Tumor endothelial ELTD1 as a predictive marker for treatment of renal cancer patients with sunitinib

Abstract

Background: Patients with metastatic renal cell cancer (mRCC) are commonly treated with the tyrosine kinase inhibitor sunitinib, which blocks signalling from vascular endothelial growth factor (VEGF) -and platelet-derived growth factor-receptors, inhibiting development of new blood vessels. There are currently no predictive markers available to select patients who will gain from this treatment. Epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) is up-regulated in tumor endothelial cells in many types of cancer and may be a putative predictive biomarker due to its association with ongoing angiogenesis. Methods: ELTD1, CD34 and VEGF receptor 2 (VEGFR2) expressions were analysed in tumor vessels of renal cancer tissues from 139 patients with mRCC using immunohistochemistry. Ninety-nine patients were treated with sunitinib as the first or second-line therapy. Early toxicity, leading to the termination of the treatment, eliminated 22 patients from the analyses. The remaining (n = 77) patients were included in the current study. In an additional analysis, 53 sorafenib treated patients were evaluated. Results: Patients with high ELTD1 expression in the tumor vasculature experienced a significantly better progression free survival (PFS) with sunitinib treatment as compared to patients with low ELTD1 expression (8 versus 5.5 months, respectively). The expression level of CD34 and VEGFR2 showed no correlation to sunitinib response. In sorafenib treated patients, no association with ELTD1 expression and PFS/OS was found. Conclusions:Our results identify tumor vessel ELTD1 expression as a positive predictive marker for sunitinibtreatment in patients suffering from mRCC. The negative results in the sorafenib treated group supports ELTD1 being a pure predictive and not a prognostic marker for sunitinib therapy.

ELTD1—An Emerging Silent Actor in Cancer Drama Play

“…The GPCR superfamily of ELTD1 influences different processes, like: smell, taste, vision, chemotaxis, hormone secretion, and inflammation [ 36 , 37 ]. The orphan ELTD1 receptor was reported to be involved in angiogenesis [ 18 , 22 , 24 , 38 ] and cardiac hypertrophyin rat [ 21 ], sensitivity of anesthetics [ 39 ], subcutaneous fat thickness in pig [ 40 ], and tick burden in cattle [ 41 ].…”

“…One of the most recent research conducted by Niivirta et al provided data regarding ELTD1, as a predictive marker for the treatment of renal cancer patients. Their results identified ELTD1 expression in tumor vessels as a positive predictive marker for sunitinib–treatment in metastatic renal cell cancer patients [ 22 ].…”

“…In 2020, Niinivirta et al linked the ELTD1 expression level to the progression free survival (PFS) after sunitinib treatment. The expression of ELTD1 in tumor vessels was a positive predictive marker for the sunitinib treatment in patients with renal cancer [ 22 ]. A significantly higher PFS after sunitinib treatment was observed in patients with high ELTD1 expression compared to low ELTD1 expression (8 months vs. 5.5 months).…”

“…On the contrary, the expression level of VEGFR2 had no correlation with sunitinib response. Moreover, this study showed that for sunitinib therapy, ELTD1 may be considered a predictive and not a prognostic marker [ 22 ].…”

“…Furthermore, its expression in normal vasculature was found to be regulated by two angiogenic pathways: increased by vascular endothelial growth factor (VEGF) pathway and repressed by Delta–like ligand 4 (DLL4) from NOTCH intercellular signaling pathway [ 18 , 19 , 20 ]. Since its discovery, ELTD1 was associated with cardiac and renal function, glioblastoma, and colorectal cancer [ 18 , 21 , 22 , 23 , 24 , 25 ].…”