The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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8. Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax.
Waclawiczek, A., Leppä, A.-M., Renders S. et al. Cancer Discovery. 13:1408–27. (2023).
doi: 10.1158/2159-8290.CD-22-0939.
Summary of the findings
Treatment with BCL-2 inhibitor Venetoclax (VEN) and Hypomethylating agents (HMA) has transformed therapies for elderly AML patients and relapsed/refractory disease. While mutational profiling enriches for good and poor response, no personalized biomarker predicting HMA/VEN response exists to date. Waclawiczek et al., show that GPR56+ Leukemic stem cells (LSCs) but not bulk AML cells predicts response to HMA/VEN in vitro. We then examined intracellular expression level of the three BCL2-family members, BCL-2, BCL-xL and MCL-1 within LSCs in >70 HMA/VEN treated patients by flow cytometry. This revealed that high BCL-2 expression in LSCs with concomitant low expression of BCL-xL or MCL-1 predicted good response to HMA/VEN. In contrast, low BCL-2 and high BCL-xL/MCL-1 expression in LSCs was strongly associated with poor response. Using these insights, we combined the intracellular expression level of these three BCL-2-family members into a MAC-Score. Applying MAC-scoring in LSCs, but not bulk AML cells, provided a clear distinction between patients responding or failing HMA/VEN therapy and was associated to time to relapse. MAC-Scoring also predicted HMA/VEN response in a salvage setting and its predictive power of 97% outperformed genetic markers. MAC-scoring is fast and affordable and thus qualifies as a personalized predictive biomarker to guide AML therapy.
The graphical illustration was taken from Figure 5K from the original article (https://aacrjournals.org/cancerdiscovery/article/13/6/1408/726964/Combinatorial-BCL2-Family-Expression-in-Acute), published as an open access article and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license (https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en). The graphical illustration was created using a BioRender.com license.
Future impact
Currently MAC-scoring is being integrated into the clinical flow cytometry pipelines to validate this technology prospectively and in real life conditions. Following validation MAC-Scoring allows biomarker based clinical trials to deescalate induction therapy for younger, fit AML patients. In the future, information on BCL-xL and MCL-1 gathered through MAC-Scoring can guide patient selection for clinical trials with new BCL-xL or MCL-1 inhibitors or combinatorial approaches in a front line or relapsed refractory setting. MAC-scoring is not limited to AML but could also be adapted and applied to other diseases sensible to proapoptotic therapy such as CLL or lymphoma.
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The Cancer Researcher is an online magazine for the cancer research community from the European Association for Cancer Research.
The EACR, a registered charity, is a global community for those working and studying in cancer research. Our mission is “The advancement of cancer research for the public benefit: from basic research to prevention, treatment and care.”
Summary of the findings
Summary of the findings
