Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, (MDCM )retired, MSEd
The Bottom Line:
Profiling the metabolites produced by cells in Richter transformation could help researchers develop new targeted therapies in the future.
Who Performed the Research and Where Was it Presented:
Dr. Prajish Iyer from City of Hope National Comprehensive Cancer and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Richter transformation is a rare complication of chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), where the disease turns into a much more aggressive, fast-growing lymphoma. Though we don’t entirely understand why Richter transformation grows so fast, one of the potential contributors may be changes in the mitochondria, the power centers of cells. Mitochondria produce energy that allows cells to grow, and in cancer, there is a rewiring of cellular metabolism that allows cancer cells to grow faster. Little is known about the changes in cellular metabolism and mitochondrial function that drive Richter transformation. To better understand these changes, researchers looked at the different metabolites produced in various preclinical models of Richter transformation.
Methods and Participants:
This study used preclinical mouse models and human cell lines that were genetically modified to mimic Richter transformation. Metabolomic profiling was performed to measure an array of different compounds that are produced by the body or cells.
Results
- In a mouse model of Richter transformation, treatment with a CDK9 inhibitor and an oxidative phosphorylation inhibitor improved overall survival. CDK9 inhibitors target the cell cycle, which is the process by which cells grow and divide. Oxidative phosphorylation (OXPHOS) is a cellular process through which oxygen and nutrients are turned into energy.
- While these drugs produced good results, they cannot currently be used because they lack selectivity. CDK9 inhibitors disrupt gene transcription (using DNA to make RNA) in all cells. OXPHOS inhibitors block energy production through the mitochondria in all cells. This lack of specificity leads to off-target effects and increased side effects. As of today, no CDK9 or OXPHOS inhibitors are approved for any medical indications due to toxicities.
- To identify potential targets for the mitochondria in Richter transformation, researchers profiled the metabolites produced in models of Richter transformation.
- Metabolites glycerol-3-phosphate and carnitine were both significantly elevated in Richter transformation compared with CLL, both in mouse models and human cell line models.
- Future research could help with understanding the pathways that lead to the production of these metabolites and potentially target associated genes with therapies.
Conclusions:
Profiling the metabolites produced by cells in Richter transformation could help researchers develop new ways to target therapies in the future. Richter transformation remains a substantial unmet need, and new strategies like this are needed to help develop new treatments. This work was supported by a Young Investigator Award from the CLL Society: Delineating the Role of Mitochondrial Dysregulation in Richter’s Transformation.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Integrating Metabolomics and Molecular Pathways to Uncover Therapeutic Vulnerabilities in Richter’s Transformation
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