A key challenge for a relevant advance in ccRCC management could derive from a deeper molecular biology characterization of these neoplasms. Recently, we evidenced that miR-210-3p is deregulated in ccRCC tissues and highlighted this miRNA as a potential urine biomarker useful in ccRCC management. MiR-210 was previously described as the major hypoxamir under the regulation of HIF-1alpha and the identification of HIF-1alpha/miR-210-3p-associated pathway could greatly improve not only our knowledge on ccRCC cell growth regulation, cell invasion and metastasis but also lead to the identification of novel clinical and therapeutic targets for ccRCC management.
Aims: i) evaluation of clinical relevance of HIF-1alpha/miR-210-3p-associated pathway in ccRCC management; ii) characterization of HIF-1alpha/miR-210-3p-associated pathway contribution to ccRCC phenotype and drug sensitivity.
Research plan: to explore the contribution of the HIF-1alpha/miR-210-associated pathway in promoting ccRCC phenotype we will focus our attention to metalloproteinase (MMPs) and their tissue inhibitors (TIMPs) that recently were described in relation with this pathway. The major points of our research plan are: i) analysis of HIF-1alpha, miR-210-3p, MMP-9, MMP-2, TIMP-1 and TIMP-2 expression level in neoplastic tissues, peritumoral normal parenchyma and serum and urine of patients diagnosed with ccRCC, and evaluation of associations existing between these factors and clinical outcome; ii) evaluation of HIF-1alpha, miR-210-3p, MMP-9, MMP-2, TIMP-1 and TIMP-2 contribution to ccRCC tumorigenesis; iii) evaluation of the functional relevance of HIF-1alpha/miR-210-3p-associated pathway in the response to conventional cytotoxic drugs treatments.
The identification of HIF-1alpha/miR-210-3p-associated pathway contribution to ccRCC phenotype may be relevant to pave the way for the identification of novel biomarkers for ccRCC management and to design innovative clinical approaches in this tumor.
Nowadays most of kidney tumors are incidentally diagnosed. Among renal neoplastic diseases, ccRCC is the most common malignancy and its early diagnosis remains challenging. This is secondary to the fact that there are still not specific tools that allow identifying patients at risk for ccRCC in their clinical history. Furthermore, there is a lack of tools that can be used to accurately understand the progression of this disease. Currently, no clinically validated biomarkers are available to aid the diagnosis, disease monitoring and treatment efficacy in ccRCC. Furthemore, in the last years, various targeted therapies have been approved for ccRCC. Although these therapies have been shown to partially improve overall survival, disease progression is observed in a very high percentage of patients with advanced ccRCC. This research project aims at providing novel insights in the diagnosis, prognosis of ccRCC. In addition the project aims at evaluating whether multi-targeting anti-neoplastic approach shows efficacy in the treatment of ccRCC-derived cells.
Under a clinical point of view, the availability of efficacious adjuvant therapies and a specific knowledge of patient¿s prognosis based on histological and molecular characterization, might induce even more surgeons to apply conservative treatments and nephron sparing surgery in subjects with ccRCC. An increased rate of patients eligible for nephron sparing surgery could further increase the overall survival of patients suffering from ccRCC, and generally from kidney tumors. The combination of nephron sparing surgery and efficacious adjuvant pharmacological treatments could represent in the future the gold standard approach for patients with ccRCC. This consideration is based on the fact that also cytoreductive treatments significantly improve the survival of patients with metastatic ccRCC even in the targeted therapy era.
The advancement of knowledge in ccRCC biology, guaranteed by this project, will provide useful information for the understanding of ccRCC tumorigenesis and for the identification of innovative tools or targets to design novel therapeutic strategies. The identification of miRNAs-dependent molecular networks relevant for ccRCC phenotype will provide the biological basis for the translation of this knowledge from bench to bedside. Furthermore, identification of potential biomarkers of diagnosis and responsiveness to the ccRCC targeted therapy, found in tissue and also in the peripheral blood of ccRCC patients may provide insights into the biology of the tumor and the effects of therapeutic interventions. Finally, the identification of a relevant biomarker may contribute to the stratification of patients according to progression risk and to a better assessment of the risk / benefit drug administration.