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Uncovering the molecular and cellular mechanism of tumor dormancy for the rational design of theranostic nanomedicines

Final Report Summary - POLYDORM (Uncovering the molecular and cellular mechanism of tumor dormancy for the rational design of theranostic nanomedicines)

Tumor progression is dependent on a number of sequential steps, including initial tumor-vascular interactions and recruitment of blood vessels, as well as established interactions of tumor cells with their surrounding microenvironment and its different immune, endothelial and connective cellular and extra-cellular components. Failure of a microscopic tumor, either primary, recurrent or metastatic, to complete one or more of these early stages may lead to delayed clinical manifestation of the cancer. Micrometastasis, dormant tumors, and minimal residual disease, contribute to the occurrence of relapse, and constitute fundamental clinical manifestations of tumor dormancy that are responsible for the majority of cancer deaths. However, although the tumor dormancy phenomenon has critical implications for early detection and treatment of cancer, it is one of the most neglected areas in cancer research and its biological mechanisms are mostly unknown.
To that end, we created several models of patient-derived cancer models mimicking pairs of dormant versus fast-growing, primary versus metastatic and drug-sensitive versus drug-resistant cancers using cutting-edge techniques of patient-derived xenografts, 3D printing and genetically-modified mouse models. We investigated the molecular changes in tumor-host interactions that govern the escape from dormancy and contribute to tumor progression. Those led to the discovery of novel targets and provided important tools for the design of novel cancer nano-sized theranostics (therapeutics and diagnostics). The libraries of precision nanomedicines designed and synthesized in our lab in the scope of the PolyDorm project were used to successfully deliver various therapeutic agents to multiple cancer types including osteosarcoma, glioblastoma and pancreatic cancer. These novel nanomedicines specifically accumulated at the tumor site, inhibited tumor growth and prolonged survival, without inducing adverse effects.
We hypothesize that the acquired knowledge from this multidisciplinary research strategy will revolutionize the way we diagnose and treat cancer.