- This paper reports on a case of WHO grade 3 IDH2-mutant astrocytoma that was clinically aggressive and lethal but in which no newly acquired pathogenic single-nucleotide variants were observed in recurrent tumor
- PDGFRA gain, CDK4 and MDM2 amplifications, and upregulated phospho-Rb were detected in the recurrent tumor and in a xenograft mouse model
- PDGFR and CDK4/6 inhibitors potently suppressed the viability of recurrent tumor cells
- Similar to IDH1-mutant astrocytoma, co-existing copy number alterations that activate the PDGFR and retinoblastoma (RB) signaling pathways may critically drive tumor progression in IDH2-mutant astrocytoma
Astrocytomas, a subgroup of gliomas, are defined by mutations in the IDH gene family. The vast majority (>95%) have mutations in IDH1. Only rarely do these tumors exhibit mutations in the IDH2 gene.
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Researchers at Yokohama City University and Massachusetts General Hospital collaborated in the study of a patient with a unique case of astrocytoma that allowed them to investigate how genomic alterations promote the progression of IDH2-mutant astrocytoma and to identify potential therapeutic targets. The team at Yokohama also established the first IDH2-mutant astrocytoma xenograft model derived from recurrent disease.
Kensuke Tateishi, MD, PhD, formerly a researcher in the Department of Neurosurgery, and now an associate professor of Neurosurgery at Yokohama City University, Daniel P. Cahill, MD, PhD, a neurosurgeon at Mass General, Hiroaki Wakimoto, MD, PhD, associate professor of Neurosurgery at Mass General, and colleagues report in Acta Neuropathologica Communications.
A 44-year-old man with persistent headache was found on MRI to have a tumor in the right frontal lobe, which, after resection, was identified as astrocytoma carrying heterogenous mutations of IDH2R172K and TP53R248W.
Despite radiation and chemotherapy, the tumor recurred 32 months later, exhibiting a greater burden of the same mutations. The patient underwent a second surgery and additional chemotherapy, but unfortunately passed away due to tumor progression 48 months after the initial diagnosis.
Comparisons of the Tumors
Genomic analysis revealed CDKN2A/B hemizygous deletion in the recurrent tumor, unchanged from the primary tumor. Because of that and the lack of necrosis or microvascular proliferation, both tumors were CNS WHO grade 3.
Because these tumors are rare, previously studied IDH2-mutant astrocytomas have been CNS WHO grade 2 and have not contained putative driver single-nucleotide variants. Therefore, the team decided to try to understand the molecular mechanisms of tumor progression in this case.
Gain of PDGFRA and amplifications of CDK4 and MDM2 were newly acquired copy number alterations in the recurrent tumor. PDFGRA is a receptor tyrosine kinase that stimulates the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways. CDK4 and MDM2 amplification deregulates the retinoblastoma (RB) tumor suppression pathway.
Indeed, expression of the phospho-proteins PDGFRA, AKT, mTOR, MEK, ERK and Rb was higher in recurrent tumor than primary tumor, and CDK4 and MDM2 were also upregulated.
Cell Viability Assays
Cell cultures derived from the primary and recurrent tumors showed:
- Investigational PDGFR inhibitors and the FDA approved CKD4/6 inhibitors abemaciclib and palbociclib potently decreased the viability of recurrent tumor cells but not primary tumor cells
- There was no difference in response to treatment with investigational PI3K, AKT or mutation-specific IDH2 inhibitors
Xenograft Mouse Model
The research team at Yokohama was able to develop a xenograft mouse model of the recurrent tumor, although not the primary tumor. The IDH2R172K and TP53R248W mutations were retained in the xenografts, along with the gain of PDGFRA and the amplifications of CDK4 and MDM2.
The hemizygous deletion of CDKN2A/B observed in both the primary and recurrent parent tumors was changed to homozygous deletion in the xenograft model. The researchers thus generated the first IDH2R172K-mutant astrocytoma, CNS WHO grade 4 xenograft mouse model from a recurrent tumor.
Interpreting the Findings
Similar to previously published findings in IDH1-mutant astrocytoma, co-existing copy number alterations that activate the PDGFR and RB signaling pathways may critically drive tumor progression and xenograft formation in IDH2-mutant astrocytoma.
The finding that CDK4/6 and PDGFR inhibitors suppressed the viability of recurrent tumor cells further supports the critical role of cell-cycle deregulation in progression in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. These genomic alterations may represent therapeutic targets.
Interestingly, mutation-specific IDH2 inhibitors did not decrease tumor cell viability in laboratory studies. Longer-term administration or combination with other agents might prove to have antitumor effects.
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