Dataset Information

CAM-Xenograft Model Provides Preclinical Evidence for the Applicability of [⁶⁸Ga]Ga-Pentixafor in CRC Imaging.

ABSTRACT: Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Increased expression of CXCR4 has been associated with liver metastasis, disease progression, and shortened survival. Using in vitro cell binding studies and the in ovo model, we aimed to investigate the potential of [⁶⁸Ga]Ga-Pentixafor, a radiotracer specifically targeting human CXCR4, for CRC imaging. Specific membrane binding and internalisation of [⁶⁸Ga]Ga-Pentixafor was shown for HT29 cells, but not for HCT116 cells. Accordingly, [⁶⁸Ga]Ga-Pentixafor accumulated specifically in CAM-xenografts derived from HT29 cells, but not in HCT116 xenografts, as determined by µPET/MRI. The CAM-grown xenografts were histologically characterised, demonstrating vascularisation of the graft, preserved expression of human CXCR4, and viability of the tumour cells within the grafts. In vivo viability was further confirmed by µPET/MRI measurements using 2-[¹⁸F]FDG as a surrogate for glucose metabolism. [⁶⁸Ga]Ga-Pentixafor µPET/MRI scans showed distinct radiotracer accumulation in the chick embryonal heart, liver, and kidneys, whereas 2-[¹⁸F]FDG uptake was predominantly found in the kidneys and joints of the chick embryos. Our findings suggest that [⁶⁸Ga]Ga-Pentixafor is an interesting novel radiotracer for CRC imaging that is worth further investigation. Moreover, this study further supports the suitability of the CAM-xenograft model for the initial preclinical evaluation of targeted radiopharmaceuticals.

SUBMITTER: Bencurova K

PROVIDER: S-EPMC9688097 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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CAM-Xenograft Model Provides Preclinical Evidence for the Applicability of [68Ga]Ga-Pentixafor in CRC Imaging.

Benčurová Katarína K Friske Joachim J Anderla Maximilian M Mayrhofer Manuela M Wanek Thomas T Nics Lukas L Egger Gerda G Helbich Thomas H TH Hacker Marcus M Haug Alexander A Mitterhauser Markus M Balber Theresa T

Cancers 20221111 22

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Increased expression of CXCR4 has been associated with liver metastasis, disease progression, and shortened survival. Using in vitro cell binding studies and the in ovo model, we aimed to investigate the potential of [68Ga]Ga-Pentixafor, a radiotracer specifically targeting human CXCR4, for CRC imaging. Specific membrane binding and internalisation of [68Ga]Ga-Pentixafor was shown for HT29 ce ...[more]

PMID: 36428644

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Project description:PurposeThis study aimed to explore the significance of 68Ga-pentixafor PET/CT in guiding surgical treatments for primary aldosteronism (PA) patients, by identifying functional lesions and determining the dominant side of aldosterone secretion.Materials and methodsWe prospectively included 91 PA patients receiving surgical treatments based on the results of 68Ga-pentixafor PET/CT. The 68Ga-pentixafor PET/CT images were evaluated by visual and semi-quantitative analysis. The relationship between radionuclide imaging characteristics and postoperative outcomes was assessed following surgery.ResultsThe positive detection rate of 68Ga-pentixafor PET/CT in 91 PA patients was 85.7 % (78/91) with a median maximum standardized uptake value (SUVmax) of 10.2 (6.0-16.0). The SUVmax was positively correlated with lesion diameter (r = 0.497, P < 0.001), while negatively correlated with the blood potassium level (r = -0.450, P < 0.001) and plasma renin activity (r = -0.297, P = 0.004). 63 cases of 73 PA patients with unilateral adrenal lesion were identified positive by 68Ga-pentixafor PET/CT, and 95.2 % of the 63 positive cases benefited from surgical resection of the identified positive lesions. Among 18 PA patients with bilateral lesions, 68Ga-pentixafor PET/CT identified positive lesions in 15 cases, and 86.7 % (13/15) of the positive cases benefited from total or partial adrenalectomy guided by 68Ga-pentixafor PET/CT. There was no significant difference in postoperative outcomes between patients undergoing partial adrenalectomy with those subjected to total adrenalectomy. The accuracy rate of 68Ga-pentixafor PET/CT in determining the dominant side of aldosterone secretion for PA was 85.7 %, which was comparable to the 71.4 % of adrenal vein sampling (AVS).Conclusions68Ga-pentixafor PET/CT could effectively guide the surgical management for PA patients, achieving favorable postoperative outcomes. The accuracy rate of 68Ga-pentixafor PET/CT in identifying the dominant side of aldosterone secretion was not inferior to that of AVS.

