Impact of mitochondrial folate metabolism activity on the sensitivity to methotrexate in leukaemia

Dr Vignir Helgason (Cancer Sciences, University of Glasgow) http://www.gla.ac.uk/researchinstitutes/cancersciences/staff/vignirhelgason/
Dr Alexei Vazquez (CRUK Beatson Institute)

The transformation from a normal cell to a cancerous one requires metabolic changes to fuel the high metabolic demands of cancer cells. In recent years there have been a number of new discoveries connecting known aberrations in oncogenic and tumour suppressor pathways with metabolic alterations required to sustain cell proliferation and migration. However, an understanding of the selective advantage of these metabolic alterations and their relevance for the treatment of cancer is still lacking. This innovative PhD project aims to discover new therapies targeting the metabolism of blood cancers. The cross-disciplinary project is build upon recent discoveries in cancer metabolism and previous knowledge of the treatment of blood cancers with antifolates (drugs that block the action of folic acid and thereby inhibit proliferation of cancer cells).

The PhD candidate will gain an understanding of genomics, cellular biology, metabolism, pathophysiology and pharmacology in the context of blood cancers. The candidate will learn and apply state-of-the-art metabolomics protocols to interrogate cancer metabolism in in vitro cell culture systems and in vivo mouse models of cancer. The candidate will advance his/her career development towards becoming and independent researcher in the fields of leukaemia biology and/or cancer metabolism.

Keywords: Leukaemia, Acute lymphoblastic leukaemia, One-carbon metabolism, Methotrexate

References:

Horne G, Jackson L, Helgason V, Holyoake TL. Stem Cell Guardians – Old and New Perspectives in LSC Biology. Curr Drug Targets. 2016 Jul 11

Karvela M, Baquero P, Kuntz EM, Mukhopadhyay A, Mitchell R, Allan EK, Chan E, Kranc KR, Calabretta B, Salomoni P, Gottlieb E, Holyoake TL, Helgason GV. ATG7 regulates energy metabolism, differentiation and survival of Philadelphia-chromosomepositive cells. Autophagy. 2016 Jun 2;12(6):936-48.

Holyoake TL, Helgason GV. “Do we need more drugs for chronic myeloid leukemia?” Immunol Rev. 2015 Jan;263(1):106-23

Pellicano F, Scott MT, Helgason GV, Hopcroft LE, Allan EK, Aspinall-O’Dea M, Copland M, Pierce A, Huntly BJ, Whetton AD, Holyoake TL. “The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors” Stem Cells. 2014 Sep;32(9):2324-37.

Hamilton A*, Helgason GV*, Schemionek M*, Zhang B, Myssina S, Allan EK, Nicolini FE, Müller-Tidow C, Bhatia R, Brunton VG, Koschmieder S, Holyoake TL. “Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival” Blood. 2012 Feb 9;119(6):1501-10. *Equal contribution.

Meiser J, Tumanov S, Maddocks O, Labuschagne CF, Athineos D, Van Den Broek N, Mackay GM, Gottlieb E, Blyth K, Vousden K, Kamphorst JJ, Vazquez A. Serine one-carbon catabolism with formate overflow. Sci Adv 2016; 2:e1601273

Tedeschi PM, Johnson-Farley N, Lin H, Shelton LM, Ooga T, Mackay G, Van Den Broek N, Bertino JR, Vazquez A. Quantification of folate metabolism using transient metabolic flux analysis. Cancer Metab. 2015;3: 6

Tedeschi PM, Vazquez A, Kerrigan JE, Bertino JR. Mitochondrial Methylenetetrahydrofolate Dehydrogenase (MTHFD2) Overexpression Is Associated with Tumor Cell Proliferation and Is a Novel Target for Drug Development. Molecular cancer research : MCR 2015, 13:1361-1366

Tedeschi PM, Markert EK, Gounder M, Lin H, Dvorzhinski D, Dolfi SC, Chan LY-Y, Qiu J, DiPaola RS, Hirshfield KM, Boros LG, Bertino JR, Oltvai ZN and Vazquez A. Contribution of serine, folate and glycine metabolism to the ATP, NADPH and purine requirements of cancer cells. Cell Death & Disease 2013; 4:e877

Vazquez A, Markert EK, Oltvai ZN. Serine biosynthesis with one carbon catabolism and the glycine cleavage system represents a novel pathway for ATP generation. PLoS One 2011; 6:e19538

Back