Nanossistemas lipídicos para inibição da via RANK na terapia direcionada ao cancro da mama

Although the RANK pathway is an appealing target in breast cancer (BC), targeting the RANK ligand (RANKL) has proven to have limited efficacy in BC itself due to ligand-independent receptor activation. However, no RANKL-independent inhibitors of RANK have been developed to date. This is an innovative biotechnological project, whose primary goal is to advance the treatment of BC by developing a BC-specific nanosystem designed to downregulate RANK or inhibit the recruitment of its downstream effectors (TRAFs), blighting the pathway activity and its deleterious effects across BC subtypes. We propose a system comprising lipid nanoparticles (LNP) conjugated with folate for BC-specific delivery via the folate receptor (overexpressed in cancer cells), and functionalized with RANK inhibitors, either anti-RANK siRNA or TRAF6-binding peptides. To accelerate the translational applicability of the project results, we will conduct comprehensive in vitro and in vivo screening of the therapeutic efficacy of the nanosystem. We will use normal and cancer cells in 2D and 3D assays, including heterotypic cultures, to demonstrate BC specificity and RANK inhibition, followed by a comprehensive analysis in disease-mimetic animal models to demonstrate the therapeutic efficacy in diverse clinical scenarios. Furthermore, we will complement efficacy studies with endpoint transcriptomic analysis, which intends to identify predictive biomarkers, paving the way for more targeted and effective therapeutic strategies in the management of BC. To accomplish our main goal, we outlined a set of specific objectives, each accompanied by a carefully planned experimental TASK. Objective 1: A robust and specific nanosystem that selectively targets BC cells and delivers its load efficiently by targeting RANK (TASK1, M1). Objective 2: To validate the capacity of the nanosystem to abolish RANK pathway activity and RANK-mediated phenotypes in BC (TASK2, M2). Objective 3: To confirm the properties of the nanosystem to deliver therapy in vivo without toxicity (TASK3, M3). Objective 4: Endorse the therapeutic efficacy of the nanosystem in monotherapy or as an add-on to standard-of-care treatments in different clinical scenarios, primary and metastatic disease (TASK4, M4). Objective 5: To provide a thorough quantification of transcriptomic alterations associated with therapy response, ultimately delivering companion biomarkers for precision medicine (TASK5). In summary, the primary objective of this proposal is to develop a new effective and non-toxic therapy to eliminate the deleterious effects of RANK signaling as an add-on to standard-of-care treatments in BC. Additionally, there is potential to extend this therapy to other tumor types, including as immunomodulatory adjuvant. Altogether, this project has the potential to deliver a breakthrough therapeutic strategy to many cancer patients.