New insights into the discovery of drugs for triple-negative breast cancer metastasis

ABSTRACT

Introduction

Triple-negative breast cancer (TNBC) is of great concern due to its aggressiveness and lack of targeted therapy. For these reasons, TNBC is one of the main causes of death in women, mainly due to metastases. Tumor dissemination has highlighted a set of possible targets, with extensive research into new single-target drugs, in addition to drug repurposing strategies, being undertaken to discover new classes of potential inhibitors of metastasis.

Areas covered

The authors here describe the main proposed targets and the bases of their pharmacological inhibition with different chemical compounds. The authors also discuss the state-of-the-art from the latest clinical trials and highlight other potential targets for metastatic TNBC.

Expert opinion

In the last decade, oncology research has changed its focus from primary tumors to moving tumor cells, their products, and to the secondary tumor and its surroundings, for the purpose of finding targets to treat metastasis. Consequently, our comprehension of the complexity of the metastatic process has increased drastically, with, furthermore, the discovery of new potential targets. Although promising, the wide range of strategies is still not effective to suppress TNBC metastasis in terms of increasing patient survival or decreasing the number of metastases. Treating or preventing metastasis continues to be a great challenge.

KEYWORDS:

• Breast cancer
• liquid biopsy
• metastasis
• molecular targets
• triple-negative breast cancer

Abbreviations

ANXA2, annexin A2, ANXA6, annexin-A6; APC, antigen-presenting cell;

BC, breast cancer;CA IX, carbonic anhydrase IX; CAF, cancer-associated fibroblast;

cfmiRNA, cell-free microRNA; CK, creatine kinase; CNA, circulating nucleic acids; CSC; cancer stem cell; CTC, circulating tumor cells; ctDNA, circulating tumor DNA; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; DNA, desoxyribonucleic acid; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; EpCAM, epithelial cellular adhesion molecule; EV, extracellular vesicles; FAP, fibroblast activating protein; FDA, US Food and Drug Administration; HER2, human epidermal growth factor receptor 2; HIF, hypoxia-inducible factor; LAR, luminal androgen receptor; LPS, lipopolysaccharide; MAF, metastasis-associated fibroblast; MDSC, myeloid-derived stem cells; miRNA, microRNA; MMP, matrix metalloproteinases; mRNA, messager RNA; NBC, bicarbonate cotransport; NCCN, National Comprehensive Cancer Network; ncRNA, noncoding RNA; NHE, Na+/H+ exchanger; OS, overall survival; PARP, poly (ADP-ribose) polymerase; pCR, pathological complete response; PCR, polymerase chain reaction; PD-1, programmed cell death-1; PD-L1, programmed death ligand-1; PFS, progression-free survival; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PISD, phosphatidylserine decarboxylase; pRb, retinoblastoma protein; RNA, ribonucleic acid; SEV, small extracellular vesicle; siRNA, silencing interfering RNA; SIRPα, signal regulatory protein alpha; SPANXB1, sperm protein associated with the nucleus on the X chromosome B1; TAM, tumor-associated macrophage; TGF-β, tumor growth factor beta; TIME, tumor immune microenvironment; TME, tumor microenvironment; TNBC, triple-negative breast cancer; Trop-2, trophoblast cell-surface antigen 2; V-ATPase, V-type H+-ATPase; VEGF, vascular endothelial growth factor; ZFPM1 or FOG1, zinc finger protein member 1.

Article Highlights box

• Current TNBC treatment focuses on conventional cancer chemotherapy, as no targeted therapies have been identified so far

• Migrating cells, circulating tumor cells, extracellular vesicles, and nucleic acids shed light on the development of new drugs for TNBC metastasis

• Primary and secondary tumor microenvironments and immune escape by cancer cells are crucial in the search of targets for TNBC metastasis

• Targeted therapy for TNBC is promising for personalized treatment

• Despite their potential, the wide range of strategies has, thus far, still been ineffective in suppressing TNBC metastasis in terms of increasing patient survival and/or decreasing the number of metastases.

Acknowledgments

The authors acknowledge BioRender (biorender.com) as the platform for designing original Figures 1–4.

Reviewer disclosure

Peer reviewers of this manuscript have no relevant financial or other relationships to disclose.

Conflict of Interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Supplementry material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 429235/2018-6 and 306225/2017-4), the São Paulo Research Foundation (FAPESP, 2013/00798–2; 2014/18747-8; 2019/11437-7; 2021/01983-4), and the Ministério da Saúde (879848/2018), Brazil. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.