Institute of Microbiology, Chinese Academy of Sciences
Acute myeloid leukemia (AML) is a heterogeneous disease of bone marrow, accounting for about 80% of adult acute leukemia. Multi drug combination chemotherapy will not only bring serious side effects, but also face the problems of easy recurrence and drug resistance. Although some patients can get complete remission after initial treatment, the recurrence rate is as high as 50-70% within three years, and after recurrence, they are resistant to the original drugs, so we have to increase the dose and replace the more toxic chemotherapy drugs.
At the same time, because AML involves thousands of cytogenetic abnormalities and gene mutations, the research and development of targeted drugs for gene mutation is full of challenges, so far, the number of AML patients entering clinical practice is extremely limited. At present, the overall five-year survival rate of AML patients is only about 25%, which is the highest mortality of leukemia.
Clinical evidence shows that some common resistance related proteins are overexpressed on the surface of different types of AML cells, and the expression level is closely related to the poor prognosis of AML patients. Chemokine receptor CXCR4 is one of them. It is highly expressed in many types of AML cells, and CXCL12 is secreted by stromal cells in bone marrow and spleen.
CXCR4 on the surface of AML cells interacts with its ligand CXCL12 to homing to bone marrow, from which the proliferation and drug resistance signals are obtained and infiltrated into extramedullary organs.
The team of Xu Haiyan from Institute of basic medicine, Chinese Academy of Medical Sciences, cooperated with Wang Chen team of National Nanotechnology center and Wang Jianxiang team of Hematology Hospital of China Medical University, combined the chemosynthetic CXCR4 antagonist peptide (E5) with domestic cultured phosphatidylethanolamine (DSPE) to prepare E5 loaded nano micelles (m-e5), which not only improved the dissolution of E5 in the physiological environment It is more stable and has a half-life of more than 14 hours in rats, which is better than the same target antagonistic peptide in clinical trials.
The research team applied m-e5 to AE & c-kitd816v leukemia mouse model with AML1-ETO fusion gene and c-kit d816 mutation gene; this model has the characteristics of rapid development of disease course, relapse and refractory, and different from xenotransplantation model, it can more truly simulate the bone marrow microenvironment needed for the occurrence and development of leukaemia.
The results showed that m-e5 could bind to the N-terminal of CXCR4 extracellular domain and prevent the effect of CXCL12. When CXCR4 is highly expressed in bone marrow cells of AML mice, m-e5, as a single drug, can significantly affect its downstream signals by antagonizing CXCR4, effectively inhibit the colonization of AML cells in spleen and bone marrow, and mobilize AML cells into peripheral blood circulation, making it difficult to homing and renewing, thus promoting apoptosis or differentiation, and making the proportion of AML cells in spleen, bone marrow and peripheral blood The survival time of mice was significantly prolonged.
On the other hand, when the level of CXCR4 in bone marrow cells of AML mice is in the low level, m-e5 can also be combined with clinical first-line chemotherapy drugs to significantly improve the effect of chemotherapy. This study shows that m-e5 is expected to become a safe and effective CXCR4 targeted drug, and has clinical transformation prospects and application value in the treatment of AML.
The results were published in small (DOI: 10.1002/small.202001890). Associate Professor Meng Jie, Ph.D. students Ge Yangyang and Xing Haiyan were the co first authors, and Prof. Xu Haiyan, Wang Chen and Wang Jianxiang were the co correspondents. This research was supported by national key R & D Program (2017yfa020504), medical and health science and technology innovation project of Chinese Academy of Medical Sciences (2016-i2m-3-004) and National Natural Science Foundation (NSFC) (81870133, 31771005 and 21721002).
Paper links:
https://onlinelibrary.wiley.com/doi/10.1002/smll.202001890 )
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