IDH "Encyclopedic" Research Review Debuts in Academic Journal, Cancer Cell

BEIJING, Aug. 21, 2018 /PRNewswire/ -- Recently, a review paper on the "Biological Role and Therapeutic Potential of IDH Mutations in Cancer" was published in Cancer Cell, the authoritative international academic journal. The paper was led by Yan Hai, chair professor at Duke University and co-founder & chief scientist of Genetron Health, and co-written by the Preston Robert Tisch Brain Tumor Center.

Here is the IDH "encyclopedia" interpretation in detail:

This review provides a detailed review on the preclinical and clinical studies of IDH inhibitors in gliomas and acute myeloid leukemia (AML) as well as other potential alternative therapies and immunotherapies for people carrying IDH1/2 mutant tumors.

The paper has demonstrated through a large number of preclinical and clinical evidence that the development and validation of IDH mutation therapy strategies is very important and will provide the patients with therapeutic benefits in the future.

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Starting from Brain Tumor
Professor Yan Hai Pioneers in IDH Research

IDH (isocitrate dehydrogenase) is an important metabolic enzyme in the tricarboxylic acid cycle. Mutations of IDH1/2 will cause the generation of a new enzyme that can convert αKG into D2HG (D-2-hydroxyglutarate) and accumulate in cells, and increased D2HG concentrations can be detected in the serum of patients with brain gliomas due to IDH mutations and with acute myeloid leukemia (AML). Since D2HG content in normal tissues is extremely low, D2HG can serve as a very good biomarker for clinical testing.

The hotspot mutations of the IDH1/2 were firstly found in 2009 by Professor Yan Hai and his partners in patients of adult glioblastoma (a malignant brain tumor), and the results were published in Science and NEJM. Since then, IDH has come to the attention of scientists of cancer genomics.

In subsequent research reports, the clinical significance of IDH1/2 genetic mutations has gradually been detected in a number of cancers including acute myeloid leukemia (AML), intrahepatic cholangiocarcinoma, chondrosarcoma, thyroid cancer, prostate cancer, paraganglioma, and melanoma.

Based on this, IDH1/2 were included in the guidance on WHO Classification of Tumors of the Central Nervous System as the record in human history to use molecular classification as a gold standard for brain tumor diagnosis.

In 2013, Professor Yan Hai discovered that TERT promoter mutation is a key driver of many common tumors and can serve as another important basis for molecular classification of brain glioma.

In 2018, Professor Yan Hai led his team to complete the gene map of TERTpwt-IDHwt for the first time through whole genome sequencing. The results were published in a sub-journal of Nature. So far, based on the new key promoter gene for malignant glioma discovered by the team led by Professor Yan Hai and its partners, the molecular classification standard for such malignant brain tumor is expected to be further updated.

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Kits, New Drugs Keep Emerging
Rapid Breakthroughs in Clinical Diagnosis and Clinical Treatment around IDH

In most AML studies on adults, the frequency of IDH1 mutations is approximately 5.5% - 10.4%, while that of IDH2 mutations is approximately 8.6% - 17.7%. The potential effects of targeted therapies for IDH mutations in AML have been demonstrated in a number of in vitro and in vivo pre-clinical studies.

The first result of phase-1 and phase-2 clinical tests on the safety and tolerability performed in human bodies showed that patients used 100 mg/d of enasidenib (IDH2 inhibitor) with an OS ratio of 38.5%; about 20.2% of patients achieved CR. According to the result of a study on relapsed and refractory AML in Blood in 2017, among patients treated with enasidenib, the total effective rates reached 40.3%. The duration of 19.3% patients (34) achieving CR and OS was 19.7 months.

Based on such positive findings, in August 2017, the FDA approved enasidenib (trade name Idhifa, formerly known as AG-221), the IDH2 inhibitor produced by Celgene and Agios for the treatment of IDH2 variation and relapsed and refractory AML. And Abbott's RealTime IDH2 test kit was approved for companion diagnostics.

Besides, IDH1 inhibitors have achieved good pre-clinical results in some mouse models, and at present, some small molecule pharmaceuticals for AML treatment of IDH1 mutations are under development, including ivosidenib (AG-120), the oral targeted inhibitor for IDH1 mutations developed by Agios for the treatment of relapsed or refractory AML due to IDH1 mutations, whose new drug application is subject to FDA's priority review, with the PDUFA Date being August 21, 2018.

