Trabectedin, a Drug Acting on Both Cancer Cells and the Tumor Microenvironment

Abstract

In the last decades the cancer cell-centric paradigm has changed to consider the tumor micro-environment (TME) as a whole. Immune cells present in the TME establish a complex relationship with cancer cells and may strongly influence disease progression. However, myeloid cells infiltrating tumor tissues promote, rather than stop, cancer progression. Tumor-Associated Macrophages (TAMs) are abundantly present at the TME and here they trigger and perpetrate a state of chronic inflammation which ultimately supports cancer proliferation and distant spreading, as well as contributes to an immune-suppressive milieu. Active research frontlines of the last years have provided novel therapeutic strategies aimed at depleting TAMs and/or modulating their pro-tumor effects. Some experimental approaches have indeed been successful in pre-clinical tumor models and have now entered early clinical trials, with encouraging results. Nevertheless, targeting only the tumor-promoting macrophages may not be sufficient to definitely eradicate cancer. The finding that the anti-tumor agent trabectedin has wider mechanisms of action than previously perceived, opened novel interesting viewpoints. Trabectedin presents the unique feature of being able to simultaneously kill cancer cells and to affect several features of the inflammatory TME, most notably inducing the rapid and selective apoptosis of monocytes and macrophages. Anti-tumor drugs acting not only on tumor cells but also able to modify the whole TME deserve particular interest in the oncology field.