Targeting tumor microevironment by a translational multivalent nanomedicine: towards an effective anticancer combination immunotherapy.
The aim of the PhD thesis is to develop an integrative and multivalent Nanotechnology-based therapeutic strategy to manipulate the multiple pro-tumorigenic mechanisms within colorectal tumor microenvironment.
The heterogeneity of cancer cells has impaired the successful outcome of several therapeutic approaches, including surgery, chemotherapy and radiotherapy, especially in the advanced stage of the disease. The 5-years survival rate for patients presenting metastatic disease is still very low, being 13% for patients with advanced colorectal (CRC) cancer. This is an important unmet medical need and effective alternative approaches are thus essential. Immunotherapeutic approaches have shown very positive outcomes in other disseminated malignant diseases and might therefore be promising strategies against CRC cancer. However, an effective strategy against the heterogeneous population of cancer cells requires a combinatory approach to modulate different cells and signalling pathways to overcome the multiple factors (e.g. cytokines, chemokines and growth factors) and mechanisms involved in tumor growth and dissemination. Nanotumim will tackle this goal by developing an integrative and multivalent Nanotechnology-based therapeutic strategy to manipulate the multiple pro-tumorigenic mechanisms within tumor microenvironment (TME). We will follow a modular and stepwise approach to develop a chemically-defined nanoplatform able to conjugate engineered targeting moieties at specific sites of their molecular structure to in vivo target and modulate distinct cell populations within stromal TME: i) myofibroblasts, to specifically deliver a cytotoxic drug leading to a fragile stromal TME; ii) CRC cells to downregulate their proliferation; iii) dendritic cells to potentiate tumor associated antigen presentation and regulate immunosuppressive processes and tumor-growth related pathways, to overall revert tumor-immune network to a pro-inflammatory Type I environment.
This highly innovative and technologically advanced chemically-defined nanoplatform will allow us to have a safe multivalent nanomedicine able to combine the effect of a cytotoxic drug at cancer site with a balanced and multi-targeted immunotherapy, which overall outcome can constitute a real hope for patients with metastatic cancer disease. By controlling the formulation process of this translational multivalent nanosystem at intracellular, modelling and computational levels, we will also establish new practices to support faster and cost-effective transfer of advanced nanotechnologies to target industries.