Targeting the non-coding genome and temozolomide signature enables CRISPR-mediated glioma oncolysis
I-Li Tan,
Alexendar R. Perez,
Rachel J. Lew,
Xiaoyu Sun,
Alisha Baldwin,
Yong K. Zhu,
Mihir M. Shah,
Mitchel S. Berger,
Jennifer A. Doudna,
Christof Fellmann
Affiliations
I-Li Tan
Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA
Alexendar R. Perez
Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94131, USA; Silico Therapeutics, San Francisco, CA 94131, USA
Rachel J. Lew
Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA
Xiaoyu Sun
Silico Therapeutics, San Francisco, CA 94131, USA
Alisha Baldwin
Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA
Yong K. Zhu
Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA
Mihir M. Shah
Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Mitchel S. Berger
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94131, USA
Jennifer A. Doudna
Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
Christof Fellmann
Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author
Summary: 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.
