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

doi:10.1016/j.celrep.2023.113339

Targeting the non-coding genome and temozolomide signature enables CRISPR-mediated glioma oncolysis

Cell Rep. 2023 Nov 28;42(11):113339. doi: 10.1016/j.celrep.2023.113339. Epub 2023 Nov 2.

Authors

Affiliations

¹ 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.
² Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94131, USA; Silico Therapeutics, San Francisco, CA 94131, USA.
³ Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA.
⁴ Silico Therapeutics, San Francisco, CA 94131, USA.
⁵ 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.
⁶ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94131, USA.
⁷ 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.
⁸ 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. Electronic address: christof.fellmann@gladstone.ucsf.edu.

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.

Keywords: CP: Cancer; CRISPR-Cas9; cancer shredding; genome shredding; glioblastoma; hypermutated glioma.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Alkylating / pharmacology
Brain Neoplasms* / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm
Glioblastoma* / pathology
Glioma* / drug therapy
Glioma* / genetics
Humans
Neoplasm Recurrence, Local / drug therapy
Temozolomide / pharmacology
Temozolomide / therapeutic use

Substances

Temozolomide
Antineoplastic Agents, Alkylating

Abstract

Publication types

MeSH terms

Substances

Grants and funding