Hong Kong – A research team led by Professor Anskar Leung Yu-hung, from the Department of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, the University of Hong Kong (HKUMed), has identified PLK4 as a novel therapeutic target for acute myeloid leukaemia (AML) carrying the TP53 mutation. AML is a deadly disease, for which there is currently a lack of effective treatment options. The results may provide the mechanistic foundation for setting up clinical trials in this AML subtype with a view to improving the patient outcome. Queen Mary Hospital is one of the treatment sites in which the effect of a PLK4 inhibitor in AML patients will be tested. The study was published in Blood.
Background
AML is a type of blood cancer caused by genetic changes in blood stem cells in bone marrow. Its symptoms include fever, bleeding and infection. Without treatment, AML patients may deteriorate rapidly and die. Conventional treatments include intensive chemotherapy and blood stem cell transplantation. Overall, only 40% of patients can be cured and enjoy long-term survival. A subtype of AML, carrying a mutation of a tumour suppressive gene, known as TP53, responds poorly to conventional treatment, resulting in a high mortality rate within a year after diagnosis. At present, there is no specific treatment available for this AML subtype, underscoring the urgent need to develop novel and specific therapies for this disease.
Research method and findings
A comprehensive analysis of gene expression and pharmacological vulnerabilities in different AML subtypes identified a gene known as polo-like kinase 4 (PLK4), which is specifically active in TP53 mutated AML. PLK4 is a major regulator of cell division. TP53 mutated AML is resistant to chemotherapy and highly vulnerable to prolonged PLK4 inhibition. PLK4 inhibition also induces DNA damage, cell ageing and abnormal cell division. The team discovered that the combined effects of histone modification and polyploidy activate the cGAS-STING pathway, which triggers the immune system. These findings have been consistently observed in both the laboratory setting and animal models. The combination of the PLK4 inhibitor with a monoclonal antibody against CD47 enhanced macrophage killing capability, synergistically reducing the leukemic burden and resulting in prolonged animal survival.
Significance of the study
This is the first study to demonstrate the therapeutic effect of PLK4 inhibition on TP53 mutated AML and the novel therapeutic mechanism pertaining to the activation of the cGAS-STING pathway and the immune system. These observations lay a foundation for evaluating the clinical effects of PLK4 inhibitor in patients with this AML subtype. In addition to hospitals in the US and Canada, the Haematology Division at Queen Mary Hospital will become a treatment site that is participating in global clinical trials to test the effects of PLK4 inhibitor in AML patients.
About the research team
The research team is led by Professor Anskar Leung Yu-hung, Chair Professor of Haematology, Department of Medicine, School of Clinical Medicine, HKUMed. The first-authors include Dr Cheuk Him-man, Research Assistant Professor, and Eunis Lam and Dr Kenny Dang, MPhil and PhD students, respectively, Department of Medicine, School of Clinical Medicine, HKUMed. Major collaborators include Dr Carmen Wong Chak-lui, Associate Professor, Department of Pathology, School of Clinical Medicine, HKUMed; Professor Michael Huen Shing-yan, Professor, School of Biomedical Sciences, HKUMed; Professor Eric So, King’s College London, UK; and Professor Mak Tak-wah, Princess Margaret Cancer Centre, Toronto, Canada.
Acknowledgements
The research is supported by the Theme-based Research Scheme (T12-702/20-N) of the Hong Kong Research Grants Council; the Centre for Oncology and Immunology under the Health@InnoHK Initiative, funded by the Innovation and Technology Commission, the Government of Hong Kong SAR; and the Li Shu Fan Medical Foundation; the Croucher Foundation; the S K Yee Medical Foundation; the Tang King Yin Research Fund; the Mr. Ying Wan Leung Research Fund; the Madam Madeline Tong Lai-Sheung Cancer Research Fund; and the Blood Cancer Fund.
Contact
Jaymee Ng
The University of Hong Kong
[email protected]