Harnessing CRISPR-Cas9 within Oncology Clinical Research

CRISPR-Cas9 is a breakthrough gene-editing technology that is radically simpler, cheaper and more potent than its predecessors, thus arming researchers with a powerful tool in their fight against cancer. The uses for the technology range widely from screening for potential drug targets to editing disease-causing genes and delivering those modified cells back to the patient as part of immune therapies.   Discovery and development programs are already underway, with one company predicting clinical trials of the first CRISPR-Cas9 guided therapy will start in 2017. The promising technology has the potential to improve upon the more traditional gene therapy approaches, which have faced safety and efficacy challenges.   How is CRISPR-Cas9 currently being used to fight cancer and what hurdles still need to be overcome to successfully use the technology in the clinic? Let’s survey the landscape.   Harnessing CRISPR for cancer   Healthy cells can accumulate DNA errors that may eventually lead to the formation of a malignant tumor. Many researchers are using CRISPR-Cas9 to examine the role of these genes in cancer development in order to identify targets against which therapies could be developed.   For example, Project Achilles, a large-scale screening effort by the Broad Institute and the Dana-Farber Cancer Institute, is using gene editing to silence individual genes in 500 cancer cell lines derived from both solid and hematopoietic tumors. The goal of this project is to discover targets that may lead to better therapies and to identify corresponding patient populations that might benefit. Meanwhile, the National Cancer Institute is using CRISPR-Cas9 to screen genes involved in lymphoma cells to differentiate between those that drive cancer growth versus those that might be innocuous.   Studies such as these can be conducted in cell lines but some may mature into animal models for examination of the disease process or treatments in living organisms. Traditionally, creating such animal models was difficult because it meant modifying the DNA in germ line cells to generate diseased offspring. Now, with CRISPR-Cas9’s dramatic reductions in the time and costs required, this new technology can edit a mouse’s somatic cells to produce “a much more robust and representative animal model of carcinogenesis,” according to Jennifer Doudna, a co-discoverer of the gene-editing technology, in an editorial in JAMA. Already, 17 cancer mouse models using CRISPR–Cas9 based genome editing have been catalogued. These cover lung, liver and pancreatic cancers, as well as Burkitt lymphoma, acute myeloid leukemia and glioblastoma.   Solving remaining questions   CRISPR, like any technology, has limitations. All gene-editing technology is capable of making mistakes, known as “off-target” edits. Efforts are underway to limit these effects, as well as to improve ways to detect them. Another issue is delivery. Currently, viruses deliver CRISPR-Cas9 into target cells, but more effective methods are needed, particularly for use in tissues of living organisms.   And before we see CRISPR therapies in cancer clinical trials, there are several hurdles to overcome, including the usual drug development challenges concerning safety and manufacturing. Additionally, the ethics and policies surrounding the capability of CRISPR-Cas9 to edit the DNA of any cell will need to be sorted through.   For more information on the applications, ramifications and limitations of CRISPR-Cas9 in cancer research, visit Novella’s website. http://novellaclinical.com/   Chris Smyth, PhD, MBA, is the Managing Director, European & Asian Operations with Novella Clinical.