We summarise a recent review, published in J. Pers. Med., that explored relevant research aimed at repurposing pre-existing drugs to treat triple-negative breast cancer.
Triple-negative breast cancer
Breast cancer is the second most common cancer and the second leading cause of cancer deaths among women in the US. It is a very heterogenous disease that is classified using immunohistochemical techniques. These techniques measure the presence of three receptors: oestrogen receptor (ER), progesterone receptor (PR) and overexpression of the human epidermal growth factor receptor 2 (HER2). In triple-negative breast cancer (TBNC), there is a lack of expression of all of these receptors and therefore, no approved targeted therapies available. This type is associated with poor prognosis and high risk of relapse compared to other breast cancer subtypes. Therefore, applying personalised medicine is necessary. However, the process of creating and testing new drugs for TNBC is costly and time-consuming, with high failure rates. Consequently, drug repurposing has become an increasingly successful and popular approach for developing new therapies.
Current treatments for triple-negative breast cancer
Chemotherapy is the only treatment currently approved by the FDA for non-metastatic TNBC. This includes microtubule inhibitors, anthracyclines, alkylating agents, antimetabolites and platinum. Despite the initial chemosensitivity of these tumours, patients frequently develop chemoresistance later on. This is related to the high presence of cancer stem cells (CSCs). Other therapeutic options are available when patients do not respond to traditional treatments. For example, PARP inhibitors – olaparib and talazoparib.
Immune escape is a key hallmark of cancer, where tumour cells are able to decrease immune recognition and progress. Immunotherapy has become a fundamental element of cancer therapy. In TNBC, combinations of checkpoint inhibitors and targeted therapies and/or chemotherapy have been shown to be more effective than monotherapy. Unfortunately, only a small percentage of patients respond to them.
Antibody-drug conjugates (ADCs) have lots of potential to improve cancer treatment. These conjugates allow toxic drugs to be directly targeted to cancer cells by using specific receptors. Sacituzumab govitecan is the newest therapeutic option available for TNBC, yet is only given after the failure of at least two other treatments.
Drug repurposing for TNBC
The discovery and development of new drugs is time-consuming and requires great investment. Most importantly, it comprises high failure rates in clinical trials. Drug repurposing is a strategy for identifying new uses for existing drugs. This strategy significantly shortens the time and costs of drug development. Several approaches for drug repurposing exist, from non-computational approaches (including high-throughput screening and methods based on experimental findings) to computational strategies.
There is an urgent need to find effective molecularly targeted treatments for TNBC. As a result, the research community has undergone efforts to characterise and divide TNBC into different subtypes with more approachable profiles. Below, we have summarised the main repurposed therapies currently being investigated for TNBC treatment based on their molecular targets.
Luminal androgen receptor (LAR) subtype is highly enriched in hormonally regulated pathways. It has been proposed that AR overexpression may replace ER signalling, resulting in similar functional effects. AR plays a central role in regulating gene expression. In TNBC, it has been suggested that AR activation alters the tumour microenvironment, suppresses antitumour response and stimulates tumour growth and progression. Different AR-targeted agents, first intended for the treatment of metastatic castration-resistant prostate cancer, are now being repurposed and tested in clinical trials on TNBC. These include: bicalutamide, enzalutamide, abiraterone acetate, orteronel and seviteronel. Additionally, selective AR modulators, first intended to be used as alternatives to testosterone therapies, are also being tested in clinical trails for both prostate cancer and TNBC.
Adrenergic receptors belong to the GPCR superfamily. They can be classified as α or β receptors. These receptors are activated in several stress response signalling pathways that are key in maintaining physiological homeostasis. However, increasing evidence is showing that altered adrenergic receptor stimulation may play a significant role in breast cancer progression, proliferation, metastasis, tumour invasion and angiogenesis. Several preclinical studies have explored the effect of both α and β receptor antagonists in TNBC. Moreover, several retrospective epidemiological studies have investigated whether TNBC cancer patients under treatment with beta-blockers for hypertension have a better outcome than non-treated patients.
STAT3 is a tumour marker for early diagnosis. The activation of its pathway is related to breast cancer aggressiveness and involves several cytokines and growth factors. Upregulation of IL-6/STAT3/ROS can lead to the transcription of genes involved in breast cancer progression. Furthermore, the activation of JAK2/STAT3 promotes proliferation and motility of breast cancer cells. Due to its complexity and wide regulation of breast cancer cells, STAT3 is an interesting target candidate to treat in TNBC. Several compounds that inhibit different mechanisms are currently being investigated. These include: bazedoxifene, flubendazole, niclosamide, osthole and zoledronic acid.
Nitric Oxide Synthase
Nitric oxide (NO) is a small molecule involved in several functions within organisms. It can be synthesised by three isoforms of nitric oxide synthase (NOS) – neuronal, inducible and endothelial. NO interacts with different targets that can induce DNA damage. Studies have shown that increased expression of iNOS in ER- breast cancer is correlated with poor survival. Other findings have reported that iNOS inhibitors, such as pan-NOS inhibitor L-NMMA, can dimmish cancer cell proliferation and migration and also CSC self-renewal in vitro.
Anexelekto (AXL) is one of the TAM family of receptor tyrosine kinases. Its activation results in several downstream cascades and targets that can stimulate tumourigenic processes. In TNBC patients, higher expression of AXL is a predictor of poor prognosis and higher chemoresistance. Several drugs are being considered as possible therapies, including phenoitazines.
Targeting Cancer Stem Cells (CSCs)
CSCs can sustain tumour growth, progression and recurrence. The CSC model explains intra-tumour heterogeneity and dormant behaviour of several cancer types. Researchers have found that CSCs are more abundant in TNBC than any other breast cancer subtype. Therefore, efforts are being focussed on developing CSC-targeted therapies. Researchers are currently exploring EMT inhibitors and Wnt inhibitors as potential CSC-targeted therapies.
The absence of targeted therapies for TNBC reduces the chance of patient recovery and life expectancy. Therefore, finding effective molecularly targeted treatments has become imperative. As a result, researchers are currently exploring several pre-existing drugs for repurposing on the basis of molecular mechanisms and signalling pathways. Furthermore, because of their ability to drive tumour aggressiveness and clinical outcomes, a lot of focus has been on CSCs and identifying molecules for repurposing that specifically target this cell population.
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