ANTIBODY-DRUG CONJUGATES (ADC) AGAINST CANCER STEM-LIKE CELLS (CSC) – IS THERE STILL ROOM FOR OPTIMISM?
- 1Department of Pharmacological and Biomolecular Sciences, Department of Pharmacological and Biomolecular Sciences, Faculty of Pharmacy, University of Milan, Italy
- 2University of Milan, Italy
Cancer-stem like cells (CSC) represent a subpopulation of tumor cells with peculiar functionalities that distinguish them from the bulk of tumor cells, most notably their tumor-initiating potential and drug resistance. Given these properties, it appears logical that CSCs have become an important target for many pharma companies. Antibody-drug conjugates (ADC) have emerged over the last decade as one of the most promising new tools for the selective ablation of tumor cells. Three ADCs have already received regulatory approval and many others are in different phases of clinical development. Not surprisingly, also a considerable number of anti-CSC ADCs have been described in the literature and some of these have entered clinical development. Several of these ADCs, however, have yielded disappointing results in clinical studies. This is similar to the results obtained other anti-CSC drug candidates, including native antibodies, that have been investigated in the clinic. In this article we review the anti-CSC ADCs that have been described in the literature and, in the following, we discuss reasons that may underlie the failures in clinical trials that have been observed. Possible reasons relate to the biology of CSCs themselves, including their heterogeneity, the lack of strictly CSC-specific markers, and the capacity to interconvert between CSCs and non-CSCs; second, inherent limitations of some classes of cytotoxins that have been used for the construction of ADCs; third, the inadequacy of animal models in predicting efficacy in humans. We conclude suggesting some possibilities to address these limitations.
Keywords: Cancer stem cell, Epithelial – mesenchymal – transition, Resistance, antibody - drug conjugate, resting, Proliferating
Received: 27 Dec 2018;
Accepted: 25 Feb 2019.
Edited by:Cyril Corbet, Catholic University of Louvain, Belgium
Reviewed by:Ron Firestein, Hudson Institute of Medical Research, Australia
Cynthia Guidi, ImmunoGen (United States), United States
Copyright: © 2019 Marcucci, Romeo, Caserta and Rumio. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Fabrizio Marcucci, Department of Pharmacological and Biomolecular Sciences, Faculty of Pharmacy, University of Milan, Department of Pharmacological and Biomolecular Sciences, Milan, 20133, Italy, email@example.com