Abstract
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 with 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.
Highlights
Specialty section: This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology
In this article we review the anti-Cancer stem-like cells (CSC) Antibody-drug conjugates (ADC) 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
Summary
Anti-delta-like Ligand (DLL) 3 ADC This target is of particular interest in these days, because the development of an ADC against DLL3, rovalpituzumab tesirine, which had reached phase III clinical studies, has failed to show benefit in third-line small-cell lung cancer (SCLC) [30]. Rovalpituzumab tesirine had been constructed for the targeting of CSCs of high-grade pulmonary endocrine tumors [31] These tumors include SCLC and large cell neuroendocrine carcinoma, highly malignant neoplasms with few and inefficacious therapeutic options [32]. Despite the expression of PTK7 in certain normal tissues, no target-dependent toxicities were observed in monkeys, possibly because microtubule inhibitors require high antigen expression and actively cycling cells to exert a cytotoxic effect [50]. Protein analysis of normal organs, primary breast tumor specimens and TNBC PDX tumor models demonstrated that EFNA4 was elevated in TNBC vs normal tissues and other subtypes of breast cancer [36] This expression pattern suggested the possibility of targeting EFNA4 with an ADC.
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