Genome-wide CRISPR/cas9 Knock-out Screens in Human Glioblastoma Identify Genetic Vulnerabilities
SAN DIEGO, Calif., September 27, 2016 — Imran Noorani MD, MRCS, of Cambridge, England, received the Brainlab Community Neurosurgery Abstract Award at the Congress of Neurological Surgeons Annual Meeting in San Diego. Each year, merit-based awards are granted to acknowledge the achievements of residents, fellows, and attending neurosurgeons in various categories. Dr. Noorani’s study uses genetics to understand the biology of brain tumors. The paper, Genome-wide CRISPR/cas9 Knockout Screens in Human Glioblastoma Identify Genetic Vulnerabilities, uses the functional role of genes to develop future meaningful therapeutic drug targets.
Glioblastoma (GBL) is the most common type of brain tumor and also one of the deadliest. At the current time there is no cure for GBL, with the average lifespan following diagnosis at only 14 months. Cancer is a genetic disease; changes in genes (typically mutations) can cause cells to grow uncontrollably and start invading nearby tissues. At this time, the genetic vulnerabilities of glioblastoma are poorly understood.
Identifying the genetic vulnerabilities of cancer is a novel method for discovering new therapeutic targets. The genetic sequencing of glioblastomas has recently been invaluable in teaching about the pattern of mutation in patient tumors. However, it is difficult to establish which genetic changes are important for the survival of the cancer and may potentially represent drug targets from sequencing studies alone.
Over the last few years, the CRISPR/cas9 system has emerged as a highly efficient and targeted approach for genetic knockout. The CRISPR guide is short sequence of RNA that the cas9 enzyme uses to direct itself to the corresponding location in the host genome to create a knockout of a specific gene. This can be used to help elucidate the role of individual genes. It’s comprised of two components: the cas9 enzyme that cuts DNA and then uses a CRISPR genetic sequence to guide it to a precise location in the genome.
This study researched using novel genetic engineering technologies in order to help determine which of the known genetic changes in glioblastomas would represent viable therapeutic targets. In a preliminary study, the CRISPR/cas9 genetic engineering system was used to systematically knock out all genes in patient-derived glioblastoma cells. Hopefully some of them will stop and slow down tumor growth.
The system uses lentiviruses to carry genetic material into the cancer cells and induce a knockout at the specified gene. A small proportion of genes are essential for survival of the cancer cells, so knocking out these genes leads to slowed growth (or death) of the cancer cells in vitro. This study provides an initial understanding of how glioblastomas may be susceptible to genetic targeting as a form of therapy and is the first step in an ongoing series of studies which are using similar genetic engineering techniques in a mouse model of this cancer. These studies will provide an understanding of which genes drive this cancer forward in vivo and are likely to represent future therapeutic targets. By combining what is known from the genetic changes in patients’ tumors with a developing knowledge of genetic susceptibilities and drivers in model systems, a deeper understanding of how to reliably treat these tumors in patients will be developed.