Designing precision nanomedicines to treat melanoma brain metastases in three dimensions

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.

We created 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-printed tumors 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.

Using our in vitro, ex vivo and in vivo models, we discovered novel targets which provided important tools for the design of novel libraries of cancer nano-sized theranostic and image-guided surgery smart probes that have the potential to be translated to the clinic. Our libraries of precision nanomedicines are synthesized as highly controlled micellar, nanogels, coiled or globular particulated supramolecular structures consisting of linear, hyperbranched or dendritic polymers based on polyglutamic acid (PGA), polyethyleneglycol (PEG), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA) copolymer, polyglycerol, poly(lactic-coglycolic acid) (PLGA), polyglycerols (dPG) or hybrid systems.

For the treatment of melanoma brain metastases, we used a combination of PLGA/PLA-based nanovaccines carrying MART-1 peptides with PGA-BRAFi-MEKi and immune checkpoint inhibitors αPD-1/αOX40. The synergy between the three components provides essential insights to devise alternative regimens and combination therapies to improve the efficacy of immune checkpoint modulators in solid tumors, by regulating the endogenous immune response. We expect that the acquired knowledge from this multidisciplinary research strategy will revolutionize the way we diagnose, excise and treat cancer.