KEY TAKEAWAYS
- The PROTECT interventional phase 3 study aimed to uncover tumor microenvironment purinergic regulators for targeted therapy and biomarkers.
- The result demonstrated that Cx26 overexpression in ccRCC is associated with poor outcomes, suggesting its potential as a biomarker or therapeutic target.
Exploring and addressing additional mechanisms of immunosuppression in clear cell renal cell carcinoma (ccRCC) is imperative. Adenosine, recognized as a mediator of immunosuppression in the tumor microenvironment (TME), has shown promising outcomes with an adenosine 2A receptor antagonist in preclinical models and an early-phase 1 clinical trial for advanced ccRCC.
In the phase 3 study, Elizabeth Ellis and her research group aimed to unveil additional modulators of purinergic signaling in the TME for their potential as therapeutic targets or clinically relevant biomarkers.
Researchers utilized whole-gene microarray data from 236 ccRCC tumors in the placebo arm of the PROTECT trial (NCT01235962), and a differential expression of the gene (DEG) analysis was conducted on 90 genes related to extracellular purines and purinergic signaling. The R package “limma” (version 3.32.10) facilitated DEG analysis, incorporating adjusted p values (q values) for multiple comparisons correction.
The study ensued validation through RNA sequencing data from the TCGA-KIRC cohort. By annotating gene expression data into quartiles, Kaplan-Meier analyses assessed disease-free survival (DFS) and overall survival (OS) associations via log-rank testing. Single-cell RNA sequencing of ccRCC tumors (n = 6) from MSKCC was performed to discern cell populations expressing Connexin-26 (Cx26).
The results demonstrated that RNA upregulation of gap junction beta-2 (GJB2) in purinergic gene profiles displayed the most significant association with metastatic recurrence (q = 6.5e-10). GJB2 encodes Connexin-26 (Cx26), a transmembrane protein fostering gap junctions and hemichannels for ATP and calcium ion release from cells. TCGA-KIRC validation established an indirect correlation between GJB2, DFS (P= 3.5e-3), and OS (P = 8e-4). Single-cell RNA-sequencing highlighted expression primarily confined to tumor and proximal renal epithelial cells.
Elevated Cx26 expression was linked to adverse outcomes in ccRCC across two patient cohorts, prominently present in ccRCC tumor cells. The heightened expression of Cx26 hemichannels within these cells may contribute to increased intratumoral adenosine levels, potentially fostering immunosuppression. A thorough investigation is essential to unravel the mechanistic association between Cx26-mediated ATP release and ccRCC progression and to assess the potential of Cx26 as a valuable biomarker or therapeutic target in patients with ccRCC. This study is sponsored by Novartis Pharmaceuticals.
Source: https://suo-abstracts.secure-platform.com/a/gallery/rounds/18/details/3001
Clinical Trial: https://clinicaltrials.gov/study/NCT01235962
Ellis E, Kuo F, Hakimi AA, et al. “CONNEXIN-26 EXPRESSION IS ASSOCIATED WITH DISEASE OUTCOMES IN CLEAR CELL RENAL CELL CARCINOMA AND MAY BE A SOURCE OF INTRATUMORAL ADENOSINE.” Presented at SUO 2023. (Poster: 4)
