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Neurosurgery:
doi: 10.1227/NEU.0b013e3181ae7e28
Science Times

Tumor-Specific Targeted Therapy in Pediatric Astrocytoma Demonstrated in a Murine Model

Parry, Phillip V.; Engh, Johnathan A.

Free Access

The molecular characterization of adult brain tumors over the past decade has revolutionized the field of neurooncology, facilitating development of targeted therapies for tumors with a specific genetic fingerprint. For example, the identification of a methylated MGMT promoter gene in glioblastoma patients has been shown to be an independent predictor of improved survival in patients treated with temozolomide.1 Additionally, 1p/19q codeleted anaplastic oligodendrogliomas appear to respond more favorably to both chemotherapy and radiation therapy than oligodendrogliomas that do not share this genetic profile.2,3 However, similar advances in targeted therapy for pediatric malignant astrocytomas have been hindered by a lack of information regarding the genetic makeup and signaling pathways of these tumors.

Prior research performed at University of California San Francisco and Georgetown University has demonstrated that approximately 20% of pediatric astrocytomas (WHO grades II-IV) feature mutations in v-raf murine sarcoma viral oncogene homolog B1, also known as BRAFV600E.4 By comparison, genetic profiling for adult glioblastomas estimates BRAFV600E mutations to be present in only 1% to 3% of all cases, and has not been reported in adult anaplastic astrocytomas. Their most current research demonstrates that homozygous deletions of the CDKN2A gene encoding for the tumor suppressor gene p16Ink4a are commonly found in conjunction with this BRAFV600E mutation.5

Using a murine model, this group determined that the coincident expression of a heterozygous BRAFV600E mutation and complete loss of p16Ink4a represent obligatory steps for the initiation or promotion of certain pediatric astrocytomas. With these specific protumorigenic steps delineated, the group tested the therapeutic effects of PLX4720, a BRAFV600E inhibitor, and PD0332991, a cyclin dependent kinase inhibitor of p16Ink4a, on their tumor cell lines in a murine model. Specifically, intracranial xenografts of an astrocytic cell line were implanted into immunodeficient mice, which were then treated with each of the above agents administered orally or via intra-peritoneal injection. Their data show a statistically significant survival benefit in mice treated with both mono and dual therapy (Figure). Additionally, they demonstrate a statistically significant decrease in the number of Ki67+ cells per microscopic field in the treated groups.5

Figure. Kaplan-Meier...
Figure. Kaplan-Meier...
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The ability to treat malignant astrocytomas is limited by our lack of understanding of the molecular pathophysiology of these tumors. However, this research is suggestive of a potential combination approach for chemotherapy in the treatment of pediatric malignant astrocytomas. Preclinical and clinical trials will hopefully establish the feasibility of this approach in humans. The 2 research teams should be heralded for their contributions, as their work provides a potential new avenue for tumor-specific targeted therapy.

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REFERENCES

1. Hegi ME, Diserens AC, Godard S, et al.. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res. 2004;10(6):1871–1874.

2. Lassman AB, Iwamoto FM, Cloughesy TF, et al.. International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro Oncol. 2011;13(6):649–659.

3. Cairncross JG, Ueki K, Zlatescu MC, et al.. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998;90(19):1473–1479.

4. Schindler G, Capper D, Meyer J, et al.. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121(3):397–405.

5. Huillard E, Hashizume R, Phillips JJ, et al.. Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proc Natl Acad Sci U S A. 2012;109(22):8710–8715.

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