Targeting phosphoglycerate dehydrogenase in multiple myeloma
Samah Elsaadi1, Ida Steiro2, Pegah Abdollahi2,3
1Center for Myeloma Research, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Prinsesse Kristinas gate 1, 7030, Trondheim, Norway. Samah.elsaadi@ntnu.no.
Experimental Hematology & Oncology
|January 5, 2021
Summary
Targeting phosphoglycerate dehydrogenase (PHGDH) with inhibitors like NCT-503 shows promise in treating multiple myeloma (MM). This approach can overcome resistance to proteasome inhibitors and improve therapeutic outcomes in MM.
Area of Science:
- Hematology
- Oncology
- Biochemistry
Background:
- Multiple myeloma (MM) is an incurable plasma cell malignancy.
- Novel therapeutic strategies are urgently needed.
- Phosphoglycerate dehydrogenase (PHGDH) is implicated in bortezomib resistance in MM.
Purpose of the Study:
- To investigate the therapeutic potential of PHGDH inhibition in multiple myeloma.
- To evaluate PHGDH inhibitors in combination with proteasome inhibitors.
- To explore PHGDH inhibition as a strategy to overcome drug resistance.
Main Methods:
- Tested PHGDH inhibitors (CBR5884, NCT-503) on MM cell lines and primary patient cells.
- Assessed combination therapy with proteasome inhibitors, including in resistant cell lines.
- Utilized PHGDH knockdown and an in vivo mouse model (5T33MM) to confirm findings.
Main Results:
- MM cell lines expressed PHGDH and were sensitive to NCT-503.
- Synergistic effects observed with NCT-503 and bortezomib combination therapy.
- PHGDH inhibition reduced intracellular redox capacity and showed in vivo therapeutic advantage.
Conclusions:
- Targeting PHGDH is a promising therapeutic strategy for multiple myeloma.
- PHGDH inhibition can overcome resistance to proteasome inhibitors.
- Combination therapy with PHGDH inhibitors offers a potential new treatment avenue.
