A team of scientists, comprising researchers from the Institute of Molecular and Cell Biology (IMCB), a research institute under the Agency for Science, Technology and Research (A*STAR), Singapore, and the VIB Laboratory of Molecular Cancer Biology (VIB/KU Leuven), has revealed the mechanism by which tumor cells elevate levels of MDM4, a protein that is highly expressed in cancer cells but not in normal adult tissues. The team has also found that the mechanism can be interfered with antisense oligonucleotides (ASOs) to suppress cancer growth. The study which paves the way for the development of novel cancer therapeutics was published in the leading Journal of Clinical Investigation (JCI).
MDM4 in cancer cells inhibits p53 protein
P53 is a tumor suppressor which cancer cells need to inhibit in order to multiply. In the case of skin-related melanoma, it had been proposed that tumor cells accomplish the inhibition with an overexpression of MDM4.
The research team had previously proven MDM4’s ability to bind directly to p53 and inhibit its tumor suppressor function in Metastatic Melanoma (MM), a rare but most aggressive type of skin cancer. While the study served as a useful proof-of-concept therapeutics, it was still unclear how the findings could be useful in a clinical setting. Finding small molecules that can interfere directly with MDM4 function has proven to be an enormous challenge and there is no clinically-compatible alternative to selectively and efficiently disrupt the MDM4-p53 complexes. There is also an increasing body of evidence that MDM4 can facilitate tumor formation without necessarily binding to p53.
Prof Jean-Christophe Marine, who heads VIB and has been studying MDM4 for several years, said, “As an alternative to pharmacological inhibition of the MDM4-p53 protein interaction we reasoned that targeting MDM4 protein abundance — rather than its interaction with p53 — may be easier to achieve pharmacologically. In addition, it may also have broader and more robust antitumor effects as this would inhibit both p53-dependent and independent oncogenic functions of MDM4.”
Targeting MDM4 abundance with antisense oligonucleotides (ASOs)
Headed by Dr Ernesto Guccione, the laboratory in IMCB has been researching on the use of ASOs technology to interfere with pre-mRNA splicing and protein abundance. Leveraging IMCB’s expertise in the field of ASOs and through a collaborative effort, the scientists found in the latest study that targeting MDM4 protein abundance using antisense oligonucleotides (ASOs) could impair tumour growth, reduce cell proliferation and increase cell death. This novel discovery suggests that MDM4 is indeed a promising clinically-compatible therapeutic target which can be suppressed with ASOs, and offers alternative therapeutic avenues not only for melanoma, but also for a wide range of other MDM4-expressing cancers such as breast cancer, ovarian cancer, B-cell lymphoma or retinoblastoma.
Dr Guccione, Senior Principal Investigator at IMCB and co-lead for the study, said, “This work is a good example of how ASOs can target proteins that are hard to inhibit by traditional approaches such as small molecule inhibitors, and it greatly expands our options for therapeutic intervention.”
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About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that spearheads economic oriented research to advance scientific discovery and develop innovative technology. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit society.
As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by contributing to societal benefits such as improving outcomes in healthcare, urban living, and sustainability.
We play a key role in nurturing and developing a diversity of talent and leaders in our Agency and Research Institutes, the wider research community and industry. A*STAR oversees 18 biomedical sciences and physical sciences and engineering research entities primarily located in Biopolis and Fusionopolis.
For more information on A*STAR, please visit www.a-star.edu.sg.
About A*STAR’s Institute of Molecular and Cell Biology (IMCB)
The Institute of Molecular and Cell Biology (IMCB) was launched on 23 January 1985, with its official opening ceremony held on 2 October 1987 at the National University of Singapore (NUS). It subsequently became an autonomous research institute (RI) of A*STAR, moving to Biopolis in 2004. IMCB’s vision is to be a premier cell and molecular biology institute which addresses the mechanistic basis of human diseases and its mission is to conduct cutting-edge discovery research in disease pathways; to groom early career researchers to be future leaders in research; and to collaborate with medical and industry communities for research impact. IMCB plays an important role training and recruiting scientific talents, and has contributed to the development of other research entities in Singapore. Its success in fostering a biomedical research culture in Singapore has catalysed Singapore’s transformation into an international hub for biomedical research, development and innovation.
Funded primarily by the Biomedical Research Council (BMRC) of A*STAR, IMCB’s current discovery research includes cell biology in health and disease; animal models of development & disease; cancer & stem cell genetics & genomics; and structural biology & drug discovery. IMCB’s translational research includes humanised model organisms for human diseases; systems approach for disease target identification & validation; and protein engineering & antibody development for diagnostics & therapeutics. Research activities in IMCB are supported by cutting edge infrastructure and facilities including quantitative proteomics; humanised mice; mouse models of human cancer; protein crystallography X-ray; zebrafish for drug metabolism & toxicology; advanced molecular histopathology; imaging & electron microscopy; and DNA sequencing.
For more information about IMCB, visit www.imcb.a-star.edu.sg.
About the VIB Laboratory of Molecular Cancer Biology
VIB is a non-profit research institute in life sciences. About 1,400 scientists conduct strategic basic research on the molecular mechanisms that are responsible for the functioning of the human body, plants, and microorganisms. Through a close partnership with four Flemish universities − UGent, KU Leuven, University of Antwerp, and Vrije Universiteit Brussel − and a solid funding program, VIB unites the forces of 74 research groups in a single institute. The goal of the research is to extend the boundaries of our knowledge of life. Through its technology transfer activities, VIB translates research results into products for the benefit of consumers and patients and contributes to new economic activity. VIB develops and disseminates a wide range of scientifically substantiated information about all aspects of biotechnology. More information: www.vib.be.
About KU Leuven
KU Leuven (University of Leuven) is a leading European research university dedicated to excellent research, education and service to society. It is a founding member of the League of European Research Universities and has a strong European and international orientation. Its sizeable academic staff conducts basic and applied research in a comprehensive range of disciplines. University Hospitals Leuven, its network of research hospitals, provides high-quality healthcare and develops new therapeutic and diagnostic insights with an emphasis on translational research. The university welcomes more than 40,000 students, of which 15.5% are international from more than 140 countries. Its doctoral schools organise internationally oriented PhD programmes for over 4,000 doctoral students. www.kuleuven.be/english/
