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Victoria M Richon - One of the best experts on this subject based on the ideXlab platform.

  • Abstract PL06-01: Targeted inhibition of chromatin‐modifying enzymes as cancer therapeutics: The HDAC inhibitor Vorinostat and beyond
    Molecular Cancer Therapeutics, 2009
    Co-Authors: Victoria M Richon
    Abstract:

    Histone deacetylase (HDAC) inhibitors represent a promising new class of anti‐tumor agents. HDACs are enzymes that catalyze the removal of acetyl groups from the lysine residues of proteins, most notably the core nucleosomal histones. Four classes of HDACs have been identified, and include Class I human HDACs (HDAC1, HDAC2, HDAC3, and HDAC8). Class II HDACs are subdivided into Class IIa enzymes (HDAC4, HDAC5, HDAC7 and HDAC9) and Class IIb enzymes (HDAC6 and HDAC10). The third class of human HDACs or sirtiuins consists of homologues of yeast Sir2 (SIRT1–7). The catalytic site of this third HDAC class is not similar to the catalytic site of the Class I and Class II enzymes. HDAC11 is the sole member of the fourth HDAC class and shares homology with both the class I and class II HDACs. Defects in the enzymes regulating histone acetylation have been found in a variety of cancers. These defects can cause an imbalance in histone acetylation that may lead to changes in chromatin structure and transcriptional dysregulation of genes involved in the control of cell cycle progression, differentiation, and apoptosis. Histone acetyltransferases have been found to be mutated in a variety of cancer while HDACs have been shown to be overexpressed, aberrantly recruited to oncogenic transcription factors and mutated in cancer. HDACs thus represent potential targets for small molecule inhibitors. The substrates for HDACs HDAC inhibitors are currently undergoing evaluation for the treatment of cancer and can be divided into four classes based on their structure. The classes include the short chain fatty acids (e.g., valproate, phenylbutyrate); hydroxamic acid derivatives (e.g., Vorinostat (SAHA), belinostat (PXD‐101), panobinostat (LBH‐589), JNJ‐26481585, PCI‐24781); benzamides (e.g., entinostat (SNDX‐275, MS‐275); mocetinostat (MGCD0103)); and cyclic tetrapeptides (e.g., romidepsin (FK‐228)). The HDAC inhibitors under clinical development for cancer do not inhibit the class III enzymes rather they inhibit, in general, either both class I and II enzymes (hydroxamate derivatives) or selectively inhibit class I enzymes (benzamides). Vorinostat inhibits the enzymatic activity of Class I HDACs, (HDAC1, HDAC2, and HDAC3) and the Class II HDAC, HDAC6, at low nanomolar concentrations (IC50 The molecular mechanisms of Vorinostat‐induced growth arrest, differentiation, apoptosis and autophagy have yet to be fully clarified. The acetylation of nucleosomal histones plays an important role in the transcriptional regulation of gene expression. Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription. Conversely, acetylated histones are associated with a more open chromatin structure and activation of transcription. Vorinostat may exert its antitumor effects through by transcriptional and non‐transcriptional mechanisms. Expression profiling studies have revealed that Vorinostat treatment can also lead to both activation and repression of gene expression. The Vorinostat‐mediated transcriptional repression may involve both direct and indirect effects resulting from histone acetylation, or alternately, may involve the hyperacetylation of non‐histone proteins. Many nonhistone proteins, (e.g., tubulin, Hsp90 and p53) are known to be reversibly acetylated on lysine residues and undergo hyperacetylation following exposure to Vorinostat. Acetylation of these proteins may also contribute to the antitumor activity of Vorinostat. A more complete understanding of the spectrum of substrates for the HDAC enzymes and the role of acetylation of these substrates in cancer will aid in our understanding of how to best utilize HDAC inhibitors. Based on the antitumor mechanism of action of Vorinostat, studies evaluating the activity of Vorinostat with other cancer therapies have been performed. These studies include the evaluation of Vorinostat with radiation, kinase inhibitors, cytotoxic agents, and proteasome inhibitors. The studies have demonstrated synergistic or additive activity in a variety of cultured human transformed cell lines. Vorinostat has demonstrated anti‐tumor activity in a variety of in vivo rodent tumor models whether administered by the intraperitoneal, intravenous, or oral route in both carcinogen induced tumor formation and established tumor models. Tumor growth inhibition is observed at doses of Vorinostat that do not produce toxic side effects. Vorinostat is under evaluation in clinical trials for the treatment of cancer and was the first HDAC inhibitor approved by the US FDA for the treatment of cutaneous manifestations in patients with cutaneous T‐cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies in 2006. In the initial oral phase I Vorinostat clinical trial, accumulation of acetylated histone H3 was observed in patient peripheral blood mononuclear cells at all dose levels and was detected in tumor biopsies following administration of Vorinostat. Additionally, in a Phase II trial for recurrent glioblastoma patients, an increase in acetylation of histones was detected in surgical samples post treatment with Vorinostat. These studies demonstrate that Vorinostat is able to inhibit HDAC activity at tolerable doses in patients. The most common adverse experiences were diarrhea, fatigue, nausea, and anorexia and were mostly mild to moderate in severity. Ongoing biomarker studies are required to further define optimal dose and schedule and aid in identifying responding patient populations. Clinical activity has thus far been observed in patients with acute myeloid leukemia, multiple myeloma, non‐Hodgkin9s lymphoma, glioblastoma multiforme, and metastatic mesothelioma, as well as breast, laryngeal, nasopharyngeal, papillary thyroid, ovarian, and non‐small cell lung cancer. Further investigation of Vorinostat in phase II and III trials for patients with other hematologic malignancies and solid tumors as a single agent and in combination therapy is ongoing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PL06-01.

