Targeting AXL, by small molecule inhibitors and Nanobody-based approaches, to eliminate cancer cells and improve chemotherapeutic responses in Acute Myeloid Leukemia

Scriptie/Masterproef: Master's Thesis

Samenvatting

Background
Acute Myeloid Leukemia (AML) is a hematological cancer characterized by abnormal proliferation of immature myeloid cells and bone marrow failure. Despite major progress in understanding the biology of AML, treatment of elderly patients remains highly challenging and relapse often occurs. Recent studies indicate that AXL, a receptor tyrosine kinase, plays a key role in various processes including cancer cell survival and chemoresistance.

Aims
In this study, we aimed to further clarify the role of AXL in AML. In addition, we investigated the anti-tumor effects of currently available AXL-inhibitors and chemotherapy, focusing on viability, apoptosis and chemoresistance.

Results
Patient cohorts were assessed for the expression of TAM receptors. Axl expression was analyzed in different hematological cell lines using qRT-PCR and flow cytometry. We observed a high Axl expression in AML cell lines when compared to lymphoma and myeloma cell lines. The effects of R428, a small molecule AXL-inhibitor, on viability and induced apoptosis of AML cells was determined by Cell Titer Glo and AnnexinV/7AAD staining, respectively, and we observed a significant decrease in viability of AML cells. Chemotherapy-induced Axl expression was also investigated and we found that the chemotherapeutic agent cytarabine was able to significantly induce Axl expression in AML cells. The combination of cytarabine and R428 significantly increased apoptosis of AML cell lines when compared to single agent therapy.

Conclusion
Since AXL inhibitors significantly reduced tumor load, especially in combination with chemotherapy, we therefore conclude that AXL-targeting agents can be considered as a new therapeutic strategy in AML patients.
Datum prijs18 jun 2020
Originele taalEnglish

Citeer dit

'