26th February 2022
New therapy kills cancer without harming normal cells
A new therapy called CINDELA (Cancer-Specific InDel Attacker) is reported by scientists in South Korea, which uses CRISPR-Cas9 to kill cancer cells without harming normal tissues.
Conventional treatment options for cancer – such as radiation and chemotherapies – not only kill cancer cells, but often normal cells too, which can result in painful side effects. Radiation and chemotherapies, which destroy cells by triggering double-strand breaks in their DNA, cannot distinguish between cancer and normal cells. Indiscriminate killing of healthy cells and side effects are therefore unavoidable when using these treatments. Scientists have long been searching for a method to selectively target only cancer cells, without affecting normal cells, a crucial requirement for the ideal cancer therapy.
Two major developments have occurred in medical science in recent years. One is cancer genomics, and the other is the discovery of a site-specific endonuclease, called CRISPR-Cas9 (sometimes nicknamed “genetic scissors”). Cancer genomics studies have found that regardless of their origins, most cancer cells accumulate many mutations – including small insertion/deletion (InDel) of several nucleotides, single nucleotide changes, and large chromosomal aberrations. CRISPR-Cas9, recognised by the 2020 Nobel Prize in Chemistry, is a technology that can be used to make DNA double-strand breaks in a sequence-specific manner.
Now, scientists have combined these two concepts and proposed a new idea for cancer therapy. By using CRISPR-Cas9 to produce DNA double-strand breaks at cancer-specific mutations that only exist in cancer cells, they have presented a technique for triggering cell death in cancer cells without affecting normal cells.
First, they confirmed that enzyme-driven DNA double-strand breaks using CRISPR were able to induce cell deaths in cancer similar to physical or chemical breaks driven by radiation or chemotherapies, respectively. Then, they performed bioinformatics analysis to identify unique InDel mutations in several different cancer cell lines, including breast, colon, leukaemia, glioblastoma, which are not found in normal cells. Based on this information, they successfully made CRISPR-Cas9 reagents targeting those mutations.
Researchers from South Korea’s Institute for Basic Science (IBS) collaborated with a team from the Ulsan National Institute of Science and Technology (UNIST) to develop this new technique, which they have named “Cancer-specific InDel Attacker” (CINDELA).
Their study, published in the journal Proceedings of the National Academy of Sciences found that CINDELA can selectively kill cancer cells without affecting the nearby healthy cells. They discovered that CINDELA-driven cancer cell death is dependent on the number of DNA double-strand breaks created by CRISPR-Cas9. For example, a CINDELA reagent which induced 50 breaks in the DNA was much better at killing cancer cells than the reagent that induced only 10 breaks.
In addition to cancer cell line experiments, researchers conducted further animal studies to verify CINDELA’s efficacy in living organisms. To do so, they derived tumour cells (colon and lung cancer) from human patients and then xenografted these into mice. It was found that the CINDELA treatment can substantially suppress the growth of tumours in mice.
Notably, since CINDELA targets InDel mutations that are generated as byproducts during tumourigenesis (the initial formation of a tumour in the body), it could be applied to the majority of cancer types.
“We believe CINDELA can become a novel therapeutic application for cancer treatments as personalised and precision medicine for all cancer patients without severe side effects,” said Professor Myung Kyungjae, director of the IBS’s Center for Genomic Integrity.
As a next milestone, researchers have started applying this technology in tumours directly taken from patients, with research groups having expertise in the relevant technologies, such as gene delivery, a companion diagnostic platform, and cancer genomics.
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