Treatment for an aggressive form of myeloma could improve after scientists uncovered new insights into how a class of enzymes and its epigenetic target can make the blood cancer aggressive and resistant to treatment.
Compared with other types of myeloma, patients with t(4;14) myeloma have a poorer prognosis with shorter overall survival. The histone methyltransferase NSD2 is over-produced in t(4;14) myeloma, but attempts to target this protein with drugs have not been successful.
Now, researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) discovered PKCα is a target of NSD2, increasing its production, which makes t(4;14) translocated multiple myeloma worse.
The team discovered that NSD2 triggers elevated glycolysis through the activation of PKCα. This leads to the production of excessive lactate that fuels malignancy and undermines the response to the immunomodulatory drug lenolidomide.
Professor Wee Joo Chng, lead author of the study, said: “Our study aims to overcome the limitations of targeting the key deregulated gene in t(4;14) myeloma. It sheds light on the metabolic reprogramming of MM in response to the oxygen- and nutrient-deprived bone marrow microenvironment. By exploring the epigenome and metabolome of NSD2, we sought alternative vulnerabilities that could revolutionise treatment strategies.”
The research team say their study findings, published in Cancer Research, could influence the development of novel medicines and non-invasive diagnostic tests. For patients with t(4;14) myeloma, targeted metabolic interventions could help to bring about promising therapeutic options.
Identifying that lactate levels could serve as predictive biomarkers for drug response highlights the transformative potential of metabolite signatures in personalised medicine, they add.
Prof Chng and his team are now planning to design therapeutic intervention for t(4;14) myeloma.
Chong PSY, Chooi JY, Lim JSL, Leow ACY, Toh SHM, Azaman I, Koh MY, Teoh PJ, Tan TZ, Chung TH, Chng WJ. (2023) “Histone Methyltransferase NSD2 Activates PKCα to Drive Metabolic Reprogramming and Lenalidomide Resistance in Multiple Myeloma.” Cancer Research, doi: 10.1158/0008-5472.CAN-22-3481
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