UCLA Researchers in the Department of Neurology/Neuro-Oncology and the David Geffen School of Medicine have developed methods for the Cas9-CRISPR mediated epigenetic targeting of malignant glioma, and which results in enhanced chemosensitivity to standard chemotherapeutic agents.
BACKGROUND:
Malignant gliomas are aggressive brain tumors originating from the glial cells that support and protect neurons in the central nervous system. They are the most common primary brain tumor with approximately 20,000 new cases diagnosed each year resulting in nearly 10,000 deaths. Gliomas are one of the deadliest categories of cancer, and nearly 50% of gliomas are diagnosed with the most aggressive form, glioblastoma (GBM) which has an average five-year survival rate of less than 10%. Current treatment approaches for malignant gliomas typically involve a combination of surgery, radiation therapy, and chemotherapy; however, despite an emphasis on precision and targeted therapies, to date, the development and approval of new therapeutic modalities for gliomas and GBM has been limited. Additional approaches, which work as standalone or in combination with current standards, are still needed; specifically, there’s an absence of methods that exploit the epigenetic states of gliomas for therapeutic advantage.
INNOVATION:
UCLA Researchers in the Department of Neurology and Neuro-Oncology have developed novel protocols for the use of CRISPR-based editing tools to modulate the expression of key molecular factors involved in brain tumor pathophysiology. This approach utilizes deactivated Cas9 ( dCas9 ) based fusion proteins in conjunction with short guide RNA constructs to target specific curated regions in the genome for methylation. Epigenetic modification with these constructs of targeted genomic regions resulted in enhanced sensitivity of tumor cells to alkylating chemotherapy agents in vitro. This versatile technique can be adapted to selectively silence or activate target gene transcription, meaning it can be tailored to optimize therapeutic efficacy for specific disease context and brain tumor subtype.
POTENTIAL APPLICATIONS:
- Combination therapy for gliomas / GBM
- General method for targeting methylation in specific regions of the genome
- Therapy for other cancers that benefit from methylation-based silencing/activation
ADVANTAGES:
- Can be tailored to increase/decrease transcript gene expression
- Increases the response to DNA alkylating agents
- Does not need to edit the genome. Genome editing can result in additional complications if off-target
DEVELOPMENT-TO-DATE: Method and treatment approaches have been tested and validated in vitro. Further tested with glioma sphere cell line models and in vivo mouse models is planned and prospective.
Related Papers (from the inventors only): Zapanta Rinonos, S., Li, T., Pianka, S.T. et al. dCas9/CRISPR-based methylation of O-6-methylguanine-DNA methyltransferase enhances chemosensitivity to temozolomide in malignant glioma. J Neurooncol (2024). https://link.springer.com/article/10.1007/s11060-023-04531-z#citeas