Acute myeloid leukemia (AML) is a highly aggressive form of cancer arising from the presence of abnormal white blood cells in the bone marrow. While many AML patients initially respond well to therapy, the 5-year survival rate is poor (less than 25%), due to drug resistance and disease recurrence. Bortezomib, an inhibitor that blocks protein degradation, has shown promising results in the treatment of some AML patients. However, resistance is a clinical problem, and treatment is often associated with significant side effects and eventually drug resistance. The proteasome is an intracellular structure responsible for protein degradation. Standard proteasome inhibitors like bortezomib target ...
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Acute myeloid leukemia (AML) is a highly aggressive form of cancer arising from the presence of abnormal white blood cells in the bone marrow. While many AML patients initially respond well to therapy, the 5-year survival rate is poor (less than 25%), due to drug resistance and disease recurrence. Bortezomib, an inhibitor that blocks protein degradation, has shown promising results in the treatment of some AML patients. However, resistance is a clinical problem, and treatment is often associated with significant side effects and eventually drug resistance. The proteasome is an intracellular structure responsible for protein degradation. Standard proteasome inhibitors like bortezomib target a particular section of the proteasome, but is associated with significant side effects. We are proposing to target a different area of the proteasome, which we think will have less toxicity. Interestingly, when we reduce expression of several subunits of this particular section of the proteasome, we see increased cell death in myeloid leukemia cells but not normal cells, suggesting they may be a good targets for therapy (Bencomo-Alvarez, et al. Oncogene 2021; Lara, et al. Int J Mol Sci 2022). Data from The Cancer Genome Atlas revealed that high expression of these subunits correlates with inferior outcomes in AML, a disease with a great need for alternative treatments. However, the functional role of these subunits in survival and drug resistance of AML cells remains unexplored. In the short-term, data from this study will identify certain proteasome subunits as a novel targets for therapy in AML. These subunits are often upregulated and correlate with worse outcomes in multiple different cancers (Rubio A, et al. Cells 2021). Therefore, in the long-term, targeting of these proteasome subunits could have therapeutic relevance in myeloid malignancies and possibly extend to other types of cancers.
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