Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies.
Hanumantha Rao MadalaSurendra R PunganuruViswanath ArutlaSubhasis MisraT J ThomasKalkunte S SrivenugopalPublished in: Cancers (2018)
Isocitrate dehydrogenases 1 and 2 (IDH1,2), the key Krebs cycle enzymes that generate NADPH reducing equivalents, undergo heterozygous mutations in >70% of low- to mid-grade gliomas and ~20% of acute myeloid leukemias (AMLs) and gain an unusual new activity of reducing the α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2HG) in a NADPH-consuming reaction. The oncometabolite D-2HG, which accumulates >35 mM, is widely accepted to drive a progressive oncogenesis besides exacerbating the already increased oxidative stress in these cancers. More importantly, D-2HG competes with α-KG and inhibits a large number of α-KG-dependent dioxygenases such as TET (Ten-eleven translocation), JmjC domain-containing KDMs (histone lysine demethylases), and the ALKBH DNA repair proteins that ultimately lead to hypermethylation of the CpG islands in the genome. The resulting CpG Island Methylator Phenotype (CIMP) accounts for major gene expression changes including the silencing of the MGMT (O⁶-methylguanine DNA methyltransferase) repair protein in gliomas. Glioma patients with IDH1 mutations also show better therapeutic responses and longer survival, the reasons for which are yet unclear. There has been a great surge in drug discovery for curtailing the mutant IDH activities, and arresting tumor proliferation; however, given the unique and chronic metabolic effects of D-2HG, the promise of these compounds for glioma treatment is uncertain. This comprehensive review discusses the biology, current drug design and opportunities for improved therapies through exploitable synthetic lethality pathways, and an intriguing oncometabolite-inspired strategy for primary glioblastoma.
Keyphrases
- wild type
- high grade
- low grade
- dna repair
- dna methylation
- drug discovery
- fluorescent probe
- gene expression
- dna damage
- oxidative stress
- aqueous solution
- acute myeloid leukemia
- living cells
- genome wide
- reactive oxygen species
- liver failure
- multiple sclerosis
- dna damage response
- dendritic cells
- bone marrow
- single molecule
- early onset
- binding protein
- acute lymphoblastic leukemia
- signaling pathway
- hepatitis b virus
- amino acid
- big data
- allogeneic hematopoietic stem cell transplantation
- emergency department
- diabetic rats
- endoplasmic reticulum stress
- ischemia reperfusion injury
- immune response
- young adults
- heat shock
- intensive care unit
- induced apoptosis
- circulating tumor cells
- protein protein