The emergence of specific HDAC inhibitors and their clinical efficacy in the treatment of hematologic malignancies and breast cancer

Abstract

The dynamic balance between histone acetylation and deacetylation is an important epigenetic mechanism controlling gene expression, and is associated with the etiology and progression of many human diseases. Early success of histone deacetylase (HDAC) inhibition in the treatment of hematological cancers paved the way for the development and testing of many different pan/global histone deacetylase inhibitors (HDIs). Dose limiting toxicities in these early trials, coupled with increased understanding of the differential expression patterns of HDACs in different tissues and disease states, led to the emergence of more specific HDIs that target specific HDAC classes and isotypes. Whereas a large number of clinical trials have been undertaken using pan-HDIs, which have demonstrated varying success in the treatment of hematological and solid malignancies, both as single agents and in combination with other drugs, there have been far fewer undertaken with the emerging repertoire of specific HDIs, which could potentially overcome the limitations seen in the pan inhibitors. In this review we describe the classification and development of HDIs as well the roles of HDACs in cancers, and the rationale behind moving toward more selective inhibition. We then examine the clinical efficacy of both pan-and specific HDI treatment by reviewing a number of clinical trials, focusing on hematological malignancies, where numerous trials have demonstrated single agent and combinatory efficacy, as well as breast cancers, where fewer trials have been undertaken showing limited efficacy, but also where promising pre-clinical findings necessitate further clinical investigation.

Coupling the immunomodulatory properties of the HDAC6 inhibitor ACY241 with Oxaliplatin promotes robust anti-tumor response in non-small cell lung cancer

“…In hematologic cancers, both pan and selective HDAC inhibitors show promising therapeutic results. 41 , 42 However, solid cancers have not met with the same level of success although emerging data is encouraging. 2 , 13 , 16–18 , 22 , 43 In the present study, we evaluated ACY241, an HDAC6-selective inhibitor in a pre-clinical mouse model of NSCLC in order to determine its therapeutic potential in this disease by leveraging its identified immunomodulatory effects in new combinatorial drug regimen.…”

DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro

“…To investigate this possibility, more specific inhibitors could be used in future studies. Class-I specific HDAC inhibitors are available for such studies, but inhibiting HDAC1 or other specific class-I HDACs remains a challenge ( Schölz et al, 2015 ; Eckschlager et al, 2017 ; Shortt et al, 2017 ; Pride and Summers, 2018 ; Hess et al, 2022 ; Siklos and Kubicek, 2022 ). Interestingly, recent efforts have led to the development of more selective HDAC inhibitors, some of which inhibit certain class-I HDACs more than others ( Yang et al, 2019 ; Hess et al, 2022 ; Siklos and Kubicek, 2022 ).…”

The immunomodulatory properties of the HDAC6 inhibitor ACY241 supports robust anti-tumor response in NSCLC when coupled with the chemotherapy drug Oxaliplatin

“…In hematologic cancers, both pan and selective HDAC inhibitors show promising therapeutic results 42 43 . However, solid cancers have not met with the same level of success although emerging data is encouraging 6 16 22-25 44 .…”