Histone Deacetylase Inhibitors as a Potential Future Therapy for Breast Cancer Brain Metastasis

Introduction to Breast Cancer

Breast cancer (BC) stands as the most diagnosed malignancy among women, significantly impacting global health.1, 2 In 2018, it was estimated that approximately 2.1 million women were diagnosed with BC, leading to over 600,000 deaths. Alarmingly, the global incidence of this disease has been rising at an annual rate of 3.1%.2

BC’s complexity is further unravelled when categorised into five distinct subtypes. These classifications are based on the presence or absence of certain biomarkers: the oestrogen receptor, progesterone receptor, HER2, and Ki67. These subtypes include luminal A, luminal B, luminal B-like, HER2-positive, and triple-negative BC.3 The incidence and mortality rates vary significantly across these subtypes, with HER2-positive cases associated with the highest risk of death. This elevated risk is largely due to the increased likelihood of developing brain metastases.1, 3

Figure 1. Schematic representation of the metastatic cascade from the primary BC to brain metastasis. BBB – Blood Brain Barrier detected early – before the cancer has spread beyond the breast – the disease is considered potentially curable. However, once the cancer has metastasized, the prognosis falls considerably. Metastatic BC, often referred to as advanced BC, is deemed incurable. It is worth noting that it is not the primary tumour but rather the metastases that are the leading cause of mortality among BC patients.1-3 This stark reality underscores the critical importance of early detection and tailored treatment strategies to combat this pervasive disease.

Breast Cancer Brain Metastasis

BC’s propensity to metastasize to the brain is notably high in HER2-positive and triple-negative subtypes, progressing through a well-defined cascade.1, 4 Initially, the process begins with the epithelial-mesenchymal transition (EMT), where epithelial cells morph into motile mesenchymal stem cells, facilitated by specific gene overexpression and downregulation that affect cell attachment and proliferation. However, not all cells undergo EMT – only a select few advance to metastasis. Following EMT, tumour cells intravasate into the bloodstream by navigating through the tumour microenvironment and crossing the endothelial barrier. The third phase involves preparing the brain environment for tumour spread by priming the metastatic niche and breaching the blood-brain barrier (BBB). The culmination of this journey is the tumour cells’ extravasation into the brain, where they exploit the brain’s defences and proliferate (Summarised in Figure 1).3 Addressing BC involves a multidisciplinary approach, including conventional therapies like surgery, radiation, and chemotherapy, alongside emerging treatments targeting specific mechanisms like histone deacetylases (HDACs).

Histone Deacetylases

Recent research has illuminated that tumorigenesis is influenced not just by genetic mutations but significantly by epigenetic programming within cells. This revelation has elevated the study of the epigenetic landscape as a burgeoning field of research. At the core of epigenetic regulation lies histone acetylation, controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes play a pivotal role in gene expression: HATs enhance gene transcription by unwinding DNA, facilitating access for transcriptional machinery, whereas HDACs condense DNA, suppressing gene expression (summarised in Figure 2). Their critical involvement in gene regulation and the association of their dysregulation with various cancers, including BC, spotlight these enzymes as potential therapeutic targets. Intervening with their function offers a way to rectify epigenetic imbalances and curb cancer-promoting gene expression. There are 18 mammalian HDAC proteins, classified into four subclasses based on sequence similarity and structural characteristics. Research has shown that several HDACs contribute to cancer progression by a range of mechanisms. Often, HDAC overexpression leads to the silencing of tumour suppressor genes, enhancing oncogenic signalling—given that histone 3 acetylation is tied to the activation of many such genes. Furthermore, aberrant HDAC activity has been linked to increased cell proliferation, survival, and invasion in lab settings, as well as to tumour growth and the spread of breast cancer in animal models (summarised in Figure 2).5, 6

HDAC inhibitors

HDAC inhibitors inhibit the activity of HDACs by blocking the binding of essential molecules like Zn2+ ions or NAD+, which are crucial for the enzymatic function of HDACs. Among these inhibitors, some target specific subtypes, such as Entinostat, which is a Class I-specific inhibitor. Notably, Entinostat received Breakthrough Therapy designation from the FDA in 2013 for the treatment of metastatic oestrogen receptorpositive BC. Conversely, panHDAC inhibitors like Vorinostat and Panobinostat, which target a broader range of HDAC enzymes, have gained FDA approval for certain haematological cancers and are being explored for their potential in treating breast cancer. Despite their broader application, pan-HDAC inhibitors tend to induce more side effects, such as nausea and fatigue, driving research towards more selective HDAC inhibitors to minimize offtarget effects and toxicity.7 Various HDAC inhibitors are currently undergoing clinical trials for both haematological and solid tumours.

Although HDAC inhibitors have demonstrated tolerability in clinical settings, resistance to these drugs poses a significant challenge, and they have shown limited efficacy as standalone treatments. However, when combined with other therapeutic agents, HDAC inhibitors have displayed synergistic effects that enhance efficacy, reduce toxicity, and mitigate resistance in both pre-clinical and clinical settings. Such combination therapies, involving both pan- and selective HDAC inhibitors, have been tested alongside alkylating chemotherapy, immunotherapy, and radiotherapy, showing promising results.8 This discussion will further delve into the use of HDAC inhibitors in combination with PARP inhibitors, highlighting an innovative approach to cancer therapy.

HDAC inhibition and PARP inhibition

HDAC inhibitors play a crucial role in modulating gene expression related to DNA damage repair pathways, notably homologous recombination (HR). Similarly, the enzyme ADP-ribose (poly) polymerase (PARP), involved in HR, has been targeted by PARP inhibitors, which have shown effectiveness as anticancer treatments by blocking HR and prompting cell death. Research involving the combination of Olaparib, a PARP inhibitor, with the HDAC inhibitor Vorinostat has demonstrated that this duo significantly curtails proliferative signalling and tumour growth more effectively than when either drug is used alone, evident in both lab settings and animal models.9, 10 This synergistic effect results in enhanced apoptosis and autophagic cell death by diminishing HR efficiency.

This combination therapy holds particular promise for treating triple-negative breast cancer (TNBC). Many TNBC cases lack BRCA1 mutations, which would typically confer sensitivity to PARP inhibitors. However, HDAC inhibition can induce a state of “BRCAness” in TNBC cells that lack BRCA1, rendering them more susceptible to PARP inhibition (summarised in Figure 3).9 “BRCAness” refers to cells exhibiting molecular features akin to those with BRCA mutations, specifically deficiencies in the HR DNA repair pathway. Clinical trials exploring the combination of Olaparib and Vorinostat for metastatic breast cancer treatment are currently in progress, highlighting the potential of this innovative approach in oncology.

Conclusion

HDAC inhibitors have great potential in the treatment of cancer, especially in combination with other promising drugs such as PARP inhibitors. With significant results in BC models, their potential in treating BCBM has yet to be explored. Continuing to investigate the potential of these drugs for that purpose will then be an important future avenue of future research.

References available on request

Written by Mr. Diego Abril Carbonell (Research Assistant), Miss. Aoibheann Dowd (Research Assistant), Dr. Jason McGrath (Postdoctoral Research Fellow), Dr. Gordon Daly (Ph.D. Researcher), Dr. Damir Vareslija (Lecturer and Principal Investigator), and Prof. Leonie Young (Professor, Scientific Director Beaumont RCSI Cancer Centre). Department of Surgery, Royal College of Surgeons in Ireland & Beaumont Hospital.

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