Cancer targeted therapy via gene manipulation

Frontline Genomics magazine takes readers into the genome research world at AstraZeneca’s Boston-based Oncology Innovative Medicine Unit for a better understanding of the gene editing technology called CRISPR/Cas9

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When cancer suppressor genes are inactivated or deleted, tumour cells rely on other proteins to make up for the loss. Targeting these proteins with tailored drugs can selectively kill the cancerous cells while sparing normal cells, and developing the targeted therapy technology via gene editing such as CRISPR/Cas9 has been the career pursuit of Associate Director Sylvie Guichard of the multinational pharmaceutical and biologics company AstraZeneca.

“In my work, I try to identify the drugs of tomorrow,” she writes in the latest issue of Frontline Genomics. “I’m trying to understand why patients treated with drug X don’t respond. What is special about the makeup of their cancer cells? What are the important functions of those cells? Can we target them to try to kill the cells?”

In addition to leading drug discovery projects, another aspect of Guichard’s work involves managing the portfolio of early drug targets in oncology and identifying new genetic vulnerabilities in cancer cells that has the potential to be exploited therapeutically.

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Guichard writes of a day in her life as a CRISPR/Cas9 researcher in Frontline Genomics

“Genomics has been an essential tool to identify new drug targets or identify patient populations which would benefit from targeted agents,” she explains. “My interest in CRISPR/Cas9 started very much like many people as a tool to identify drug targets in tumours with loss-of-function mutations. However, I realised very quickly the potential of CRISPR as a therapeutic approach.”

CRISPR/Cas9 is a genome editing tool that has only recently been generating buzz as a powerful mechanism in targeting cancer cells. Its history started in the 1980s when scientists noticed an odd configuration in the naturally-occurring genomic defense mechanism found in bacteria: one DNA sequence would be repeated over and over again, with unique sequences observed in between the repeats. Scientists called this strange pattern “Clustered Regularly Interspaced Short Palindromic Repeats” – CRISPR.

The unique sequences in between the repeats was additionally found to match the DNA of viruses that target bacteria, and scientists realized that CRISPR is a part of the bacteria’s immune system that retains pieces of harmful viruses in order to recognize and defend against future attacks by those very same viruses.

A vital part of the defense mechanism comprises a set of enzymes called Cas (or CRISPR-associated proteins) which can precisely trim DNA and slice out the invading viruses. The best known Cas enzyme is Cas9 which has the unique ability to bind to any complement sequence in any genome.

Hence comprise the CRISPR/Cas9 system: Cas9 being an enzyme that snips the DNA, and CRISPR the collection of DNA sequences that tells Cas9 exactly where to cleave. When Cas9 is fed with a specific sequence called the guide RNA, scientists can practically cut and paste the DNA sequence into the genome wherever they want, hence manipulating gene function and essentially altering the genome of almost any organism with unprecedented ease and finesse.

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CRISPR/Cas9 is therefore a faster, cheaper and more accurate mechanism with vast potential to edit genes for various purposes, from revising the genomes of human embryos to create so-called designer babies, to hacking the DNA sequences to toggle genes off or on to better understand cellular systems and treating terminal disease.

“CRISPR/Cas9 gives us the ability to delete every single gene in our genome using CRISPR/Cas9 libraries and to detect if this results in cell death specifically in tumours which have lost tumour suppressors. This could help us identify a new wave of drug targets,” Guichard says.

CRISPR/Cas9 is so precise, according to Guichard, that it helps scientists’ understanding of enzymatic activity in cancer cells for them to focus on the right targets.

“Making CRISPR cell lines is by no means simple, but it is becoming much simpler…. [W]e are asking for more and more complex gene editing and the answer is, ‘It should be feasible’. And it is!” she exclaims.

“The innovation in CRISPR/Cas9 reagents has been incredible and has given us the ability to tailor reagents to specific targets,” Guichard says. Her team has been testing different CRISPR reagents to demonstrate their applicability to target validation which traditionally used siRNA. “If we want scientists across the company to use CRISPR/Cas9, we need to make it as simple and robust as possible for them,” she says.

“While some of our experiments test genes in which deletion can reduce proliferation of cancer cells, deletion of others can decrease drug sensitivity,” she adds. Some of these genes were identified using cells from KO mice, whose existing gene is replaced or disrupted (hence, ‘knocked-out’) with an artificial piece of DNA, but “the results could not be repeated using siRNA,” Guichard says.

“Now CRISPR/Cas9 gives us a chance to revisit these genes in cancer cells which are more relevant to the patients we are hoping to treat,” she concludes. AMOR

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