  • Vorinostat in solid and hematologic malignancies
    Journal of hematology & oncology, 2009
    Co-Authors: David S. Siegel, Victoria M Richon, Chandra P. Belani, Mohamad A. Hussein, Francisco Robert, Evanthia Galanis, Jose Garcia-vargas, Cesar Sanz-rodriguez, Syed Rizvi
    Abstract:

    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.

  • Mechanisms of in vitro acquired resistance to Vorinostat (suberoylanilide hydroxamic acid, SAHA)
    Cancer Research, 2007
    Co-Authors: Jennifer Roth, Victoria M Richon, Andrey Loboda, Susan Korenchuk, Theresa Zhang, James Hardwick, Elizabeth Harrington, Valeria R Fantin
    Abstract:

    AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 694 Vorinostat is a histone deacetylase (HDAC) inhibitor that induces differentiation, growth arrest and/or apoptosis of malignant cells both in vitro and in vivo . Vorinostat has demonstrated antitumor activity in both hematological malignancies and solid tumors, including an overall response rate of approximately 30% in cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following 2 systemic therapies. As not all clinical responses are permanent, we developed model systems to investigate the mechanisms of acquired resistance to Vorinostat and used these results to identify rational combination strategies to overcome this clinical issue. Using a dose escalation protocol Vorinostat resistant clones were derived from sensitive HCT116 colon carcinoma cells and A549 non-small cell lung cancer (NSCLC) cells. This method established cell lines that can be maintained in media containing Vorinostat at 2 μM (A549-VR2), 3μM (A549-VR3), 5 μM (A549-VR5) and 8 μM (HCT116-VR8) for a prolonged period of time (3 weeks) without signs of apoptosis. Gene expression profiling was performed on the parental HCT116 cells and Vorinostat-resistant cells. In addition to an unbiased analysis of the data, the status of several pathways possibly related to Vorinostat's mechanism of action were examined. Preliminary analyses revealed alterations in the expression of genes that participate in the apoptotic cascade (e.g. Bcl-2, survivin), protein acetylation (CBP/p300), redox homeostasis (SOD2, metallothionein) and Wnt/ β-catenin signaling pathway (frizzle, β-catenin and cyclin D1). The expression of candidate genes from this analysis was assessed across the panel of Vorinostat-resistant A549 clones. The results indicate that acquired resistance to Vorinostat appears to comprise mechanisms that inhibit the induction of apoptosis, including an increase in antioxidants and in anti-apoptotic Bcl-2 levels. In particular, upregulation of antioxidant enzymes and thiol modulating proteins including SOD2 and metallothioneins have been associated with clinical resistance to cytotoxic drugs and radiation therapy as well as poor prognosis. Future studies will help to address the clinical relevance of these findings. One prediction from this analysis is that compounds that inhibit the glutathione system like buthionine sulfoximine or agents that downregulate or block Bcl-2 could be used to revert these mechanisms of resistance. Combination strategies with emerging treatment modalities may help to increase Vorinostat efficacy in specific genetic contexts.

