This
information, in turn, is expected to reveal novel approaches for delaying, if not preventing, tumor recurrence.

Grant Number: 5R01NS096376-09
NIH Institute/Center: NIH
Principal Investigator: Atique Ahmed