Vorinostat in solid and hematologic malignancies
Journal of Hematology & Oncology
Vorinostat in solid and hematologic malignancies
David Siegel 2
Mohamad Hussein 1
Chandra Belani 0
Francisco Robert 6
Evanthia Galanis 5
Victoria M Richon 4
Jos Garcia-Vargas 4
Cesar Sanz- Rodriguez 3
Syed Rizvi 4
0 Penn State Cancer Institute , Hershey, PA , USA
1 H. Lee Moffitt Cancer Center , Tampa, FL , USA
2 Hackensack University Medical Center , Hackensack, NJ , USA
3 Merck Research Laboratories , Madrid , Spain
4 Merck Research Laboratories , Upper Gwynedd, PA , USA
5 Mayo Clinic College of Medicine , Rochester, MN , USA
6 University of Alabama , Birmingham, AL , USA
Vorinostat (Zolinza), a histone deacetylase inhibitor, was approved by the US Food and Drug Administration in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. This review summarizes evidence on the use of vorinostat in solid and hematologic malignancies and collated tolerability data from the vorinostat clinical trial program. Pooled vorinostat clinical trial data from 498 patients with solid or hematologic malignancies show that vorinostat was well tolerated as monotherapy or combination therapy. The most commonly reported drug-related adverse events (AEs) associated with monotherapy (n = 341) were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%), and Grade 3/4 drug-related AEs included fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.3%), and decreased platelet count (5.3%). The most common drug-related AEs observed with vorinostat in combination therapy (n = 157, most of whom received vorinostat 400 mg qd for 14 days) were nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), vomiting (31.2%), and anorexia (20.4%), with the majority of AEs being Grade 2 or less. In Phase I trials, combinations with vorinostat were generally well tolerated and preliminary evidence of anticancer activity as monotherapy or in combination with other systemic therapies has been observed across a range of malignancies. Ongoing and planned studies will further evaluate the potential of vorinostat in combination therapy, including combinations with radiation, in patients with diverse malignancy types, including non-small-cell lung cancer, glioblastoma multiforme, multiple myeloma, and myelodysplastic syndrome.
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Histone Deacetylase Inhibition with Vorinostat
as a Target in Oncology
Advanced or refractory malignancy remains an area of
high unmet medical need as patients often relapse and
curative therapy is elusive. The mainstay of treatment is
generally cytotoxic chemotherapy which can have limited
efficacy and is often associated with significant toxicity;
there is a need for novel agents that are not only effective
but also well tolerated. In particular, there has been
increasing interest in targeted therapies which work at an
epigenetic level to influence gene expression and
ultimately control tumor growth and proliferation. Histone
deacetylase (HDAC) inhibitors represent one such class of
new mechanism-based anticancer drugs [1].
Modifications to histones influence chromatin structure,
and ultimately gene transcription, including those coding
for tumor suppressor proteins. One of the key histone
modifications that controls gene transcription is
acetylation, which is regulated by two opposing enzymatic
activities (histone acetyltransferases [HATs] and HDACs) [1].
Histone acetylation leads to an open chromatin structure,
and allows access to transcription binding sites. Although
histones are one of the targets of HATs and HDACs, many
nonhistone proteins, including transcription factors,
tubulin and heat shock protein 90, can also be regulated
by acetylation [2,3].
HDACs have been shown to be overexpressed in human
cancers, such as gastric, prostate and colon cancer, and are
involved in the regulation of transcription with
recruitment by oncogenic transcription factors [4]. Therefore,
the inhibition of HDACs is a rational target for the
development of novel anticancer therapy. To date, 18 HDACs
have been identified in mammalian cells, which are
categorized into different classes, based on their homology to
yeast deacetylases [5]. By inhibiting these enzymes, HDAC
inhibitors permit chromatin to assume a more relaxed
conformational state, thereby allowing transcription of
genes involved in tumor suppression, cell-cycle arrest, cell
differentiation, and apoptosis (Figure 1[4]) [6].
A variety of HDAC inhibitors are in clinical development
and are being assessed in a number of different cancer
indications [7]. There are several chemical families among
the HDAC inhibitors, including short-chain fatty acids
(butyrate, valproic acid), hydroxamates (vorinostat,
tri
STAT5 genes
p53 genes
BCL6 genes
Cell cycle arrest and apoptosis
aThe sites of action of other antitumor agents are also shown
PFrigouporese1d mechanism of acti (...truncated)