Dataset Information

Predicting Microenvironment in CXCR4- and FAP-Positive Solid Tumors-A Pan-Cancer Machine Learning Workflow for Theranostic Target Structures.

ABSTRACT: (1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database-representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets.

SUBMITTER: Marquardt A

PROVIDER: S-EPMC9856808 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Predicting Microenvironment in CXCR4- and FAP-Positive Solid Tumors-A Pan-Cancer Machine Learning Workflow for Theranostic Target Structures.

Marquardt André A Hartrampf Philipp P Kollmannsberger Philip P Solimando Antonio G AG Meierjohann Svenja S Kübler Hubert H Bargou Ralf R Schilling Bastian B Serfling Sebastian E SE Buck Andreas A Werner Rudolf A RA Lapa Constantin C Krebs Markus M

Cancers 20230106 2

(1) <b>Background:</b> C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) <b>Methods:</b> Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database-represent ...[more]

PMID: 36672341

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Project description:The NETTER-1, VISION, and TheraP trials proved the efficacy of repeat intravenous application of small radioligands. Application by subcutaneous, intraperitoneal, or oral routes is an important alternative and may yield comparable or favorable organ and tumor radioligand uptake. Here, we assessed organ and tumor biodistribution for various radioligand application routes in healthy mice and models of cancer expressing somatostatin receptor (SSTR), prostate-specific membrane antigen (PSMA), and fibroblast activation protein (FAP). Methods: Healthy and tumor-bearing male C57BL/6 or NOD SCID γ-mice, respectively, were administered a mean of 6.0 ± 0.5 MBq of 68Ga-DOTATOC (RM1-SSTR allograft), 5.3 ± 0.3 MBq of 68Ga-PSMA11 (RM1-PSMA allograft), or 4.8 ± 0.2 MBq of 68Ga-FAPI46 (HT1080-FAP xenograft) by intravenous, intraperitoneal, subcutaneous, or oral routes. In vivo PET images and ex vivo biodistribution in tumor, organs, and the injection site were assessed up to 5 h after injection. Healthy mice were monitored for up to 7 d after the last scan for signs of stress or adverse reactions. Results: After intravenous, intraperitoneal, and subcutaneous radioligand administration, average residual activity at the injection site was less than 17 percentage injected activity per gram (%IA/g) at 1 h after injection, less than 10 %IA/g at 2 h after injection, and no more than 4 %IA/g at 4 h after injection for all radioligands. After oral administration, at least 50 %IA/g remained within the intestines until 4 h after injection. Biodistribution in organs of healthy mice was nearly equivalent after intravenous, intraperitoneal, and subcutaneous application at 1 h after injection and all subsequent time points (≤1 %IA/g for liver, blood, and bone marrow; 11.2 ± 1.4 %IA/g for kidneys). In models for SSTR-, PSMA- and FAP-expressing cancer, tumor uptake was increased or equivalent for intraperitoneal/subcutaneous versus intravenous injection at 5 h after injection (ex vivo): SSTR, 7.2 ± 1.0 %IA/g (P = 0.0197)/6.5 ± 1.3 %IA/g (P = 0.0827) versus 2.9 ± 0.3 %IA/g, respectively; PSMA, 3.4 ± 0.8 %IA/g (P = 0.9954)/3.9 ± 0.8 %IA/g (P = 0.8343) versus 3.3 ± 0.7% IA/g, respectively; FAP, 1.1 ± 0.1 %IA/g (P = 0.9805)/1.1 ± 0.1 %IA/g (P = 0.7446) versus 1.0 ± 0.2 %IA/g, respectively. Conclusion: In healthy mice, biodistribution of small theranostic ligands after intraperitoneal/subcutaneous application is nearly equivalent to that after intravenous injection. Subcutaneous administration resulted in the highest absolute SSTR tumor and tumor-to-organ uptake as compared with the intravenous route, warranting further clinical assessment.

Dataset Information

Predicting Microenvironment in CXCR4- and FAP-Positive Solid Tumors-A Pan-Cancer Machine Learning Workflow for Theranostic Target Structures.

Publications

Predicting Microenvironment in CXCR4- and FAP-Positive Solid Tumors-A Pan-Cancer Machine Learning Workflow for Theranostic Target Structures.

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