Targeted cancer therapy
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A team of scientists from A*STAR’s Institute of Molecular and Cell Biology (IMCB) and Genome Institute of Singapore (GIS) among others, have identified an important cancer progression mechanism that is observed in 90% of cancer cells. The team said in their report published in Nucleic Acids Research that by activating the human telomerase reverse transcriptase (hTERT) gene, cancer cells can continue to divide and multiply indefinitely in the body.

The life span of a normal healthy cell is determined by telomeres, protective caps at the ends of chromosomes. Each time a cell divides, the telomeres become shorter until eventually they are too short to protect the DNA and the cell dies naturally. Cancer cells, however, live through reactivating telomerase, an enzyme which can prolong telomeres, but is inactive in most adult cells.

Previous research has shown that telomerase is reactivated in as much as 90% of all cancers. That makes hTERT, through which telomerase is activated, a good therapeutic target for drug developers.

“Activation of telomerase is the most common oncogenic event providing immortality to cancer cells. We now know how to inhibit telomerase activity to target cancer cells specifically. This study will be a guide for developing next-generation cancer inhibitors,” said Semih Akincilar, senior research fellow at A*STAR’s IMCB and lead researcher of the study.

Previous efforts have sought to inhibit telomerase as a method of treating cancer, but the drugs have not progressed in trial due to their toxicity caused by the side effects produce by these drugs also affecting health cells. But the new research has identified a specific DNA structure that forms only in cancer cells and brings the necessary molecular machinery into the correct position to activate the hTERT gene. The detailed mechanism of hTERT activation provided in this study would be instrumental in designing drugs to inhibit hTERT specifically in cancer cells with less side effects.

“To circumvent undesirable cytotoxicity of telomerase enzymatic inhibitors, which block hTERT action in cancer cells and stem cells alike, it is crucial to decipher mechanisms that specifically drive hTERT reactivation in cancer cells. Transcriptional reactivation of hTERT is the rate-limiting step in tumorigenesis, which makes it a valuable candidate for cancer therapy,” the researchers wrote.

Patient-derived colorectal cancer cell lines generated by GIS were used to identify correlative gene expression for hTERT activation and ascertain the physiological relevance of the findings in this study. These models will serve as a testbed for future studies aimed at the development of cancer-specific inhibitors of telomerase. The researchers hope to collaborate in the future with biopharma companies and clinical partners to develop cancer-specific telomerase inhibitors and bring those candidates into clinical trials.

Other institutes contributing to the study included NUS Cancer Science Institute of Singapore (CSI Singapore), National Cancer Centre Singapore (NCCS), and Nanyang Technological University (NTU).

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