HKU researchers discover potential treatment for lethal form of leukaemia
A Hong Kong research team has identified a novel therapeutic target for a lethal subtype of acute myeloid leukaemia (AML) which may improve patient outcomes and lead to new treatments for other cancers as well.
Professor Anskar Leung Yu-hung of the Faculty of Medicine, University of Hong Kong (HKUMed), led a team that identified PLK4 as a novel therapeutic target for acute myeloid leukaemia (AML) carrying the TP53 mutation. The study was published in Blood.
AML is a type of blood cancer caused by genetic changes in blood stem cells in bone marrow. It is a lethal disease. Conventional treatments include intensive chemotherapy and blood stem cell transplantation. Overall, only 40 percent 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 an even higher mortality rate. There is no treatment available for this AML subtype underscoring the urgent need to develop specific therapies for this disease.
“There are around 300 new cases of AML per year in Hong Kong, and the TP53 mutation occurs in about five to 10 percent of all patients, so there are around 30 people per year with this mutation in Hong Kong alone. Once it happens, patients are pretty much doomed. Most of them will die within a year of diagnoses so we felt there was a need to see how this outcome could be improved,” said Professor Leung.
Professor Leung was a Croucher Senior Medical Research Fellow at HKU in 2017 and a Croucher Fellow at the University of Minnesota in 2000.
The research was started almost five years ago by Dr Kenny Dang, a PhD student at HKUMed, and one of the first authors of the paper. A comprehensive analysis using public data bases of gene expression and pharmacological vulnerabilities in different AML subtypes identified 45 targets, including the polo-like kinase 4 (PLK4) gene, 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.
Researchers discovered that the combined effects of histone modification and polyploidy activate the cGAS-STING pathway, which triggers the immune system. 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 survival in animal models. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis.
Professor Tak Wah Mak FRS, Professor of Medical Biophysics and Immunology at the University of Toronto and University of Hong Kong, was a major collaborator on the paper and said the research is important for three key reasons. Firstly, because TP53 mutated AML is very lethal and difficult to treat. Secondly, the research showed that when the cells are treated with the drug that blocks centriole duplication, it activates the immune system. And thirdly, the research showed that the PLK4 inhibitor combined with the anti-CD47 antibody, a “don’t-eat-me” signal, in a very efficient way.
“This is very insightful, not just scientifically, but ultimately, those three points are worthy of serious follow-up. They have important, fundamental implications that not only can help this group of leukaemia patients in dire need, but also, the whole idea that cancer cells can inadvertently activate the immune system when you treat with this drug, and that our immune system can be galvanised to prevent these cancers from taking off — this is new thinking, and we should exploit that in a more profound way,” said Professor Mak, who is also a former Chairman of the Croucher Foundation.
Hong Kong Collaboration
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 and might lead to novel therapeutic strategies for this disease.
“In Hong Kong we have a very strong basic pre-clinical research platform including zebrafish and different mouse models which allow us to work out very detailed mechanistic insights into the therapeutic basis of new targets. This serves as the molecular basis and strong foundation for clinical trials,” said Dr Carmen Wong Chak-lui, Associate Professor, Department of Pathology, School of Clinical Medicine, HKUMed, and a major collaborator on the research.
Dr Wong received the Croucher Innovation Award at HKU in 2017, and was a Croucher Fellow at Johns Hopkins University in 2009.
The team’s research into PLK4 also found that it is applicable to other cancer types.
“We work as collaborators on liver cancer as well, and found that PLK4 is very efficient in liver cancer patients in combination with anti-PD1 or anti-PDL1. This is due to the similar mechanisms of sustained activation of the STING pathway and the drug’s capacity to elicit immune response,” Dr Wong said.
PLK4 is manufactured by Treadwell Therapeutics, and an industry sponsored clinical trial is now underway in multiple hospitals in Canada, the United States and Queen Mary Hospital in Hong Kong.
“It immediately suggests thinking about a translational approach in patients, by combining PLK4 inhibition with CD47 blockade for patients with AML,” said Dr David A. Barbie, an Associate Professor of Medicine at Harvard Medical School and the Dana-Farber Cancer Institute, and Associate Director of the Robert and Renée Belfer Center for Applied Cancer Research, who is focused on developing novel cancer immunotherapies.
Dr Barbie said the combination therapy aspect of the research is of particular importance.
“This concept also has implications beyond AML, and there is potential to test similar combinations in other solid tumour types such as breast or lung cancer."