Engineered lisyl oxidase lipid-based nanovesicles for the treatment of solid tumors: on the path to clinical application TRUST

Worldwide epidemiology registry estimates that 30% of breast cancer patients and 40% of sarcoma patients will develop metastases affecting their quality of life and representing the leading cause of death for these diseases. In this regard, the 5years survival rate is 33% for metastatic breast cancer and 15% for advanced sarcoma patients. For hormone receptornegative breast cancers, which represent the breast cancer lesions with the most aggressive clinical behavior, the standard treatment includes surgery, radiation therapy and chemotherapy. For metastatic disease standard first-line agents, represented by anthracyclines or taxanes chemotherapy, are not always effective in containing metastases spreading and suffer from systemic toxicity. Considering sarcoma the current standard of care for localized disease is represented by radical surgery with the primary goal of clear margins combined with (neo)adjuvant treatments in selected cases. Although clear margins remain the primary goal of surgical resection, the specific anatomy site for some lesions make it difficult to achieve, thus adjuvant radiotherapy may be an option. In the metastatic setting the gold standard is chemotherapy but the outcomes are still very limited. In particular anthracycline-based regimen represents the first line standard for the majority of advanced and metastatic sarcoma histotypes with only a 16-27% response rate when used as single agents. Thus there is a pressing clinical need to develop new therapeutic strategies to improve patient outcomes and reduce systemic toxicity related to chemotherapy. In this scenario, nanotechnology enables the delivery of anticancer drugs improving therapeutic efficacy and reducing drug toxicity. Targeting the tumor microenvironment has only recently been explored as an option to selectively concentrate chemotherapeutics to the tumor site. Increasing evidence has demonstrated that extracellular matrix (ECM) represents a primary component of the tumor microenvironment and its remodeling promotes a number of tumor processes. Within this context, the ECM-associated enzymes, lysyl oxidase (LOX) family, represent promising candidates for selective drug delivery to tumors. These ECM-remodeling proteins are overexpressed in both primary and metastatic lesions of various tumors including breast cancer and sarcomas. Within this context we developed and patented a lipid-based vesicle functionalized with a LOX antibody (LIPO-LOX) loaded with standard anthracycline chemotherapy (PCT 144891 international application no. PCT/EP2020/077465) [De Vita, Sci Rep 2021. doi: 10.1038/s41598-021-84492-3]. We previously demonstrated the efficacy of LOX-engineered lipid vesicles loaded with anthracycline for the treatment of TNBC. We proved that a lipid-based nanocarrier targeting LOX and loaded with chemotherapy is feasible and it could successfully provide significant therapeutic advantages (i.e. increased tumor growth inhibition and reduced toxicity both in vitro and in vivo). Starting from these, TRUST proposes a totally groundbreaking approach for the improvement of TNBC and sarcoma treatment through the implementation of LIPO-LOX drug delivery system. This project will develop a win-win strategy based on a totally cutting edge approach for the treatment of solid tumors. The expected results will pave the way to design personalized therapeutic strategies and to plan tailored clinical trials for this innovative therapeutic treatment.