Project description:Background[68Ga]Ga-PentixaFor is a promising radiotracer for positron emission tomography imaging of several human tumors overexpressing the chemokine receptor-4 (CXCR4). CXCR4 overexpression has been demonstrated in patients with hematologic malignancies, solid cancers, as well as cardiovascular pathologies of inflammatory origins. However, its radio synthesis is not yet fully developed in France, and existing methods do not use our type of synthesis module. Therefore, we aimed at developing a [68Ga]Ga-PentixaFor synthesis with Gaia/Luna Elysia-Raytest module to use it in clinical purpose.Results12 syntheses were carried out by varying the temperature conditions and radiolabeling times, and led to choose specific labelling conditions with the Gaia/Luna Elysia-Raytest module: 97 °C, 4 min. The mean synthesis time of the 3 validation runs under good manufacturing practice (GMP) was 24 min 27 s (± 8 s), and the mean radiochemical yield was 87.0% [standard deviation (SD) 6.67%]. Different quality control parameters were also evaluated in accordance with European Pharmacopeia: radiochemical and radionuclidic purity, pH, sterility, stability and endotoxins levels. The average radiochemical purity was 99.1% (SD 0.25%) assessed by instant thin layer chromatography and 99.8% (SD 0.092%) assessed by high pressure liquid chromatography. average [68Ge] breakthrough was 1.48 × 10-5%, under the recommended level of 0.001%. We assessed the stability of the radiotracer up to 4 h at room temperature (no augmentation of the [68Ga] chloride in the final product, i.e. radiochemical purity (RCP) > 98.5%). The endotoxins levels were < 5 EU/mL, and the pH was 6.5 (same for the three syntheses).ConclusionThe [68Ga]Ga-PentixaFor synthesis process developed on the Gaia/Luna Elysia-Raytest module has fulfilled all acceptance criteria for injectable radiopharmaceutical products regarding the European Pharmacopeia. The radiochemical purity, stability, efficacy, as well as the microbiological quality of the three GMP batches were found to be good. The robustness of the synthesis process may be suitable for multi-dose application in clinical settings.

Project description:PurposeCXCR4 (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.MethodsCXCR4 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.ResultsTwo 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.ConclusionUsing 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.

Project description:BackgroundC-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in various solid cancers and can be targeted by CXCR4-directed molecular imaging. We aimed to characterize the in-vivo CXCR4 expression in patients affected with solid tumors, along with a comparison to ex-vivo findings.MethodsA total 142 patients with 23 different histologically proven solid tumors were imaged with CXCR4-directed PET/CT using [68 Ga]Ga-pentixafor (total number of scans, 152). A semi-quantitative analysis of the CXCR4-positive tumor burden including maximum standardized uptake values (SUVmax) and target-to-background ratios (TBR) using blood pool was conducted. In addition, we performed histopathological staining to determine the immuno-reactive score (IRS) from patients' tumor tissue and investigated possible correlations with SUVmax (by providing Spearman's rho ρ). Based on imaging, we also assessed the eligibility for CXCR4-targeted radioligand therapy or non-radioactive CXCR4 inhibitory treatment (defined as more than five CXCR4-avid target lesions [TL] with SUVmax above 10).ResultsOne hundred three of 152 (67.8%) scans showed discernible uptake above blood pool (TBR > 1) in 462 lesions (52 primary tumors and 410 metastases). Median TBR was 4.4 (1.05-24.98), thereby indicating high image contrast. The highest SUVmax was observed in ovarian cancer, followed by small cell lung cancer, desmoplastic small round cell tumor, and adrenocortical carcinoma. When comparing radiotracer accumulation between primary tumors and metastases for the entire cohort, comparable SUVmax was recorded (P > 0.999), except for pulmonal findings (P = 0.013), indicative for uniform CXCR4 expression among TL. For higher IRS, a weak, but statistically significant correlation with increased SUVmax was observed (ρ = 0.328; P = 0.018). In 42/103 (40.8%) scans, more than five TL were recorded, with 12/42 (28.6%) exhibiting SUVmax above 10, suggesting eligibility for CXCR4-targeted treatment in this subcohort.ConclusionsIn a whole-body tumor read-out, a substantial portion of prevalent solid tumors demonstrated increased and uniform [68 Ga]Ga-pentixafor uptake, along with high image contrast. We also observed a respective link between in- and ex-vivo CXCR4 expression, suggesting high specificity of the PET agent. Last, a fraction of patients with [68 Ga]Ga-pentixafor-positive tumor burden were rendered potentially suitable for CXCR4-directed therapy.

Dataset Information

CAM-Xenograft Model Provides Preclinical Evidence for the Applicability of [⁶⁸Ga]Ga-Pentixafor in CRC Imaging.

Publications

CAM-Xenograft Model Provides Preclinical Evidence for the Applicability of [<sup>68</sup>Ga]Ga-Pentixafor in CRC Imaging.

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