Novel IDH1-Targeted Glioma Therapies

Abstract

Mutations in the isocitrate dehydrogenase (IDH) 1 gene are commonly found in human glioma, with the majority of low-grade gliomas harboring a recurrent point mutation (IDH1 R132H). Mutant IDH reveals an altered enzymatic activity leading to the synthesis of 2-hydroxyglutarate, which has been implicated in epigenetic mechanisms of oncogenesis. Nevertheless, it is unclear exactly how IDH mutations drive glioma initiation and progression, and it is also not clear why tumors with this mutation generally have a better prognosis than IDH wild-type tumors. Recognition of the high frequency of IDH mutations in glioma [and also in other malignancies, including acute myeloid leukemia (AML) and cholangiocarcinoma] have led to the development of a number of targeted agents that can inhibit these enzymes. Enasidenib and ivosidenib have both gained regulatory approval for IDH mutant AML. Both agents are still in early clinical phases for glioma therapy, as are a number of additional candidates (including AG-881, BAY1436032, and DS1001). A marked clinical problem in the development of these agents is overcoming the blood-brain barrier. An alternative approach to target the IDH1 mutation is by the induction of synthetic lethality with compounds that target poly (ADP-ribose) polymerase (PARP), glutamine metabolism, and the Bcl-2 family of proteins. We conclude that within the last decade, several approaches have been devised to therapeutically target the IDH1 mutation, and that, potentially, both IDH1 inhibitors and synthetic lethal approaches might be relevant for future therapies.

Figure 1:. Summary of phenotypic changes elicited by 2-HG and/or mutated IDH1

The scheme summarizes major pathways affected by mutated IDH1 and the oncometabolite, 2-HG.

Figure 2:. Impact of 2-HG on the electron transport chain

Shown is the electron transport chain with its complexes and electron donors. The final electron acceptor in this system is oxygen that is reduced to water. The flow of the electrons from complex I to complex IV creates energy that is used for synthesis of ATP. In this regard, complex I, III, IV function as proton pumps that create a gradient, which is used by complex V to produce energy (proton-driving force). 2-HG blocks the synthesis of ATP (complex V) and electron transport at the level of complex IV.

Figure 3:. IDH1 R132H impacts the status of the Bcl-2 family of proteins

The IDH1 mutation confers a neomorphic enzymatic activity, resulting in the production of 2-Hydroxyglutarate (2-HG). 2-HG inhibits the ETC (electron transport chain) through impacting the electron flow to molecular oxygen by interference with cytochrome-c oxidase and in part by inhibition of complex V. This results in lower ATP levels, followed by reduction of protein synthesis and lower levels of protein with a short-half life, such as the anti-apoptotic Bcl-2 family member Mcl-1. Lower levels of Mcl-1 shift the survival dependency towards Bcl-xL and/or Bcl-2, creating a mitochondrial Bcl-2 family related vulnerability, which can be executed by the BH3-mimetic, ABT263, resulting in BAX/BAK activation and permeabilization of the outer mitochondrial membrane. In addition, interference with ETC itself can impact mitochondrial membrane potential prime mitochondrial for BAX/BAK mediated apoptosis. Proapoptotic Bcl-2 family members (Puma, BIM, Noxa) either directly or indirectly activate BAX/BAK to facilitate apoptosis.

Figure 4:. Structure of several IDH1 inhibitors as discussed in the present article

Shown are the chemical structures of AG-120, AG-221, AG-881, BAY1436032, and DS-1001b.