At the same time, Cornerstone Pharmaceutical and Agios have announced an exclusive partnership and licensing agreement to promote the clinical development and commercialization of ivosidenib (AG-120) through monotherapy or combination therapy in mainland China, Hong Kong, Macao and Taiwan.

The IDH1/TERT gene mutation detection kit independently developed by Genetron Health was already approved by the CFDA in December 2017. Suitable for clinical detection of IDH1 R132H mutations in tumor tissues of glioma patients, it can provide an important reference for the pathological classification of glioma patients.

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Troubles Detected
Can IDH Mutation Inhibitor Win Popularity among Public?

IDH gene is an important driving gene for brain gliomas, especially in gliomas with WHO grade II/III, where the frequency of mutation is high. Consistent efforts for the development of IDH mutation inhibitors and the treatment for gliomas are also underway.

Clinical Tests of IDH1/2 Inhibitors in Malignant Gliomas

However, it is found in multiple studies that the efficacy of IDH1/2 inhibitors is still unstable for gliomas, and the reasons are still unclear: possibly due to the blood-brain barrier, the difference in the reversibility of apparent genetic changes of IDH mutation induction in different tissue types, and the possibility of IDH to change from driver mutation to passenger mutation in the progression of glioma diseases, it is difficult for IDH1/2 inhibitors to play their roles in gliomas.

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Drawing on the Imagination
"Indirect Rescue" for IDH1/2 Mutations

In addition to the development of mutation inhibitors for IDH, some research results have shown that it is possible to find the potential therapeutic targets in patients with IDH mutations according to the activity of the new enzyme generated due to IDH mutations. Some research found, for instance, the D2HG produced by IDH mutations may result in defects in the homologous recombination function, thus causing sensitivity to PARP inhibitors.

Besides, another potential method for treating IDH mutant tumors is targeted therapy for tertiary driver gene changes occurring during tumor progression, such as the MGG152 cell line containing IDH R132H mutation and MYCN amplification and the BET inhibitor JQ1 (capable of inhibiting the expression of n-Myc and the transcription reactions dependent on n-Myc), which can inhibit the growth of cells.

The above treatment options represent the future directions for drug development for patients with IDH mutations.

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Immunotherapy
IDH Mutation Has Right of Speech

Immunotherapy has been a hot topic of discussion in the past two years, but the situation of immunotherapy for gliomas is still unclear. Multiple studies have shown that IDH1/2 hotspot mutations and L-/D-2HG isomers may have important effects on the immune systems the tumor microenvironments. Moreover, IDH1/2 mutations and the mutant product D2HG may cause immunosuppression of gliomas, which, however, may cause the tumors to be sensitive to immunotherapy.

It has also been reported that new antigenic epitopes produced by IDH1/2 mutations may provide an opportunity for the vaccination of related peptide vaccines, which may induce an anti-tumor immune response. In the mouse models receiving the treatment, 25% of the mice have had significant effects. Therefore, IDH1/2 mutations may cause immunosuppression by altering the expression of immunogenic cytokines and receptors, and specific antigens produced by IDH mutations may mediate anti-tumor immune responses when stimulated by peptide vaccination.

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Find Another Path
Alternative Treatment Strategies: Possible Alternatives for Tumor Treatment

In summary, a large number of evidence and early clinical data have suggested that the diseases of most AML patients carrying IDH1/2 mutations can be completely or partially relieved by using IDH1/2 inhibitors.

However, for the treatment of gliomas, the efficacy of IDH1/2 inhibitors is still unstable and the reasons are still unclear and need further exploration.

However, some early clinical tests have suggested good tolerability of non-contrast-enhanced glioma patients who have received treatment with IDH mutation inhibitor AG-120 (ivosidenib), and other phase-I and phase-II clinical tests for evaluating the safety of IDH mutation inhibitors in glioma patients are also in progress.

As the continuous deepening of clinical research, for pre-clinical studies, alternative treatment strategies based on metabolic load, chemosensitivity, and/or telomere maintenance mechanisms will be very important for gliomas with IDH mutations.

SOURCE Genetron Health