Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study

Ree, Anne Hansen; Dueland, Svein; Folkvord, Sigurd; Hole, Knut Håkon; Seierstad, Therese; Johansen, Marianne; Abrahamsen, Torveig Weum; Flatmark, Kjersti

doi:10.1016/s1470-2045(10)70058-9

Cited by 113 publications

(108 citation statements)

References 20 publications

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“…The initial results confirmed the safety of the combination (300 mg of vorinostat once daily in conjunction with 30 Gy of radiation over 2 weeks), but the high variability in the tumor volume regression reported (26% mean reduction, 23% SD) cannot be considered as a validation of the approach (48). Other clinical studies are ongoing in a variety of cancers including brain, lung, and pancreatic tumors (49).…”

Section: Clinical-translational Advancesmentioning

confidence: 84%

Molecular Pathways: Old Drugs Define New Pathways: Non-Histone Acetylation at the Crossroads of the DNA Damage Response and Autophagy

Botrugno

Robert

Vanoli

et al. 2012

Clinical Cancer Research

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Histone deacetylases (HDAC) modulate acetylation and the function of histone and non-histone proteins. HDAC inhibitors have been developed to block the aberrant action of HDACs in cancer, and several are in clinical use (vorinostat, romidepsin, and valproic acid). Detailed understanding of their action is lacking, however, and their clinical activity is limited in most cases. Recently, HDACs have been involved in the control of the DNA damage response (DDR) at several levels and in directly regulating the acetylation of a number of DDR proteins (including CtIP and Exo1). Mechanistically, acetylation leads to the degradation of double-strand break repair enzymes through autophagy, providing a novel, direct link between DDR and autophagy. These observations, obtained in yeast cells, should now be translated to mammalian model systems and cancer cells to reveal whether this acetylation link is maintained in mammals, and if and how it is deregulated in cancer. In addition to HDACs, DDR and autophagy have been addressed pharmacologically, suggesting that the acetylation link, if involved in cancer, can be exploited for the design of new anticancer treatments. Clin Cancer Res; 18(9); 2436-42. Ó2012 AACR.

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Section: Clinical-translational Advancesmentioning

confidence: 84%

Molecular Pathways: Old Drugs Define New Pathways: Non-Histone Acetylation at the Crossroads of the DNA Damage Response and Autophagy

Botrugno

Robert

Vanoli

et al. 2012

Clinical Cancer Research

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“…Moreover, a corresponding enhancement of therapeutic efficacy in vivo was also reported when VPA was combined with irradiation (20,21). To our knowledge, there are currently four on-going phase I clinical trials assessing the combination of HDAC inhibitors and radiotherapy: VPA with radiotherapy for pediatric glioma, VPA with radiotherapy for pediatric refractory solid and central nervous system (CNS) tumors, VPA or hydralazine with CRT for cervical cancer, and vorinostat with palliative radiotherapy (28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 98%

Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in esophageal squamous cell carcinoma

et al. 2012

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Abstract. Histone deacetylase (HDAC) inhibitors have been shown to enhance radiation response in various cancer cell lines. Valproic acid (VPA) has been used in clinical practice for the treatment of epilepsy and other seizure disorders and is also one of the most represented HDAC inhibitors. The aim of this study was to evaluate the radiosensitizing ability of VPA and its mechanisms in four esophageal squamous cell carcinoma (ESCC) cell lines (TE9, TE10, TE11 and TE14). VPA inhibited the viability of all ESCC cells in a dose-dependent manner. The 50% inhibitory concentration (IC 50 ) value of VPA in each cell line was between 1.02-2.15 mM, which is higher than clinically used safe concentrations. VPA induced the hyperacetylation of histones H3 and H4, as well as apoptosis and had a radiosensitizing effect on all four ESCC cell lines at a concentration of 0.5 mM which is equivalent to the therapeutic plasma concentration of anti-epilepsy therapy in humans. The radiosensitization was accompanied by an increase in γH2AX levels, indicating the presence of double-strand breaks (DSBs), and decrease in Rad51 expression, a DSB repair protein. These results suggest that a clinically safe dose of VPA can enhance radiation-induced cytotoxicity in human ESCC cells by chromatin decondensation with histone hyperacetylation and downregulation of Rad51. In conclusion, VPA appears to be a safe and promising radiosensitizer for esophageal cancer radiotherapy.

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“…This was taken one step further in combining vorinostat with radiotherapy and capecitabine in colorectal cancer xenografts, and the combination showed a synergistic response and further increasing radiosensitization [Saelen et al 2012]. The PRAVO (pelvic radiation and vorinostat) trial was a phase I study which combined palliative radiotherapy with the HDAC inhibitor vorinostat in patients with bulky pelvic GI tumors [Ree et al 2010]. While the higher doses of vorinostat in this study were tolerated as single therapy when assessing for maximum tolerated dose, the combination with a 2-week course of palliative radiotherapy caused severe dose-limiting GI toxicities and fatigue.…”

Section: Gastrointestinal Cpg Island Methylator Phenotype and Epigenementioning

confidence: 99%

“…While the higher doses of vorinostat in this study were tolerated as single therapy when assessing for maximum tolerated dose, the combination with a 2-week course of palliative radiotherapy caused severe dose-limiting GI toxicities and fatigue. The authors concluded that this regimen and the dosages employed were not a feasible approach [Ree et al 2010], however further trials have been initiated incorporating this strategy in multiple GI malignancies, including pancreatic and gastric cancer [ClinicalTrials.gov identifiers: NCT00983268, NCT02349867] (Table 2).…”

Section: Gastrointestinal Cpg Island Methylator Phenotype and Epigenementioning

confidence: 99%

Epigenetic therapy in gastrointestinal cancer: the right combination

Abdelfatah

Kerner

Nanda

et al. 2016

Therap Adv Gastroenterol

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Abstract:Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer.

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Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study

Cited by 113 publications

References 20 publications

Molecular Pathways: Old Drugs Define New Pathways: Non-Histone Acetylation at the Crossroads of the DNA Damage Response and Autophagy

Molecular Pathways: Old Drugs Define New Pathways: Non-Histone Acetylation at the Crossroads of the DNA Damage Response and Autophagy

Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in esophageal squamous cell carcinoma

Epigenetic therapy in gastrointestinal cancer: the right combination

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