To determine the safety, maximum tolerated dose, and pharmacokinetic-pharmacodynamic profile of a histone deacetylase inhibitor, LAQ824, in patients with advanced malignancy. Patients and Methods: LAQ824 was administered i.v. as a 3-h infusion on days 1, 2, and 3 every 21 days. Western blot assays of peripheral blood mononuclear cell lysates and tumor biopsies pretherapy and posttherapy evaluated target inhibition and effects on heat shock protein-90 (HSP90) client proteins and HSP72.
Thirty-nine patients (22 male; median age, 53 years; median Eastern Cooperative Oncology Group performance status 1) were treated at seven dose levels (mg/m(2)): 6 (3 patients), 12 (4 patients), 24 (4 patients), 36 (4 patients), 48 (4 patients), 72 (19 patients), and 100 (1 patient). Dose-escalation used a modified continual reassessment method. Dose-limiting toxicities were transaminitis, fatigue, atrial fibrillation, raised serum creatinine, and hyperbilirubinemia. A patient with pancreatic cancer treated at 100 mg/m(2) died on course one at day 18 with grade 3 hyperbilirubinemia and neutropenia, fever, and acute renal failure. The area under the plasma concentration curve increased proportionally with increasing dose; median terminal half-life ranged from 8 to 14 hours. Peripheral blood mononuclear cell lysates showed consistent accumulation of acetylated histones posttherapy from 24 mg/m(2); higher doses resulted in increased and longer duration of pharmacodynamic effect. Changes in HSP90 client protein and HSP72 levels consistent with HSP90 inhibition were observed at higher doses. No objective response was documented; 3 patients had stable disease lasting up to 14 months. Based on these data, future efficacy trials should evaluate doses ranging from 24 to 72 mg/m(2).
LAQ824 was well tolerated at doses that induced accumulation of histone acetylation, with higher doses inducing changes consistent with HSP90 inhibition.
"ECG changes, such as T-wave flattening or inversion were observed in multiple trials . In the drug safety study with romidepsin (LAQ824) on 32 patients, two patients showed QTc prolongation >500 ms accompanied by non-symptomatic ST-T-wave changes and one patient developed atrial fibrillation which led to a stop of therapy . The patients received a relatively high dosage of HDACi (up to 100 mg/m2). "
[Show abstract][Hide abstract] ABSTRACT: Cardiovascular disease (CVD) represents a major challenge for health care systems, both in terms of the high mortality associated with it and the huge economic burden of its treatment. Although CVD represents a diverse range of disorders, they share common compensatory changes in the heart at the structural, cellular, and molecular level that, in the long term, can become maladaptive and lead to heart failure. Treatment of adverse cardiac remodeling is therefore an important step in preventing this fatal progression. Although previous efforts have been primarily focused on inhibition of deleterious signaling cascades, the stimulation of endogenous cardioprotective mechanisms offers a potent therapeutic tool. In this review, we discuss class I and class II histone deacetylases, a subset of chromatin-modifying enzymes known to have critical roles in the regulation of cardiac remodeling. In particular, we discuss their molecular modes of action and go on to consider how their inhibition or the stimulation of their intrinsic cardioprotective properties may provide a potential therapeutic route for the clinical treatment of CVD.
Cellular and Molecular Life Sciences CMLS 12/2013; 71(9). DOI:10.1007/s00018-013-1516-9 · 5.81 Impact Factor
"However, when used in monotherapy, HDAC inhibitors showed limited efficacy in various solid malignancies, including PDAC , , . Indeed, LAQ824 or MS-275 have been evaluated in phase I clinical trials in solid cancers, including PDAC, without any objective clinical response , . Alternatively, HDAC inhibitors have been used in combined therapy strategies , , with some combinations generating promising effects for human PDAC in vitro
– or in experimental tumors . "
[Show abstract][Hide abstract] ABSTRACT: Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide, with no satisfactory treatment to date. In this study, we tested whether the combined inhibition of cyclooxygenase-2 (COX-2) and class I histone deacetylase (HDAC) may results in a better control of pancreatic ductal adenocarcinoma. The impact of the concomitant HDAC and COX-2 inhibition on cell growth, apoptosis and cell cycle was assessed first in vitro on human pancreas BxPC-3, PANC-1 or CFPAC-1 cells treated with chemical inhibitors (SAHA, MS-275 and celecoxib) or HDAC1/2/3/7 siRNA. To test the potential antitumoral activity of this combination in vivo, we have developed and characterized, a refined chick chorioallantoic membrane tumor model that histologically and proteomically mimics human pancreatic ductal adenocarcinoma. The combination of HDAC1/3 and COX-2 inhibition significantly impaired proliferation of BxPC-3 cells in vitro and stalled entirely the BxPC-3 cells tumor growth onto the chorioallantoic membrane in vivo. The combination was more effective than either drug used alone. Consistently, we showed that both HDAC1 and HDAC3 inhibition induced the expression of COX-2 via the NF-kB pathway. Our data demonstrate, for the first time in a Pancreatic Ductal Adenocarcinoma (PDAC) model, a significant action of HDAC and COX-2 inhibitors on cancer cell growth, which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients.
PLoS ONE 09/2013; 8(9):e75102. DOI:10.1371/journal.pone.0075102 · 3.23 Impact Factor
"Components of the JAK/STAT pathways are also susceptible to HDAC inhibition and could be considered as targets for HDI use in patients (see also Section 4.7). A phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor, indicated that Hsp90 client proteins including c- Raf as well as Hsp70 could act as surrogate markers in patients with solid tumours (de Bono et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Abnormal epigenetic control is a common early event in tumour progression, and aberrant acetylation in particular has been implicated in tumourigenesis. One of the most promising approaches towards drugs that modulate epigenetic processes has been seen in the development of inhibitors of histone deacetylases (HDACs). HDACs regulate the acetylation of histones in nucleosomes, which mediates changes in chromatin conformation, leading to regulation of gene expression. HDACs also regulate the acetylation status of a variety of other non-histone substrates, including key tumour suppressor proteins and oncogenes. Histone deacetylase inhibitors (HDIs) are potent anti-proliferative agents which modulate acetylation by targeting histone deacetylases. Interest is increasing in HDI-based therapies and so far, two HDIs, vorinostat (SAHA) and romidepsin (FK228), have been approved for treating cutaneous T-cell lymphoma (CTCL). Others are undergoing clinical trials. Treatment with HDIs prompts tumour cells to undergo apoptosis, and cell-based studies have shown a number of other outcomes to result from HDI treatment, including cell-cycle arrest, cell differentiation, anti-angiogenesis and autophagy. However, our understanding of the key pathways through which HDAC inhibitors affect tumour cell growth remains incomplete, which has hampered progress in identifying malignancies other than CTCL which are likely to respond to HDI treatment.
Ângela C A Wu, Michelle A R Freitas, Soraia de O Silva, Paula M Nogueira, Rodrigo P Soares, João Bosco Pesquero, Maria A Gomes, Jorge L Pesquero, Maria N Melo
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