A team at the National Health Research Institutes (NHRI) has discovered a novel orally available small molecule, DBPR728, that can cut off the nutrient supply for cancer cell growth, which can serve as a new targeted therapy drug.
The research team consists of scientists from the NHRI’s Institute of Biotechnology and Pharmaceutical Research, including Chi Ya-hui (紀雅惠), Yeh Teng-kuang (葉燈光), Chen Chiung-tong (陳炯東) and Chang Chun-ping (張竣評).
Chi told a news conference at the Ministry of Health and Welfare in Taipei yesterday that the occurrence of cancer is often caused by genetic aberrations that lead to uncontrolled cell proliferation.
Photo: Chen Yi-kuan, Taipei Times
An “oncogene” is a gene that has the potential to transform normal cells into cancerous ones through genetic aberrations — including mutation, fusion and amplification, she said.
Genetic amplification refers to an increase in the number of copies of the same gene, and studies have suggested that approximately 28 percent of cancers exhibit Myelocytomatosis (MYC) oncogene amplification, Chi said, adding that they include lung cancer, breast cancer, liver cancer and prostate cancer, as well as several other types.
For cancer cells to grow, the MYC oncoprotein functions as a transcription factor, facilitating the production of enzymes required for glycolysis (the process of breaking down glucose to produce energy), she said.
Therefore, MYC overexpression (too many copies of the MYC oncoprotein) allows cancer cells to metabolize energy in low-oxygen conditions, leading to uncontrolled cell growth and high post-operative recurrence rates, ultimately reducing overall patient survival rates, she said.
However, while there are many therapies that target specific genetic mutations in cancer cells, there are still challenges in developing drugs that target several oncogenes and their cancer-driving proteins, such as the MYC oncogene, due to the intrinsic properties of its proteins, Chi said.
In an effort to suppress MYC overexpression, Chi said the team tried to exploit its “good friend,” the enzyme Aurora kinase A, which stabilizes the MYC protein, by designing small molecules that disrupt the interaction between the two proteins, leading to MYC protein degradation.
They used the molecule DBPR728 to create an inactive oral drug that is stable in the gastrointestinal tract and can be bioconverted to become active when it reaches tumor cells, she said.
Chi said administering the oral drug to mice which have tumor cells with MYC genetic amplification and overexpression showed that the drug to can efficiently induce MYC reduction and cell apoptosis (the process of programmed cell death) in just 10 days.
The drug has obtained a patent in Taiwan and the team is applying for patents in other nations, and hopefully after it passes preclinical toxicity studies and clinical trials, it can be produced as a targeted drug for cancer treatment, she said.
The team’s findings were published in the June issue of Molecular Cancer Therapeutics, a leading journal published by the American Association for Cancer Research.
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