Faculty Bibliography

PURPOSE/OBJECTIVE:Exploration of novel strategies to extend the benefit of PARP inhibitors beyond BRCA-mutant cancers is of great interest in personalized medicine. Here we identified EGFR-amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for GBM patient population who will benefit from PARP inhibition therapy. EXPERIMENTAL DESIGN/METHODS:Selective sensitivity to PARP inhibitor talazoparib was screened and validated in two sets [test set (n=14) and validation set (n=13)] of well-characterized patient-derived glioma-sphere-forming cells (GSC). FISH was used to detect EGFR copy number. DNA damage response following talazoparib treatment was evaluated by γH2AX and 53BP1 staining and neutral comet assay. PARP-DNA trapping was analyzed by subcellular fractionation. The selective monotherapy of talazoparib was confirmed using in-vivo glioma models. RESULTS:EGFR-amplified GSCs showed remarkable sensitivity to talazoparib treatment. EGFR- amplification was associated with increased ROS and subsequent increased basal expression of DNA repair pathways to counter elevated oxidative stress, and thus rendered vulnerability to PARP inhibition. Following talazoparib treatment, EGFR-amplified GSCs showed enhanced DNA damage and increased PARP-DNA trapping which augmented the cytotoxicity. EGFR-amplification associated selective sensitivity was further supported by the in vivo experimental results showing that talazoparib significantly suppressed tumor growth in EGFR-amplified subcutaneous models but not in non-amplified models. CONCLUSION/CONCLUSIONS:EGFR-amplified cells are highly sensitive to talazoparib. Our data provide insight into the potential of using EGFR amplification as a selection biomarker for the development of personalized therapy.

PURPOSE/OBJECTIVE:Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient derived xenografts (PDX) and undertaken its genomic and phenotypic characterization. EXPERIMENTAL DESIGN/METHODS:PDX were established from glioblastoma, IDH-wildtype (n=93), glioblastoma, IDH-mutant (n=2), diffuse midline glioma, H3 K27M-mutant (n=1), and both primary (n=60) and recurrent (n=34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole exome sequencing (WES, n=83), RNA-sequencing (n=68), and genome-wide methylation profiling (n=76). WES data from 24 patient tumors was compared with derivative models. RESULTS:amplification. However, in four patient-PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection. CONCLUSIONS:Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.

Stereotactic radiation treatment can be used to treat spinal cord neoplasms in patients with either unresectable lesions or residual disease after surgical resection. While treatment guidelines have been suggested for epidural lesions, the utility of stereotactic radiation for intradural and intramedullary malignancies is still debated. Prior reports have suggested that stereotactic radiation approaches can be used for effective tumor control and symptom management. Treatment-related toxicity has been documented in rare subsets of patients, though the incidences of injury are not directly correlated with higher radiation doses. Further studies are needed to assess the factors that influence the risk of radiation-induced myelopathy when treating spinal cord neoplasms with stereotactic radiation, which can include, but may not be limited to, maximum dose, dose-fractionation, irradiated volume, tumor location, histology and treatment history. This review will discuss evidence for current treatment approaches.