Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma

Chifu, Irina; Heinze, Britta; Fuß, Carmina Teresa; Lang, Katharina; Kroiß, Matthias; Kircher, Stefan; Rabascio, Cristina; Altieri, Barbara; Schirbel, Andreas; Faßnacht, Martin; Hahner, Stefanie

doi:10.3389/fendo.2020.597878

Cited by 18 publications

(15 citation statements)

References 58 publications

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“…Chemokine receptor-4 (CXCR4) belongs to the superfamily of the seven-transmembrane domain, heterotrimeric G-protein-coupled receptors and is associated with cell proliferation, migration, invasion and survival. In the previous reports, it had been demonstrated that CXCR4 was upregulated in sporadic Vestibular schwannomas (VS) as well as in neurofibromatosis type 2 (NF2) tumors [28][29][30]. Besides, SDF-1 (CXCL12)/CXCR4 signaling has been verified to play a vital role in oncobiology, especially in hypoxia adaptation, metastasis and migration [31].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of C3 and CXCR4 demonstrates their potential as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC)

et al. 2021

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Background The molecular prognostic biomarkers of clear cell renal cell carcinoma (ccRCC) are still unknown. We aimed at researching the candidate biomarkers and potential therapeutic targets of ccRCC. Methods Three ccRCC expression microarray datasets (include GSE14762, GSE66270 and GSE53757) were downloaded from the gene expression omnibus (GEO) database. The differentially expressed genes (DEGs) between ccRCC and normal tissues were explored. The potential functions of identified DEGs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). And then the protein - protein interaction network (PPI) was established to screen the hub genes. After that, the expressions of hub genes were identified by the oncomine database. The hub genes’ prognostic values of patients with ccRCC were analyzed by GEPIA database. Results A total of 137 DEGs were identified by utilizing the limma package and RRA method, including 63 upregulated genes and 74 downregulated genes. It is found that 137 DEGs were mainly enriched in 82 functional terms and 24 pathways in accordance with the research results. Thirteen highest-scoring genes were screened as hub genes (include 10 upregulated genes and 3 downregulated candidate genes) by utilizing the PPI network and module analysis. Through integrating the oncoming database and GEPIA database, the author found that C3 and CXCR4 are not only overexpressed in ccRCC, but also associated with the prognosis of ccRCC. Further results could reveal that patients with high C3 expression had a poor overall survival (OS), while patients with high CTSS and TLR3 expressions had a good OS; patients with high C3 and CXCR4 expressions had a poor disease-free survival (DFS), while ccRCC patients with high TLR3 expression had a good DFS. Conclusion These findings suggested that C3 and CXCR4 were the candidate biomarkers and potential therapeutic targets of ccRCC patients.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of C3 and CXCR4 demonstrates their potential as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC)

et al. 2021

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“…Chemokine receptor expression has been suggested as a relevant target for diagnostic and therapeutic purpose in a variety of tumor entities and both CXCR4 and CXCR7 were detected at relevant levels in ACC patients with localized or advanced disease, potentially offering options for CXCR4-directed treatment. 94 , 95 In addition, antagonizing CXCR4 was able to block immune escape mechanisms to immunotherapy in other solid tumors. Very recently, also the role of somatostatin receptor (SSR) expression was assessed, and strong uptake suggesting eligibility for yttrium-90/lutetium-177 DOTATOC peptide receptor radionuclide therapy (PRRT) was found in a small proportion of patients (2/19).…”

Section: Systemic Treatment – Are We Making Progress?mentioning

confidence: 99%

Management of adrenocortical carcinoma: are we making progress?

et al. 2021

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Adrenocortical carcinoma (ACC) is a rare malignancy characterized by aggressive biology and potential endocrine activity. Surgery can offer cure for localized disease but more than half of patients relapse and primary unresectable or metastasized disease is frequent. Prognosis of metastatic ACC is still limited, with less than 15% of patients alive at 5 years. Recent advances in understanding the molecular profile of ACC underline the high complexity of this disease, which is characterized by limited drugable molecular targets as well as by a complex interplay between a yet scarcely understood microenvironment and potential endocrine activity. Particularly steroid-excess further complicates therapeutic concepts such as immunotherapy, which have markedly improved outcome in other disease entities. To date, mitotane remains the only approved drug for adjuvant and palliative care in ACC. Standard chemotherapy-based protocols with cisplatin, doxorubicin and etoposide offer only marginal improvement in long-term outcome and the number of clinical trials conducted is low due to the rarity of the disease. In the current review, we summarize principles of oncological management for ACC from localized to advanced disease and discuss novel therapeutic strategies, including targeted therapies such as tyrosine kinase inhibitors and antibodies, immunotherapy with a focus on checkpoint inhibitors, individualized treatment concepts based on molecular characterization by next generation sequencing methods, the role of theranostics and evolvement of adjuvant therapy.

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“…To date, there is only one CXCR4 antagonist (plerixafor ® ) approved in the treatment of hematologic malignancies. In this sense, CXCR4 and CXCR7 have been analyzed as potential targets in advances ACC, but further clinical trials are required [ 94 ]. Furthermore, ICI are safely administered in combination with other targets that may help to increase the activity of PD-1/PD-L1 monotherapy.…”

Section: Immunotherapy In Adrenocortical Carcinoma: Efficacymentioning

confidence: 99%

Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

et al. 2021

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Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

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Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma

Cited by 18 publications

References 58 publications

Bioinformatics analysis of C3 and CXCR4 demonstrates their potential as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC)

Bioinformatics analysis of C3 and CXCR4 demonstrates their potential as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC)

Management of adrenocortical carcinoma: are we making progress?

Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

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