A randomized phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer

Fakih, Marwan; Groman, Adrienne; McMahon, J.; Wilding, Gregory E.; Muindi, Josephia R.

doi:10.1007/s00280-011-1762-1

Cited by 40 publications

(17 citation statements)

References 43 publications

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“…Over the last three decades, increased understanding of its mechanism of action has led to the development of strategies to improve its efficacy, primarily through combination with other therapeutic drugs (65, 66). However, despite these advances, the increase in clinical response to 5-FU has been minimal and cancer cell resistance remains a major challenge in 5-FU therapy (64).…”

Section: Discussionmentioning

confidence: 99%

H3K9 Trimethylation Silences Fas Expression To Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance

Paschall

Yang

et al. 2015

The Journal of Immunology

119

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The Fas-FasL effector mechanism plays a key role in cancer immune surveillance by host T cells, but metastatic human colon carcinoma often uses silencing Fas expression as a mechanism of immune evasion. The molecular mechanism under FAS transcriptional silencing in human colon carcinoma is unknown. We performed genome-wide ChIP-Sequencing analysis and identified that the FAS promoter is enriched with H3K9me3 in metastatic human colon carcinoma cells. H3K9me3 level in the FAS promoter region is significantly higher in metastatic than in primary cancer cells, and is inversely correlated with Fas expression level. We discovered that verticillin A is a selective inhibitor of histone methyltransferases SUV39H1, SUV39H2 and G9a/GLP that exhibit redundant functions in H3K9 trimethylation and FAS transcriptional silencing. Genome-wide gene expression analysis identified FAS as one of the verticillin A target genes. Verticillin A treatment decreased H3K9me3 level in the FAS promoter and restored Fas expression. Furthermore, verticillin A exhibited greater efficacy than Decitabine and Vorinostat in overcoming colon carcinoma resistance to FasL-induced apoptosis. Verticillin A also increased DR5 expression and overcame colon carcinoma resistance to DR5 agonist drozitumab-induced apoptosis. Interestingly, verticillin A overcame metastatic colon carcinoma resistance to 5-Fluouracil in vitro and in vivo. Using an orthotopic colon cancer mouse model, we demonstrated that tumor-infiltrating cytotoxic T lymphocytes are FasL+ and FasL-mediated cancer immune surveillance is essential for colon carcinoma growth control in vivo. Our findings determine that H3K9me3 of the FAS promoter is a dominant mechanism underlying FAS silencing and resultant colon carcinoma immune evasion and progression.

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Section: Discussionmentioning

confidence: 99%

H3K9 Trimethylation Silences Fas Expression To Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance

Paschall

Yang

et al. 2015

The Journal of Immunology

119

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“…Vorinostat was the first HDACi approved by the Federal Drug Administration in 2006 for clinical use in treating patients with advanced cutaneous T‐cell lymphoma (Duvic and Vu, 2007; Marks and Breslow, 2007). Tables 2 and 3 show about 60 Vorinostat clinical trials, either alone or in combination, completed or terminated against multiple myeloma (MM) (Badros et al., 2009; Mazumder et al., 2010; Richardson et al., 2008), head and neck cancer (Borbone et al., 2010; Gillenwater et al., 2007), pelvic cancer (Bratland et al., 2011; Ree et al., 2010), lymphoma (Dummer et al., 2012; Kirschbaum et al., 2011; Stathis et al., 2011), leukemia and myelodysplastic syndromes (MDS) (Garcia‐Manero et al., 2008b; Prebet and Vey, 2011), breast cancer (Munster et al., 2011; Shi et al., 2010), small cell lung cancer (SCLC) (Gray et al., 2012), brain and central nervous system tumors (Friday et al., 2012), prostate and urothelial cancers (Schneider et al., 2012), colorectal cancer (Fakih et al., 2012), kidney cancer (Sato et al., 2010), pancreatic cancer (Tinari et al., 2012), and ovarian cancer (Modesitt et al., 2008).…”

Section: Histone Modificators In Clinical Trialsmentioning

confidence: 99%

Trials with ‘epigenetic’ drugs: An update

et al. 2012

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Epigenetic inactivation of pivotal genes involved in correct cell growth is a hallmark of human pathologies, in particular cancer. These epigenetic mechanisms, including crosstalk between DNA methylation, histone modifications and non-coding RNAs, affect gene expression and are associated with disease progression. In contrast to genetic mutations, epigenetic changes are potentially reversible. Re-expression of genes epigenetically inactivated can result in the suppression of disease state or sensitization to specific therapies. Small molecules that reverse epigenetic inactivation, so-called epi-drugs, are now undergoing clinical trials. Accordingly, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for cancer treatment have approved some of these drugs.Here, we focus on the biological features of epigenetic molecules, analyzing the mechanism(s) of action and their current use in clinical practice.

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“…On the lowdose arm, one patient had a partial response and eight patients had stable disease. However, the progression-free survival rate did not reach the prespecifi ed threshold of 27 out of 43 patients, and the combination was not deemed interesting enough for further evaluation (Fakih et al 2012 ). Two trials have been reported using vorinostat in combination therapy for the treatment of recurrent glioblastoma.…”

Section: Clinical Trials Of Vorinostatmentioning

confidence: 93%

Histone Deacetylase (HDAC) Inhibitors in Recent Clinical Trials for Cancer Therapy

Keller¹,

Jung²

2013

Epigenetic Therapy of Cancer

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Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histonemodifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects.

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A randomized phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer

Abstract: While the addition of vorinostat to 5-FU resulted in 1 partial response and in some disease stabilizations, the limited activity does not warrant the unselected use of this combination in chemotherapy-refractory colorectal cancer.

Cited by 40 publications

References 43 publications

H3K9 Trimethylation Silences Fas Expression To Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance

H3K9 Trimethylation Silences Fas Expression To Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance

Trials with ‘epigenetic’ drugs: An update

Histone Deacetylase (HDAC) Inhibitors in Recent Clinical Trials for Cancer Therapy

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