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Case Reports
. 2016 Jun 11;3(5-6):156-63.
doi: 10.18632/oncoscience.311. eCollection 2016.

Durable response of glioblastoma to adjuvant therapy consisting of temozolomide and a weekly dose of AMD3100 (plerixafor), a CXCR4 inhibitor, together with lapatinib, metformin and niacinamide

Adan Rios  1 , Sigmund H Hsu  2 , Angel Blanco  3 , Jamie Buryanek  4 , Arthur L Day  2 , Mary F McGuire  5 , Robert E Brown  4
Affiliations
Case Reports

Durable response of glioblastoma to adjuvant therapy consisting of temozolomide and a weekly dose of AMD3100 (plerixafor), a CXCR4 inhibitor, together with lapatinib, metformin and niacinamide

Adan Rios et al. Oncoscience. .

Abstract

Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site.[3]. This SDF-1 hypoxia-dependent effect can be blocked by AMD3100 (plerixafor) [4]. We report a GBM case treated after chemo- radiotherapy with plerixafor and a combination of an mTOR, a Sirt1 and an EGFRvIII inhibitor. After one year temozolomide and the EGFRvIII inhibitor were stopped. Plerixafor, and the MTOR and Sirt-1 inhibitors were continued. He is in clinical and radiologic remission 30 months from the initiation of his adjuvant treatment. To our knowledge, this is the first report of a patient treated for over two years with a CXCR4 inhibitor (plerixafor), as part of his adjuvant treatment. We believe there is sufficient experimental evidence to consider AMD3100 (plerixafor) part of the adjuvant treatment of GBM.

Significance: The adjuvant inhibition of GBM vasculogenesis(a process different from local angiogenesis) by specifically blocking the migration of BMDCs to the primary tumor site with inhibitors of the CXCR4/SDF-1 axis represents a potential novel therapeutic approach to GBM. There is significant pre-clinical evidence and validation for its use as demonstrated in a patient derived tumor xenograft model of GBM. Together with other specific anti-tumoral therapies, the active inhibition of vasculogenesis in the adjuvant treatment of GBM is deserving of further exploration.

Keywords: biomedical analytics; glioblastoma; morphoproteomics; plerixafor; preventative and targeted therapy.

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Conflict of interest statement

CONFLICTS OF INTEREST

No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1
A. Image of pre surgical MRI of September 09 2013 showing within the posterior medial right temporal and occipital lobes a 3.8 × 5.8 × 4.7 cm. mass. The mass had peripheral enhancement and effacement of the atrium of the right lateral ventricle, displaced laterally. B. Post- surgery image of September 21 2013, showing interval right parietal craniotomy with significant debulking of right temporal occipital tumor. There was a large area of restricted diffusion along the margins of the resection cavity in the right occipital lobe. There was expected postoperative enhancement of the margins of the resection cavity and along the operative tract. C. At one year post- surgical intervention and completion of temozolomide adjuvant treatment, there were evolving intrinsic T1 hyper-intensities along the margins of the resection cavity in the right parietal lobe. There was improvement in the enhancement along the margins of the operative tract and section cavity. No new areas of enhancement, hydrocephalus or midline shift. D. At thirty months follow up there were post-operative changes with no new enhancing lesions, no hydrocephalus or midline shift. The patient is neurologically functional and with a ECOG PS* of 0. *Eastern Cooperative Group Performance Status.
Figure 2
Figure 2
The patient's glioblastoma multiforme (GBM) with: H&E stained section showing tumor cells with adjacent angiogenic focus (Frame A); high expression of epidermal growth factor receptor, total and vIII on the plasmalemmal aspect of the tumor cells(Frame B); nuclear compartmentalization of phosphorylated (p ) mTOR (Ser 2448) (Frame C); variable expression of Sirt1 Frame D) and EZH2 (Frame E) in the nuclei of the tumor cells; and CXCR4 on the endothelial cells including areas of tumoral angiogenesis along with occasional scattered mononuclear cells in the adjacent tissues (Frame F, see arrows) There is also an associated expression of vascular endothelial growth factor (VEGF)-A in the tumor cells in the angiogenic region. PKC-alpha, p-Akt (Ser 473) and VEGF-A are not depicted. (DAB[3,3′-diaminobenzidine] brown chromogenic signal; original magnifications x400 for Frames A-F).
Figure 3
Figure 3
Key interactions modulated by potential pharmacogenomic agents in glioblastoma. Dashed lines: indirect interactions; Red coloration/t-bar: downregulation; Green coloration/arrow: upregulation; Blue coloration/arrow: dual- directional regulation or binding.
Figure 4
Figure 4
Treatment course from diagnosis until present. Plerixafor was initiated at a dose of 0.24mg/Kg s.c. once a week together with the initiation of the adjuvant treatment with temozolomide, lapatinib, niacinamide, and metformin. It has been given continuously since then. Lapatinib and temozolomide were discontinued after completion of one year of adjuvant treatment. During the last six months of the first year of adjuvant treatment, the patient experienced weight loss, a reactive episode of depression and a superficial phlebitis of the right leg. These symptoms required and resolved after a short course of anabolic steroids, an anti-depressant and anti-coagulation with low molecular weight heparin. After the first year of adjuvant treatment he has continued on treatment only with plerixafor, niacinamide and metformin. His ECOG PS is 0.
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