The DAC system and associations with multiple myeloma
Enrique M Ocio1, Jesús F San Miguel
1University Hospital of Salamanca, Salamanca, Spain.
Abstract:
Despite the clear progress achieved in recent years in the treatment of MM, most patients eventually relapse and therefore novel therapeutic options are still necessary for these patients. In this regard, several drugs that target specific mechanisms of the tumor cells are currently being explored in the preclinical and clinical setting. This manuscripts offers a review of the rationale and current status of the antimyeloma activity of one of the most relevant examples of these targeted drugs: deacetylase inhibitors (DACi). Several studies have demonstrated the prooncogenic activity of deacetylases (DACs) through the targeting not only of histones but also of non histone proteins relevant to tumor progression, such as p53, E2F family members, Bcl-6, Hsp90, HIF-1α or Nur77. This fact together with the DACs overexpression present in several tumors, has prompted the development of some DACi with potential antitumor effect. This situation is also evident in the case of MM as two mechanisms of DACi, the inhibition of the epigenetic inactivation of p53 and the blockade of the unfolded protein response, through the inhibition of the aggressome formation (by targeting DAC6) and the inactivation of the chaperone system (by acetylating HSP-90), provides the rationale for the exploration of the potential antimyeloma activity of these compounds. Several DACi with different chemical structure and different selectivity for targeting the DAC families have been tested in MM. Their preclinical activity in monotherapy has been quite exciting and has been described to be mediated by various mechanisms: the induction of apoptosis and cell cycle arrest mainly by the upregulation of p21; the interferece with the interaction between plasma cells and the microenvironment, by reducing the expression and signalling of several cytokines or by inhibiting angiogenesis. Finally they also have a role in protecting murine models from myeloma bone disease. Neverteless, the clinical activity in monotherapy of these drugs in relapsed/refractory MM patients has been very modest. This has prompted the development of combinations such as the one with bortezomib or lenalidomide and dexamethasone, which have already been taken into the clinics with positive preliminary results.
Insights
Histone deacetylase inhibitors (HDACi) show preclinical promise against multiple myeloma (MM) by inducing apoptosis and affecting the tumor microenvironment. However, their clinical efficacy as monotherapy is limited, necessitating combination treatments for relapsed/refractory MM patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple myeloma (MM) remains a significant challenge, with most patients experiencing relapse, highlighting the need for novel therapeutic strategies.
- Deacetylases (DACs) play a crucial role in cancer progression by modifying histones and non-histone proteins, and their overexpression in tumors like MM warrants targeted inhibition.
Purpose of the Study:
- To review the rationale and current status of deacetylase inhibitors (DACi) as a targeted therapy for multiple myeloma (MM).
- To explore the mechanisms of action and clinical efficacy of DACi in MM, both as monotherapy and in combination regimens.
Main Methods:
- Review of preclinical and clinical studies on DACi in multiple myeloma.
- Analysis of the molecular mechanisms underlying DACi activity, including effects on apoptosis, cell cycle, tumor microenvironment, and bone disease.
- Evaluation of clinical trial data for DACi, focusing on monotherapy and combination therapies.
Main Results:
- Preclinical studies demonstrate exciting antimyeloma activity of DACi through apoptosis induction, cell cycle arrest (p21 upregulation), interference with plasma cell-microenvironment interactions, and inhibition of angiogenesis.
- DACi have shown a protective role in murine models against myeloma bone disease.
- Clinical activity of DACi as monotherapy in relapsed/refractory MM patients has been modest, prompting investigation into combination therapies.
Conclusions:
- DACi represent a promising class of targeted agents for MM, with established preclinical efficacy and multiple mechanisms of action.
- Combination strategies, particularly with bortezomib or lenalidomide and dexamethasone, are showing positive preliminary results and are being advanced clinically for MM treatment.
