Carlos M. Galmarini , Maurizio D’Incalci and Paola Allavena .
Trabectedin and Plitidepsin: Drugs from the Sea that Strike the Tumor Microenvironment .Abstract:
The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc.) all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.
Keywords: trabectedin; plitidepsin; tumor-associated macrophages; tumor microenvironment
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Conclusions :In the last decades the concept that the tumor microenvironment is simply a supporting structure for the preservation of tissue architecture has dramatically changed. Indeed, microenvironmental components provide signals affecting cell adhesion, migration, proliferation, differentiation, and death. Monocytic-derived cells are key players of the cancer-related inflammation present at tumor sites. Such a reactive milieu eventually supports tumor cell proliferation and the full-blown development of neo-angiogenesis. There is increasing evidence that successful anti-cancer therapies are not only dependent on the cancer phenotype but also on the normalization of the tumor stroma. In this view, the findings showing that trabectedin and plitidepsin have wider mechanisms of action acting not only on tumor cells but also modifying the whole microenvironment is of great interest and may contribute to the development of new drugs from marine origin as anticancer therapies.
The opportunity to combine direct antiproliferative activity on tumor cells with the capacity to counteract the pro-tumoral properties of the tumor microenvironment is emerging as an especially appealing therapeutic effect of some drugs of marine origin. As reviewed above, the antitumor activity of trabectedin and plitidepsin is not only related to their effects on tumor cells, but also on their ability to affect the tumor microenvironment, in particular monocytic-derived cell (TAMs and NLCs, respectively) and their pro-tumoral functions. Of note, the effects of trabectedin on tumor microenvironment are in line with response patterns evident in several patients, such as tumor shrinkage or delayed response and prolonged stabilization even in the absence of evident tumor shrinkage [80]. Trabectedin can therefore be considered a particularly important antitumor agent with mechanisms of action that make it especially appropriate for targeting key processes in the biology of cancer. Similar considerations can be taken into account for plitidepsin.
To our knowledge, there are no other reports showing this specific activity with other marine-derived drugs. Therefore, whether this is a common feature of marine natural products or a specific mechanism for trabectedin and plitidepsin remains to be elucidated.
Future Directions :Several questions need to be further addressed concerning the activity of drugs of marine origin on tumor microenvironment. We first need to understand if the activities observed for trabectedin or plitidepsin on the tumor microenvironment can be observed for other marine-derived drugs. A second question is whether these drugs are also affecting other stromal components besides the myeloid-derived compartment. We also need to understand whether the depletion of monocytic-derived cells is similar in all treated patients or if individual variability may result in different therapeutic efficacy. Another important question is whether, by affecting myeloid cells, marine-derived drugs independently influence main pathophysiological pathways of a given tumor. For example, it would be of interest to know if the anti-angiogenic activity of trabectedin is due to a direct effect on the vessel network or is mediated via the reduction of pro-angiogenic cytokines released by TAMs. While it is clear that marine-derived drugs have favorable mechanisms on tumor cells and the tumor microenvironment, additional research into the following actions would be beneficial. All these questions need to be addressed in order to improve the drug discovery and developmental process that would translate into more effective treatments with drugs of marine origin.
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