Treating skin toxicities caused by biological cancer drugs (or cetuximab) applying topical specific inhibitors to the anti-cancer drugs
Cancer patients often receive molecularly targeted agents that cause severe dermatologic complications that limit the agent dosage and patient compliance. For example, epidermal growth factor receptor inhibitors [EGFRi such as Cetuximab/Erbitux] and small molecule tyrosine kinase inhibitors are associated with such complications that include severe rash, abnormally dry skin and skin infections. Severe rash is the most common cutaneous reaction pattern and is noted in 90% of patients receiving EGFR-targeted monoclonal antibodies (estimated at nearly 20,000 annually in the US, ~15,000 in Europe for Cetuximab and Panitumumab). Current treatment for skin toxicities caused by EGFR inhibitors is based on systemic antibiotics, topical steroids, moisturizers and sunscreens, treatments of limited benefit. Therefore, proactive strategies for the management of anti-cancer induced skin rash may help to maximize benefit for patients by minimizing the negative effects on quality of life and maintaining an optimal dose. Furthermore, the treatments recommended today are based on broad use of systemic antibiotics despite the fact that the pathogenesis of the rash is rarely caused by bacteria.
Small molecules that can be topically applied and penetrate the deep layers of the epidermis and reach the target cells.
- We screened over 3,500 small molecules and identified three potent lead molecules that were effective in reversing EGFRi-induced skin toxicities.
- The lead small molecules could reverse EGFRi-induced keratinocyte cell death as seen with viability assays.
- Biodegradable nanoparticles that penetrate the deep layers of the epidermis as demonstrated in several independent experiments in full human skin.
- Franz chamber assay demonstrated that the lead compounds do not penetrate through human skin.
A novel approach for treating skin toxicities caused by EGFRi using new compounds and a unique delivery system targeting the deep layers of the skin. The molecules can enable the use of needed dosage and improve the patients' quality of life.