Ashley Di Meo

With sunitinib treatment of metastatic renal cell carcinoma, most patients end up developing resistance over time. Recent clinical trials have shown that individualizing treatment protocols could delay resistance and result in better outcomes. We developed an in vivo xenograft tumor model and compared tumor growth rate, morphological, and transcriptomic differences between alternative and traditional treatment schedules. Our results show that the alternative treatment regime could delay/postpone cancer progression. Additionally, we identified distinct morphological changes in the tumor with alternative and traditional treatments, likely due to the significantly dysregulated signaling pathways between the protocols. Further investigation of the signaling pathways underlying these morphological changes may lead potential therapeutic targets to be used in a combined treatment with sunitinib, which offers promise in postponing/reversing the resistance of sunitinib.

Clear cell renal cell carcinoma (ccRCC) is an aggressive disease with unpredictable behaviour. Clinical parameters are not always accurate for prognosis prediction. The integration of molecular markers to prognostic models can significantly improve prognostic assessment and consequently patient management. We assessed the expression of alpha-enolase (ENO1) protein by immunohistochemistry in 360 patients with primary ccRCC and correlated its expression with multiple clinicopathological parameters including stage, grade, tumor size, disease-free and overall survival. Cox proportional hazard regression models adjusted for clinicopathological factors were used to test for a link between ENO1 expression and both disease-free and overall survival. We correlated ENO1 mRNA expression with overall survival in an independent set of 428 ccRCC cases from The Cancer Genome Atlas. ENO1 showed cytoplasmic, membranous and nuclear staining patterns. There is a statistically significant negative correlation between ENO1 expression, tumor stage, and grade. ENO1 expression also shows a statistically significant direct correlation with disease-free survival (p = 0.011) and overall survival (p = 0.030) in ccRCC. Patients with higher ENO1 expression had lower hazard ratio of recurrence, although this was not statistically significant (HR = 0.330, p = 0.060). These findings were validated at the mRNA level in an independent set of 428 ccRCC cases which also showed that low ENO1 expression is associated with significantly shorter overall survival. Down-regulation of ENO1 can be a predictor of poor prognosis in ccRCC, and it can be a potential prognostic marker.