Project Funding Details

Prostate cancer (PC) metastasis, which primarily affect bones, lungs, and lymph nodes, is a leading cause of cancer-related deaths in men worldwide. CRISPR/Cas9-mediated deletion of the IL30 gene in xeno- and syn-geneic PC models breaks a cascade of signals, which foster cancer proliferation, migration, and immune evasion, resulting in tumor suppression and prolonged survival. Although promising, the anti-tumor effects demonstrated by IL30-targeting immunoliposomes must be strengthened and be exploitable in the clinic. Co-targeting with PC progression-driver genes could improve the anti-tumor efficacy of tumor-selective IL30 deletion, while the development of a patient tumor tailored nanoplatform can make it suitable for clinical setting. - Development and production of next-generation Ab-functionalized SLNs, freeze-dryable and suitable for i.v. administration, to co-target IL30 and PC drivers, which can be knocked in, such as PTEN tumor-suppressor gene, or knocked out, such as NMYC and/or AURKA oncogenes. - Determination of the efficacy of the new SLNs in co-targeting IL30 and selected PC drivers, in human- and murine-derived PC progression models, and their ability to inhibit PC cell colonization and expansion to bone, lungs, and lymph nodes. - PC patient stratification based on IL30 expression and/or PTEN mutations, or NMYC/AURKA gene amplification and overexpression, and additional immuno-molecular characteristics of their PC samples. - Development and testing of patient tailored treatments by using multi-organs (PC-BoneMarrow-Lymph-Node) on-Chips, and 3D-bioprinting to determine the most appropriate schedule to counteract tumor progression in that specific patient. Novelty: The development of a personalized cytokine-PC drivers multi-targeting strategy is absent in the current therapeutic landscape and would meet the needs of patients at risk of, or diagnosed with, advanced disease. - Production and characterization of next-generation SLNs, which can be i.v. administered and stored in freeze-dried form, aimed at co-targeting IL30 and selected PC driver genes, such as PTEN, NMYC and/or AURKA for knockin or knockout, through the CRISPR/Cas9 genome editing approach. - Testing of the newly designed SLNs in a) 3D-bioprinted human cell-based organs (PC-Lung-Bone) on-Chips, that mimic the fundamental dynamics of PC progression, and b) orthotopic PC xenograft models. - Testing of the most effective formulation of SLNs in immunocompetent a) orthotopic models of syngeneic PC progression, and in b) Ptennullmouse model of PC, which mimics the human disease. - Selection and stratification of PC patients, based on IL30 expression and PTEN mutations, or MYCN/AURKA amplification, in their tumors and testing of SLN formulations in a) 3D-bioprinted patient-derived PC structures, and b) multi-Organs-on-Chips containing PC-structures connected to autologous BM and lymph-node samples. Provide the proof of concept that efficacy of tumor specific suppression of IL30, can be improved by co-targeting genes driving PC metastasis and resistance to therapy. The final goal will be to develop, and candidate for clinical trials, a "patient tailored" method of treatment and/or prevention of PC metastasis. Metastatic disease is currently incurable and represents a global public health challenge. Our research plan aims to develop a safe and tumor-selective immunogenomics driven multi-targeting strategy based on CRISPR-mediated gene editing and stable SLN formulations suitable for clinical trials.