In a breakthrough study published last year in Cancer Cell, scientists at the Canadian Light Source (CLS) have managed to kill leukemia cancer cells in in vitro and in vivo models by increasing the activity of their natural cell disposal systems. These systems normally remove misfolded proteins, but researchers were able to increase their activity to selectively target leukemia cells.
Acute myeloid leukemia (AML) is a form of white blood cell cancer that progresses rapidly and requires immediate treatment. Current treatment options mainly involve chemotherapy, with possible bone marrow or stem cell transplants, to try and kill as many leukemia cells as possible. According to the American Cancer Society, there will be around 60,000 new cases of AML and 23,100 deaths in the USA in 2020.
For the study, the team used crystallography to probe sub-nanometer structures. Facilities like the CLS use synchrotron light produced by storage rings and particle accelerators to visualize the actions between cells and drugs down to the tiniest structures. Through this method, the team were able to prove that experimental drugs, called impiridones, could bind and cause the death of cancer cells. Visualizing this wasn’t previously possible and is a massive step forward for the future of leukemia therapies.
The pathway targeted by impiridones attacks cancer cells but leaves normal cells alone by targeting an enzyme (ClpP) found in mitochondria that acts as quality control for various cellular proteins. If the protein is misfolded during production, ClpP destroys it to prevent harm caused by the faulty protein. When Jo Ishizawa and his team hyperactivated ClpP, it was shown to specifically destroy leukemia cells by destroying proteins involved in mitochondrial respiration, preventing the cancer cells from carrying out essential biological processes.
ONC201, an impiridone used in this study, is currently in phase 2 clinical trials for the treatment of various forms of glioma (a type of brain tumor), but these results suggest it could have wider applications. There is currently an appeal for glioma patients to join the trials here.
The team also note some limitations to their study: "Our data suggest that patient samples with the lowest levels of ClpP are less sensitive to ClpP hyperactivation Thus, levels of ClpP could serve as a biomarker to select AML patients most and least likely to respond to this therapy. Further studies with larger numbers of patients would be required to establish thresholds of ClpP expression that best predict response."
The researchers hope that further study into these pathways and impiridones will yield even more positive results. In the meantime, the collaboration between the CLS and other cancer institutes aim to continue to image interactions in leukemia cells to look for more therapeutic targets.
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