CXCR4 expression in glioblastoma tissue and the potential for PET imaging and treatment with [68Ga]Ga-Pentixafor /[177Lu]Lu-Pentixather

Abstract

Purpose CXCR4 (over)expression is found in multiple human cancer types, while expression is low or absent in healthy tissue. In glioblastoma it is associated with a poor prognosis and more extensive infiltrative phenotype. CXCR4 can be targeted by the diagnostic PET agent [68Ga]Ga-Pentixafor and its therapeutic counterpart [177Lu]Lu-Pentixather. We aimed to investigate the expression of CXCR4 in glioblastoma tissue to further examine the potential of these PET agents. Methods CXCR4 mRNA expression was examined using the R2 genomics platform. Glioblastoma tissue cores were stained for CXCR4. CXCR4 staining in tumor cells was scored. Stained tissue components (cytoplasm and/or nuclei of the tumor cells and blood vessels) were documented. Clinical characteristics and information on IDH and MGMT promoter methylation status were collected. Seven pilot patients with recurrent glioblastoma underwent [68Ga]Ga-Pentixafor PET; residual resected tissue was stained for CXCR4. Results Two large mRNA datasets (N = 284; N = 540) were assesed. Of the 191 glioblastomas, 426 cores were analyzed using immunohistochemistry. Seventy-eight cores (23 tumors) were CXCR4 negative, while 18 cores (5 tumors) had both strong and extensive staining. The remaining 330 cores (163 tumors) showed a large inter- and intra-tumor variation for CXCR4 expression; also seen in the resected tissue of the seven pilot patients—not directly translatable to [68Ga]Ga-Pentixafor PET results. Both mRNA and immunohistochemical analysis showed CXCR4 negative normal brain tissue and no significant correlation between CXCR4 expression and IDH or MGMT status or survival. Conclusion Using immunohistochemistry, high CXCR4 expression was found in a subset of glioblastomas as well as a large inter- and intra-tumor variation. Caution should be exercised in directly translating ex vivo CXCR4 expression to PET agent uptake. However, when high CXCR4 expression can be identified with [68Ga]Ga-Pentixafor, these patients might be good candidates for targeted radionuclide therapy with [177Lu]Lu-Pentixather in the future.

Current Status of 68Ga-Pentixafor in Solid Tumours

“…Several studies have demonstrated that CXCR4 expression in glioblastoma is associated with a poorer prognosis and more infiltrative phenotypes. For an example, Jacobs et al showed that CXCR4 mRNA expression correlates with WHO glioma grade, with a relatively higher expression of CXCR4 in high grade gliomas (obtained from 284 samples), whereas normal brain tissue was CXCR4 mRNA negative [ 23 ]. In their study, variable CXCR4 expression was demonstrated in 38% of the cores in glioblastoma cells, and CXCR4 expression was high in only a subset of glioblastomas.…”

“…Jacobs et al went on to correlate in vitro CXCR4 expression with in vivo 68 Ga-Pentixafor uptake on PET/CT imaging in seven patients [ 23 ]. Five (71%) of the seven patients showed low to moderate tracer uptake, which did not fully correspond with CXCR4 IHC where all patients showed large intra-tumour variation for CXCR4 staining, even within one section.…”

“…These studies show that 68 Ga-Pentixafor does accumulate in prostate cancer; however, studies comparing this tracer to 68 Ga-PSMA are needed to see if CXCR4 targeted imaging and therapy can replace PSMA, especially with the suboptimal response of 177 Lu-PSMA in patients with bone metastasis. The advantage of 177 Lu-Pentixather over PSMA might be that 177 Lu-Pentixather can be directed at tumour cells and neovasculature when CXCR4 is present, unlike PSMA which only targets the neovasculature [ 23 ].…”

“…Molecular imaging of CXCR4 using the CXCR4-specific positron emission tomography (PET) tracer, 68 Ga-labeled cyclopentapeptide, [ 68 Ga]CPCR4-2 or 68 Ga-Pentixafor developed by Demmer et al [ 22 ] has become a well-established method to non-invasively measure CXCR4 expression in vivo. 68 Ga-Pentixafor attaches to both the CXCR4 and macrophage inhibitory factor (MIF) [ 23 ].…”

In Vivo Targeting of CXCR4—New Horizons

“…However, in contrast to the sometimes-pronounced CXCR4 expression observed in ex vivo immunohistochemistry studies using tumor biopsies, the corresponding in vivo [ 68 Ga]Pentixafor PET/CT studies demonstrated a very heterogeneous, often modest, and in some cases even absent CXCR4-mediated tracer uptake in solid cancers [ 26 , 27 , 28 , 29 ], limiting the broad diagnostic application of this imaging approach. To date, only few solid tumor entities have shown pronounced overexpression of CXCR4, as assessed by PET/CT.…”