Endothelial follicle stimulating hormone receptor in primary kidney cancer correlates with subsequent response to sunitinib

Abstract

Sunitinib is an anti-angiogenic receptor tyrosine kinase inhibitor used to treat advanced metastatic renal cell carcinoma and other types of cancer. Sutent is effective in only approximately 70% of clear cell renal cell carcinoma (CCRCC) patients, has significant adverse side effects and no method is available to predict which patients will not respond. Our purpose was to explore the possibility of introducing an effective prediction method based on a marker of the tumour vasculature, the follicle stimulating hormone receptor (FSHR). Fifty patients diagnosed with advanced metastatic CCRCC have been subjected to surgery for removal of the primary tumour and were subsequently treated with sunitinib. After three months of therapy the patients were categorized as ‘responsive’, ‘stable’ or ‘non-responsive’ based on the RECIST guidelines. The blood vessel density and the percentage of FSHR-positive vessels were determined by immunofluorescence on sections from the primary tumours removed by surgery, prior to the sunitinib treatment. The percentage of FSHR-stained vessels was on average fivefold higher for the patients who responded to the treatment in comparison with the stable group and almost eightfold higher than in the non-responsive group. The percentage allowed the detection of responders with 87–100% sensitivity and specificity. No significant differences were detected in the total density of vessels among the three groups. The data suggest that FSHR expression levels in the blood vessels of CCRCC primary tumours can be used to predict, with high sensitivity and specificity, the patients who will respond to sunitinib therapy.

Hormone signaling pathways as treatment targets in renal cell cancer (Review)

“…The response threshold between the two groups of patients was defined at 23% FSHR-positive vessels. Not only was a higher density of FSHR-expressing vessels observed in the primary tumors of patients who responded to sunitinib treatment, but the von willebrand factor (vwF) was detected in these vessel (FSHR + /vwF + ) (30). Plausible mechanisms that could explain this correlation have been hypothesized.…”

“…The most notable current results indicate that hypothyroidism can serve as a predictive marker of therapy outcome in patients with metastatic RCC (28). In summary, ccRCC patients without paraneoplastic syndromes and no endocrinologic disease have frequent abnormalities in steroid and peptide hormones and expression of their receptors in renal cancer tumor masses, which in consequence influence disease progression (29,30).…”

“…It was later suggested that FSHR expression in the blood vessels of ccRCC primary tumors can be used to predict if patients will respond to sunitinib treatment (56). Another possible explanation for the correlation between FSHR expression and sunitinib efficacy is that FSHR activates one or more of the other kinases known to be inhibited by sunitinib like c-Kit, PDGFR, CSF-1R, FLT3 or RET (30).…”

“…In order to do so, several classes of antagonizing compounds have been identified, most of which are negative allosteric modulators. An example is the thiazolidinone analogues, whose modifications in the chemical structure of the thiazolidinone backbone allow it to divide its generation into positive, mixed, and negative allosteric modulators of FSHR (30). Several studies have explored the use of FSHR allosteric modulators in vivo.…”

The follicle-stimulating hormone receptor: A novel target in genitourinary malignancies

“…A recent study has demonstrated that FSHR expression in the tumor endothelium of renal carcinoma correlates with response to sunitinib [28]. Fifty patients who had undergone radical nephrectomy for advanced clear-cell renal carcinoma and had subsequently been treated with sunitinib in the first-line setting were identified.…”