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Published on: October 11, 2017
Targeting the non-coding genome and temozolomide signature enables CRISPR-mediated glioma oncolysis
I-Li Tan1, Alexendar R Perez2, Rachel J Lew3
1Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
Abstract:
Glioblastoma (GBM) is the most common lethal primary brain cancer in adults. Despite treatment regimens including surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, growth of residual tumor leads to therapy resistance and death. At recurrence, a quarter to a third of all gliomas have hypermutated genomes, with mutational burdens orders of magnitude greater than in normal tissue. Here, we quantified the mutational landscape progression in a patient's primary and recurrent GBM, and we uncovered Cas9-targetable repeat elements. We show that CRISPR-mediated targeting of highly repetitive loci enables rapid elimination of GBM cells, an approach we term "genome shredding." Importantly, in the patient's recurrent GBM, we identified unique repeat sequences with TMZ mutational signature and demonstrated that their CRISPR targeting enables cancer-specific cell ablation. "Cancer shredding" leverages the non-coding genome and therapy-induced mutational signatures for targeted GBM cell depletion and provides an innovative paradigm to develop treatments for hypermutated glioma.
Insights
This study introduces "genome shredding," a novel CRISPR-based therapy that targets repetitive DNA sequences to eliminate glioblastoma cells. This approach shows promise for treating recurrent, hypermutated brain tumors resistant to conventional therapies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Glioblastoma (GBM) is a lethal brain cancer with poor outcomes despite standard treatments.
- Recurrent GBM often exhibits hypermutated genomes, presenting therapeutic challenges.
- Existing therapies face resistance due to residual tumor growth.
Purpose of the Study:
- To analyze the mutational landscape progression in primary and recurrent GBM.
- To identify novel therapeutic targets within the non-coding genome of GBM.
- To develop a CRISPR-based strategy for targeting hypermutated glioma.
Main Methods:
- Quantified mutational landscape progression in a patient's primary and recurrent GBM.
- Identified Cas9-targetable repeat elements in GBM genomes.
- Utilized CRISPR-mediated targeting of repetitive loci for GBM cell elimination.
- Validated cancer-specific cell ablation in recurrent GBM with unique repeat sequences.
Main Results:
- Discovered unique repeat sequences in recurrent GBM with temozolomide (TMZ) mutational signatures.
- Demonstrated CRISPR targeting of these sequences enables cancer-specific cell ablation.
- Showcased rapid elimination of GBM cells via CRISPR-mediated targeting of repetitive loci.
- Developed an approach termed "genome shredding" for GBM treatment.
Conclusions:
- "Genome shredding" leverages the non-coding genome and therapy-induced mutational signatures for targeted GBM cell depletion.
- This innovative paradigm offers a new treatment strategy for hypermutated glioma.
- CRISPR targeting of unique repeat sequences provides a novel approach for recurrent GBM therapy.
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