Abstract
Simple SummaryDespite advances in cancer treatment, difficult-to-treat tumor subtypes remain a challenge. New multidisciplinary approaches can help overcome current obstacles posed by tumor heterogeneity, activation and enrichment of cancer stem cells, and acquired drug resistance development. Epigenome modulation, currently unsuccessful in solid tumors due to epigenetic drug instability, toxicity, and off-target effects, might be enabled by implementing nano-based delivery strategies aiming to improve breast cancer patient outcomes.Epigenetic dysregulation has been recognized as a critical factor contributing to the development of resistance against standard chemotherapy and to breast cancer progression via epithelial-to-mesenchymal transition. Although the efficacy of the first-generation epigenetic drugs (epi-drugs) in solid tumor management has been disappointing, there is an increasing body of evidence showing that epigenome modulation, in synergy with other therapeutic approaches, could play an important role in cancer treatment, reversing acquired therapy resistance. However, the epigenetic therapy of solid malignancies is not straightforward. The emergence of nanotechnologies applied to medicine has brought new opportunities to advance the targeted delivery of epi-drugs while improving their stability and solubility, and minimizing off-target effects. Furthermore, the omics technologies, as powerful molecular epidemiology screening tools, enable new diagnostic and prognostic epigenetic biomarker identification, allowing for patient stratification and tailored management. In combination with new-generation epi-drugs, nanomedicine can help to overcome low therapeutic efficacy in treatment-resistant tumors. This review provides an overview of ongoing clinical trials focusing on combination therapies employing epi-drugs for breast cancer treatment and summarizes the latest nano-based targeted delivery approaches for epi-drugs. Moreover, it highlights the current limitations and obstacles associated with applying these experimental strategies in the clinics.
Highlights
The most common cancer diagnosed among women is breast cancer (BC), the second leading cause of cancer deaths [1]
January are for metastatic orchallenges locally advanced epithelioid sarcoma, there is no of epigenetic profiles, currently the main hampering the wider clinical application epigenetictherapy agents approved for solid tumors, which are considered more epigenetically complex
The DAC-chemotherapy combination has been widely studied in BC preclinical studies, and the results suggest enhanced sensitivity compared to cytotoxic therapy alone [144,145,146]
Summary
The most common cancer diagnosed among women is breast cancer (BC), the second leading cause of cancer deaths [1]. EMT is triggered by extracellular signals, including extracellular matrix proteins and soluble growth factors, or by intracellular cues It is mediated by a group of pleiotropic transcription factors (TFs), which control a heterogeneous network of epigenetic effectors, allowing potent gene expression changes [4]. Promising preclinical results suggest that epigenetic drugs (epi-drugs) can sensitize resistant cancer cells to traditional approaches These results have not yet been confirmed by clinical studies, as the early-generation epi-drugs were basically broad-spectrum reprogrammers, causing large-scale gene expression changes. This “one size fits all” approach has mostly failed due to off-target effects, significant toxicities, the risk of large-scale epigenomic repatterning, and the lack of appropriate biomarkers for patient selection. We highlight the promise of nanomedicine with regard to overcoming obstacles associated with the successful use of epi-drugs for the treatment of solid tumors
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