A research team led by Professor Anskar Leung Yu-hung, from the Department of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, University of Hong Kong (HKUMed), has identified PLK4 as a novel therapeutic target for leukemia acute myeloid disease (AML) carriers of the TP53 mutation. AML is a fatal disease, for which effective treatment options are currently lacking.
The results of the study were published in Blood.
Acute myeloid leukemia: hope for the development of new therapies
The findings could provide the mechanistic basis for setting up clinical trials in this subtype of AML with the goal of improving patient outcomes. Queen Mary Hospital is one of the treatment centers where the effect of a PLK4 inhibitor will be tested in patients with the disease.
Acute myeloid leukemia is a type of blood cancer caused by genetic changes in blood stem cells in the bone marrow. Its symptoms include fever, bleeding and infection. Without treatment, patients with the disease can rapidly worsen and die.
Conventional treatments include intensive chemotherapy and blood stem cell transplant. Overall, only 40% of patients can be cured and enjoy long-term survival.
A subtype of acute myeloid leukemia, carrying a mutation of a tumor suppressor gene, known as TP53, responds poorly to conventional treatment, resulting in a high mortality rate within a year of diagnosis.
There is currently no specific treatment available for this subtype of AML, underscoring the urgent need to develop new and specific therapies for this disease.
A comprehensive analysis of gene expression and pharmacological vulnerabilities in different subtypes of acute myeloid leukemia has identified a gene known as polo-like kinase 4 (PLK4), which is specifically active in TP53-mutated acute myeloid leukemia.
PLK4 is an important regulator of cell division. TP53 mutated AML is resistant to chemotherapy and highly vulnerable to prolonged PLK4 inhibition. Inhibition of PLK4 also induces DNA damage, cellular aging, and abnormal cell division.
The team found that the combined effects of histone modification and polyploidy activate the cGAS-STING pathway, which activates the immune system. These results have been consistently observed both in laboratory settings and in animal models.
The combination of the PLK4 inhibitor with a monoclonal antibody against CD47 improved the ability to kill macrophages, synergistically reducing the leukemic burden and resulting in prolonged animal survival.
This is the first study to demonstrate the therapeutic effect of PLK4 inhibition on TP53-mutated acute myeloid leukemia and the novel therapeutic mechanism related to the activation of the cGAS-STING pathway and the immune system. These observations lay the foundation for evaluating the clinical effects of the PLK4 inhibitor in patients with this subtype of AML.
In addition to hospitals in the United States and Canada, Queen Mary Hospital's Division of Hematology will become a treatment center participating in global clinical trials to test the effects of the PLK4 inhibitor in patients with acute myeloid leukemia.
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