IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives

Figures & data

Figure 1 Enzymatic activities of wild type and mutated IDH enzymes.

Notes: The IDH family of enzymes comprises three proteins located in the cytoplasm and peroxysomes (IDH1), and mitochondria (IDH2 and IDH3). IDH1 and IDH2 catalyze the reversible NADP+-dependent oxidative decarboxylation of isocitrate to αKG. IDH3 catalyzes the NAD+-dependent conversion of isocitrate to αKG in the TCA cycle. IDH1 and IDH2 mutant enzymes gain neomorphic enzymatic activity, converting NADPH and αKG to NADP+ and D-2HG. D-2HG acts as a weak competitive inhibitor of αKG-dependent dioxygenases. αKG-dependent dioxygenases are involved in various cellular processes such as hypoxia, angiogenesis, maturation of collagens of the extracellular matrix, and regulation of epigenetics. Excess of D-2HG is associated with increased histone and DNA methylation, altering cancer cells differentiation.
Abbreviations: αKG, alpha ketoglutarate; D-2HG, D-2-hydroxyglutarate; IDH, isocitrate dehydrogenase; DNA, deoxyribonucleic acid; mut, mutated; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; TCA cycle, tricarboxylic acid cycle.

Table 1 IDH mutations estimates in solid tumors and hematologic malignancies

Mutation	Histology	Incidence, %	References
IDH1 (R132)	Grade II/III gliomas and secondary GBM	70–80	^Citation3, ^Citation45
	Hematologic malignancies		^Citation58
	de novo AML	6–16
	MPN	<1
	MDS	2–3
	Chondrosarcoma	~40	^Citation8
	Intrahepatic cholangiocarcinoma	7–20	^Citation6
IDH2 (R140, R172)	Grade II/III gliomas and secondary GBM Hematologic malignancies	<5	^Citation3, ^Citation45
	de novo AML	8–19	^Citation58
	MPN	2
	MDS	2–7	^Citation59
	AITL	20–42
	Chondrosarcoma	~16	^Citation8
	Intrahepatic cholangiocarcinoma	3	^Citation6

Abbreviations: IDH, isocitrate dehydrogenase; GBM, glioblastoma; AML, acute myeloid leukemia; MPN, myeloproliferative neoplasms; MDS, myelodysplastic syndrome; AITL, angioimmunoblastic T-cell lymphoma.

Table 2 Ongoing clinical trials evaluating IDH inhibitors

Drug	Neoplasm	Design	Clinicaltrials.gov identifier
AG-120	Advanced hematologic malignancies with IDH1 mutation	Phase I/II	NCT02074839
AG-120	Cholangiocarcinoma	Phase I/II	NCT02073994
	Chondrosarcoma
	Glioma
	Other advanced solid tumors with IDH1 mutation
AG-221	Advanced hematologic malignancies with IDH2 mutation	Phase I/II	NCT01915498
AG-221	Solid tumor	Phase I/II	NCT02273739
	Glioma
	Angioimmunoblastic T-cell lymphoma
	Intrahepatic cholangiocarcinoma
	Chondrosarcoma with IDH2 mutation
AG-221	Refractory or relapsed AML with IDH2 mutations	Randomized Phase III: AG-221 vs physician’s choice	NCT02577406
		Patients ≥60 years of age after second or third line of treatment
AG-120 or AG-221	Newly diagnosed AML with IDH1 and/or IDH2 mutations	Phase I	NCT02632708
		In combination with induction and consolidation therapy
AG-120 or AG-221	Newly diagnosed AML with IDH1 and/or IDH2 mutations	Phase Ib/II	NCT02677922
		In combination with subcutaneous azacitidine
		In patients unfit for intensive chemotherapy
AG-881	Advanced hematologic malignancies with IDH1 and/or IDH2 mutation	Phase I/II	NCT02492737
AG-881	Cholangiocarcinoma	Phase I/II	NCT02481154
	Chondrosarcoma
	Glioma with IDH1 and/or IDH2 mutation
IDH305	Advanced malignancies with IDH1R132 mutations	Phase I/II	NCT02381886
IDH1 peptide vaccine	Grade III–IV gliomas with IDH1R132H mutation	Phase I/II	NCT02454634
IDH1 peptide vaccine	Recurrent grade II glioma with IDH1 mutation	Phase I/II	NCT02193347

Abbreviations: IDH, isocitrate dehydrogenase; AML, acute myeloid leukemia.

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