New platform may become a potential approach for personalized cancer treatments

Killing cancer cells without affecting surrounding normal cells is the most desirable approach to targeted cancer therapy. However, this cannot be easily achieved due to the similarities in properties between normal and cancerous cells. IBS researchers have developed an innovative approach called CINDELA (Cancer-specific INDEL Attacker), which attacks cancer-specific mutations and causes multiple DNA double-strand breaks to specifically induce cancer cell death. It is hoped that CINDELA may become a potential approach for personalized cancer treatments in most tumors.

The diagnosis of cancers can be one of the worst news for patients and their families. Conventional treatment options such as radiation therapy and chemotherapy often kill not only cancer cells but normal cells as well, leading to painful side effects. Radiation therapy and chemotherapy destroy cancer cells by producing DNA double-strand breaks in their DNA. Because both treatments target the DNA of normal and cancer cells, radiation therapy and chemotherapy drugs cannot distinguish between cancer cells and normal cells. Thus, indiscriminate destruction of healthy cells and side effects are inevitable when using these treatments. Therefore, scientists have long searched for a method to selectively target only cancer cells without affecting normal cells, which is a crucial requirement for ideal cancer therapy.

There have recently been two major developments in the fields of biomedical sciences. One is cancer genomics, and the other is the discovery of a site-specific endonuclease, called CRISPR-Cas9 (commonly known as genetic scissors). Cancer genomics projects have found that, regardless of their origin, most cancer cells accumulate numerous mutations, including small insertions/deletions (InDel) of multiple nucleotides, single nucleotide changes, and large aberrations. chromosomal. CRISPR-Cas9, the discovery that was recognized by the 2020 Nobel Prize in Chemistry, is a technology that can be used to create DNA double-strand breaks in a sequence-specific way.

South Korean researchers from the Center for Genomic Integrity (CGI) of the Institute for Basic Sciences (IBS) have combined these two concepts and come up with a new idea for cancer treatment. By using CRISPR-Cas9 to produce DNA double-strand breaks at cancer-specific mutations that only exist in cancer cells, they proposed a possibility to trigger cell death in cancer cells without affecting normal cells. . Three CGI research groups (labs led by MYUNG Kyungjae, KWON Taejon, and CHO Seung Woo) located at the Ulsan National Institute of Science and Technology (UNIST) teamed up and proved that it was indeed possible.

First, researchers confirmed that enzyme-induced DNA double-strand breaks using CRISPR were able to induce cell deaths in cancer similar to physical or chemical breaks caused by radiation or chemotherapy, respectively. Next, they performed bioinformatics analysis to identify unique InDel mutations in several different cancer cell lines, including breast, colon, leukemia, glioblastoma, which are not found in normal cells. Based on this information, they succeeded in making CRISPR-Cas9 reagents targeting these mutations.

Scientists named this new treatment CINDELA, which stands for “Cancer-specific InDel Attacker”. CINDELA has been shown to selectively kill cancer cells without affecting normal cells. CINDELA-induced cancer cell death was found to depend on the number of DNA double-strand breaks created by CRISPR-Cas9. For example, the CINDELA reagent that induced 50 DNA breaks was much better at killing cancer cells than the reagent that only induced 10 breaks.

In addition to cancer cell line experiments, researchers conducted other animal studies to verify the effectiveness of CINDELA in living organisms. To do this, tumor cells (colon and lung cancer) were derived from patients and xenografted into mice. It was found that CINDELA treatment can substantially suppress tumor growth in these mice.

In particular, since CINDELA targets InDel mutations that are generated as by-products during tumorigenesis, CINDELA can be applied to treat most tumors.

We believe that CINDELA can become a new therapeutic application for cancer treatments as personalized and precision medicine for all cancer patients without serious side effects. »


Myung Kyungjae, CGI Director

As a next step, researchers have begun to apply this technology in tumors directly taken from patients, with research groups having expertise in relevant technologies, such as gene delivery, companion diagnostic platform and genomics of the Cancer.

However, one obstacle the researchers encountered during all of these experiments was the delivery of the CINDELA reagents to the tumors. Although researchers were able to achieve significant tumor growth inhibition by using a high titer of virus to deliver CRISPR in mice, this may not yet be enough to directly treat human patients. However, such an obstacle is one of the major problems in the current CRISPR-Cas9 field. The researchers believe that in the near future, the development of new delivery systems will eventually help establish the CINDELA cancer treatment technology in cancer patients.

Source:

Journal reference:

Taejoon Kwon, Jae Sun Ra, Soyoung Lee, In-Joon Baek, Keonwoo Khim, Eun A Lee, Eun Kyung Song, Daniyar Otarbayev, Woojae Jung, Yong Hwan Park, Minwoo Wie, Juyoung Bae, Himchan Cheng, Jun Hong Park, Namwoo Kim, Yuri Seo, Seongmin Yun, Ha Eun Kim, Hyo Eun Moon, Sun Ha Paek, Tae Joo Park, Young Un Park, Hwanseok Rhee, Jang Hyun Choi, Seung Woo Cho and Kyungjae Myung, Precision Targeting Tumor Cells with cancer aid- specific InDel mutations with CRISPR-Cas9, PNAS (2022)

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