N6-Methyladenosine (m6A) RNA modification has emerged in the recent years as a new layer of regulation controlling gene expression during normal and pathological cell fate determination, including cancer development. Specifically, proteins responsible for m6A modification have been found altered in many malignancies, included clear cell Renal Cell Carcinoma (ccRCC).
Renal cell carcinoma (RCC) represents the tenth most common cancer worldwide. The most common subtype of RCC is the ccRCC. It accounts for 70-80% of all renal malignancies representing the third most common urological cancer after prostate and bladder cancer. On the basis of the emerging pathological roles of m6A modification and the potential of targeting m6A regulators for cancer therapy, our group aims at identifying novel m6A-related molecular biomarkers for ccRCC clinical management. To this end, since 2016 we enrolled 60 patients undergoing surgery and histologically classified as ccRCC. For each patient enrolled in this study we have obtained FFPE and fresh frozen tumor and normal parenchyma tissue samples, serum and urine samples (collected on the day of the surgery and after 1/3-6-12 months during the follow-up). Research plan: i) evaluation of m6A levels and m6A regulators expression in normal and neoplastic tissues; ii) evaluation of m6A modification levels in serum and urine collected at the day of surgery during the follow-up of patients diagnosed with ccRCC, to clarify if clinical outcomes may correlate with the presence of m6A levels; iii) evaluation of m6A regulators contribution to ccRCC phenotype; iii) evaluation of the functional relevance of m6A regulators in the response to conventional drug treatments.
The comprehension of the contribution of m6A modification and its molecular pathways to ccRCC phenotype may be relevant to pave the way for the identification and design of 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 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. Furthermore, 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 for the diagnosis and 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 m6A regulators contribution to 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, such as m6A modification and m6A regulators, found in tissue and also in the peripheral blood and/or urine of ccRCC patients may provide insights into the biology of the tumor and the effects of therapeutic interventions. Finally, a biomarker such as m6A may contribute to the stratification of patients according to progression risk and to a better assessment of the risk / benefit drug administration.