Researchers at the Duke-NUS Graduate Medical School in Singapore have identified ways to inhibit the function of a key protein linked to stem cell-like behavior in terminal-stage chronic myeloid leukemia (CML), giving new hope to future treatments for this deadly form of cancer.
SINGAPORE, June 4, 2013 – A Singapore-led team spearheaded by medical oncologist and clinician scientist Associate Professor ONG Sin Tiong at the Duke-NUS Graduate Medical School (Duke-NUS) in Singapore has identified ways to inhibit the function of a key protein linked to stem cell-like behavior in terminal-stage chronic myeloid leukemia (CML), making it possible to develop drugs that may extend the survival of these patients.
The study, published in the prestigious international journal Proceedings of the National Academy of Sciences (PNAS), is the result of a long-standing collaboration between Duke-NUS, the Experimental Therapeutics Centre (ETC) at the Agency for Science, Technology and Research (A*STAR), and the Singapore General Hospital (SGH) that is focused on developing effective therapies in CML.
CML is a blood cancer that has seen tremendous improvement in treatment outcomes following the introduction of tyrosine kinase inhibitor (TKI) drugs that specifically target the BCR-ABL fusion gene, a genetic abnormality that is characteristic of CML. However, when CML progresses to its terminal stage, known as the blast crisis phase, TKI drugs become ineffective and patients with blast crisis CML rapidly succumb to the disease.
“TKI therapy is highly effective in chronic phase CML, and enables most patients to survive many years. In contrast, patients with blast crisis CML usually succumb to their disease within one year, with most patients dying because they develop drug resistance to TKI therapy,” explained Professor Ong, who helms the Laboratory of Hematologic Malignancies in the Cancer and Stem Cell Biology Program at Duke-NUS.
Since a subset of cells associated with blast crisis CML exhibit characteristics of self-renewing stem cells, it was proposed that targeting this particularly malignant and drug-resistant population would be effective in treating blast crisis CML. The team therefore searched for novel targets that will specifically eliminate these cancer stem cells.
Through their efforts, the team identified a protein enzyme, the MNK kinase, that was abnormally activated in clinical samples taken from patients with blast crisis CML. Experiments conducted in the lab further unraveled how MNK kinase activation plays a critical role in the progression of CML to the blast crisis phase, and confers stem cell-like behavior on blast crisis cells.
The team tested a panel of drugs that inhibit MNK kinase activity and found that these MNK inhibitors were effective in preventing blast crisis cells from behaving like cancer stem cells in both in vitro laboratory tests and animal studies.
“Our studies identify the MNK kinases as an important therapeutic target in blast crisis CML, and suggest that drug inhibition of MNK kinase will be useful in overcoming TKI resistance, and improving the survival of patients with blast crisis CML,” said Professor Ong, who is also a Visiting Consultant at the National Cancer Center Singapore and Singapore General Hospital.
Importantly, the MNK inhibitor drugs do not appear to be toxic to normal blood stem cells, indicating that drugs targeting MNK kinases may not cause harmful side effects. Professor Ong hopes that the findings from this study will open new research directions in the treatment of blast crisis CML.
“We are currently collaborating with the ETC and SGH to develop new drugs to simultaneously target the MNK and the BCR-ABL kinases. The development of dual MNK and BCR-ABL kinase inhibitors to treat patients with blast crisis CML may enhance the survival of patients with this deadly disease,” said Professor Ong, who estimates that it will take a few years before these drugs can enter into clinical trials for blast crisis CML.
Dr. Sharon Lim, a research fellow at Duke-NUS, is the first author of the study. Funding for the study was provided by the Duke–National University of Singapore Signature Research Program funded by A*STAR; the Ministry of Health (Singapore); and the National Research Foundation Singapore Clinician Scientist Award (CSA), awarded to Professor Ong by the National Medical Research Council (NMRC).
Caption: L-R: Dr. Sharon Lim, research fellow at Duke-NUS, and Associate Professor ONG Sin Tiong, principal investigator at Duke-NUS. (Photo credit: Tang Yew Chung/Duke-NUS)
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Citation:
Sharon LIM et al. “Targeting of the MNK-eIF4E Axis in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem Cell Function,” Proceedings of the National Academy of Sciences, online in the week of June 3, 2013.
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About Duke-NUS Graduate Medical School Singapore (Duke-NUS):
The Duke-NUS Graduate Medical School Singapore (Duke-NUS) was established in 2005 as a strategic collaboration between the Duke University School of Medicine, located in N. Carolina, USA and the National University of Singapore (NUS). Duke-NUS offers a graduate entry, 4-year M.D. (Doctor of Medicine) training program based on the unique Duke model of education, with one year dedicated to independent study and research projects of a basic science or clinical nature. Duke-NUS also offers M.D./PhD and PhD programs. As a player in Singapore’s biomedical community, Duke-NUS has identified five Signature Research Programs: Cancer & Stem Cell Biology, Neuroscience and Behavioral Disorders, Emerging Infectious Diseases, Cardiovascular & Metabolic Disorders, and Health Services and Systems Research. For more information, please visit www.duke-nus.edu.sg.
About the Experimental Therapeutics Centre (ETC):
ETC was set up in 2006 to play an increasingly important role in translating early stage scientific discoveries into practical applications. From engaging in early stage drug discovery and development to developing innovative research tools for clinical analysis, as well as setting up public-private partnerships to facilitate the advancement of drug candidates, ETC augments Singapore’s capabilities and resources in the drug discovery process. ETC’s capabilities and resources are currently focused on oncology and infectious diseases. It also incubates new technologies for commercialisation and mentors young scientists for careers in the pharmaceutical and biotech industry. For more information about ETC, visit www.etc.a-star.edu.sg
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 fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy. In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore’s manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry.
A*STAR oversees 20 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis as well as their vicinity. These two R&D hubs house a bustling and diverse community of local and international research scientists and engineers from A*STAR’s research entities as well as a growing number of corporate laboratories. For more information about A*STAR, please visit www.a-star.edu.sg
About Singapore General Hospital (SGH):
Singapore General Hospital, a member of Singapore Health Services (SingHealth), is the public sector's flagship hospital. Established in 1821, SGH is Singapore's largest acute tertiary hospital with 1,700 beds and national referral centre, offering a comprehensive range of 36 clinical specialties on its campus. Every year, about 1 million Singaporeans benefit from advanced medical care delivered by its 800 specialists. As an academic healthcare institution and the bedrock of medical education, SGH plays a key role in nurturing doctors, nurses and allied health professionals, and is committed to innovative translational and clinical research in her continual strive to provide the best care and outcomes to her patients. For more information, visit www.sgh.com.sg
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Press release distributed by Asian Scientist Publishing for Duke-NUS Graduate Medical School Singapore www.duke-nus.edu.sg.