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Clear cell Renal Cell Carcinoma (ccRCC) represents 80% of kidney cancers. Around 80% of ccRCC present an inactivation of the von Hippel-Lindau gene (VHL) gene, leading to the stabilization the Hypoxia Inducible Factors 1 and 2 alpha (HIF-1 and 2α) and to the overexpression of their targeted genes such as the «Vascular Endothelial Growth Factor (VEGF)», the principal angiogenic factor. Thus, ccRCC are one of the most vascularized cancers and represent a paradigm for anti-angiogenic treatments (AAT). Currently, 15 different AATs have obtained FDA and EMA approval. They are divided into three different families:- antibodies targeting VEGF- tyrosine-kinase inhibitors (TKi) that target receptors involved in neo-angiogenesis such as the current reference therapy, sunitinib- decoy receptors that trap VEGFA and PlGF such as aflibercept. Overexpression of VEGF (involved in angiogenesis) and of the other member of the VEGF family, VEGFC (involved in lymphangiogenesis) is also a key phenomenon of immune tolerance. Therefore, immune-checkpoint inhibitors (anti PD-1, anti PD-L1 and anti CTLA-4) also obtained an approval for the treatment of ccRCC. However, relapse on TKi are frequently observed after a few months and immune-checkpoint inhibitors present a long-lasting effect only in 20% of patients. Hence, ccRCC is still an uncurable disease and new therapeutic strategies targeting concomitantly angiogenesis/lymphangiogenesis and immune tolerance are urgently needed. Neuropilins (NRP1 and NRP2) are co-receptors of VEGF and VEGFC and are expressed on vascular and lymphatic endothelial cells, on tumor cells and on immune cells. Hence, they may represent ideal targets to inhibit the drivers of ccRCC aggressiveness. My thesis describes the relevance of targeting the NRP1 and NRP2 signaling pathways in ccRCC by a genetic (invalidation of the two genes by CRISPR/Cas9) and by a pharmacological approach (development of a NRPs inhibitor). The preclinical results generated represent an essential first step for the initiation of early phase clinical trials for patients with treatment failure.
Clear cell renal cell carcinomas (ccRCCs) represent 801 TP3Ts of renal cell carcinoma. Approximately 801 TP3Ts of ccRCCs exhibit inactivation/mutation of the Von Hippel-Lindau (VHL) gene, leading to the stabilization of inducible hypoxia-1 and 2 alpha (HIF1 and 2α) factors and the overexpression of their target genes, such as vascular endothelial growth factor (VEGF), the primary angiogenesis factor. Thus, ccRCCs are the most vascularized cancers and represent a paradigm for anti-angiogenic therapies (AATs). To date, 15 different AATs have received FDA and EMA approval. They are divided into three families: antibodies targeting VEGFs; tyrosine kinase inhibitors (TKi), which target receptors involved in neo-angiogenesis, such as sunitinib; and decoy receptors that trap VEGFA and PlGF, such as aflibercept. Overexpression of VEGF (involved in angiogenesis) and other members of the VEGF family, VEGFC (involved in lymphangiogenesis), is a key phenomenon in immune tolerance. Thus, immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, and anti-CTLA-4) have also received approval from health authorities for the treatment of ccRCC. However, relapse after a few months of treatment with TKIs is often observed, and immune checkpoint inhibitors are effective in only 201% of patients. Thus, ccRCC remains incurable in a majority of patients, and new therapeutic strategies targeting angiogenesis, lymphangiogenesis, and immune tolerance are needed. Neuropilins (NRP1 and NRP2) are co-receptors of VEGF and VEGFC and are expressed on vascular and lymphatic endothelial cells, tumor cells, and immune system cells. Therefore, neuropilins are relevant new targets for the treatment of ccRCC. My thesis describes the relevance of targeting the NRP1 and NRP2 signaling pathways in ccRCC using a genetic approach (inactivation of both genes by CRISPR/Cas9) and a pharmacological approach (development of an NRP inhibitor). The preclinical results generated represent an essential first step for initiating early-phase clinical trials for patients who have failed other treatments.