  • Vorinostat a histone deacetylase inhibitor enhances the response of human tumor cells to ionizing radiation through prolongation of γ h2ax foci
    Molecular Cancer Therapeutics, 2006
    Co-Authors: Anupama Munshi, Victoria M Richon, Toshimitsu Tanaka, Marvette L Hobbs, Susan L Tucker, Raymond E Meyn
    Abstract:

    Vorinostat (suberoylanilide hydroxamic acid) is the prototype of a family of hybrid polar compounds that can induce growth arrest in transformed cells and shows promise for the treatment of cancer. Vorinostat specifically binds to and inhibits the activity of histone deacetylases resulting in acetylation of nucleosomal histones and an activation of gene transcription. Because histone deacetylases modulate chromatin structure and gene expression, both of which can influence radioresponse, this study was designed to examine the capacity of Vorinostat to influence radiation response in human tumor cells and investigate the mechanism underlying these interactions. Vorinostat induced hyperacetylation of histone H4 in a dose-dependent manner. We tested its ability to radiosensitize three human tumor cell lines (A375, MeWo, and A549) using clonogenic cell survival assays. Clonogenic cell survival assay showed that Vorinostat significantly radiosensitized all three tumor cell lines, substantially reducing the surviving fraction at 2 Gy. We examined potential mechanisms that may contribute to the enhanced radiation response induced by Vorinostat. Vorinostat and radiation alone did not induce apoptosis in the melanoma cell line. However, enhanced apoptosis was observed when cells were exposed to both Vorinostat and radiation, suggesting that Vorinostat renders tumor cells more susceptible to radiation-induced apoptosis. Results from DNA damage repair analysis in cultured A375 cells showed that Vorinostat had a strong inhibitory effect on the nonhomologous end joining pathway after radiation. A detailed examination of the involvement of the DNA repair pathway following Vorinostat treatment showed that Vorinostat reduced the expression of the repair-related genes Ku70, Ku80, and Rad50 in A375 cells as detected by Western blot analysis. We also examined gamma-H2AX phosphorylation as a predictive marker of radiotherapy response to Vorinostat and observed that the combination of Vorinostat and radiation caused a prolongation of expression of DNA repair proteins such as gamma-H2AX. Overall, we conclude that Vorinostat enhances tumor radioresponse by multiple mechanisms that may involve antiproliferative growth inhibition and effects on DNA repair after exposure to radiation.

Madeleine Duvic - One of the best experts on this subject based on the ideXlab platform.

  • Vorinostat for the treatment of cutaneous T-cell lymphoma
    Expert Review of Dermatology, 2010
    Co-Authors: Chunlei Zhang, Madeleine Duvic
    Abstract:

    Vorinostat (suberoylanilide hydroxamic acid) is the first US FDA-approved histone deacetylase inhibitor for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphomas (CTCLs). In two Phase II trials, Vorinostat was safe and effective at an oral dose of 400 mg/day, with an overall response rate of 24–30% in refractory advanced CTCL patients, including large-cell transformed mycosis fungoides and Sezary syndrome. Most patients with CTCL also experience significant itching relief with Vorinostat therapy. Moreover, a recent follow-up study reported long-term safety and clinical benefits of Vorinostat in heavily pretreated patients with CTCL, regardless of previous treatment failures. The most frequent side effects of Vorinostat include gastrointestinal symptoms, fatigue and thrombocytopenia. These side effects are dose-related and reversible upon cessation of therapy. Translational studies have shown that Vorinostat has in vitro and in vivo anti-tumor activities against CTCL, includ...

  • Molecular and Biological Characteristics of Acquired Vorinostat-Resistant Cutaneous T-Cell Lymphoma Cells.
    Blood, 2009
    Co-Authors: Chunlei Zhang, Xiang Zhang, Madeleine Duvic
    Abstract:

    Abstract 1732 Poster Board I-758 Vorinostat (suberoylanilide hydroxamic acid, SAHA), a pan-histone deacetylase (HDAC) inhibitor, has an overall response rate of 24-30% in two phase II studies of patients with cutaneous T cell lymphoma (CTCL). Since a considerable proportion of CTCL patients did not reach a partial response and loss of response could occur after only a few months, development of resistance became an important clinical problem. Although we have shown that constitutive activation of STAT signaling may be involved in resistance to Vorinostat, the other mechanisms of resistance to Vorinostat in CTCL are largely unknown. To further investigate mechanisms of Vorinostat resistance, we have generated a Vorinostat-resistant CTCL cell line (HH/VOR) from a parent Vorinostat-sensitive HH CTCL cell line by long term exposure to stepwise increasing concentrations of Vorinostat. The HH parental cells were cultured in increasing concentrations of Vorinostat starting at 10 nM. Viable cells were then passaged into a higher concentration of Vorinostat in 10 nM increments until a concentration of 1 μM Vorinostat was reached. The HH/VOR cells were then maintained in complete RPMI1640 medium containing 1 μM Vorinostat. We studied the molecular and biological characteristics of the Vorinostat-resistant CTCL cells. Compared with the parental Vorinostat-sensitive HH cells, the Vorinostat-resistant HH/VOR cells were highly resistant to Vorinostat-mediated growth inhibition and apoptosis. Of interest, the HH/VOR also exhibited cross resistance to another pan-HDAC inhibitor panobinostat and a class I HDAC inhibitor SNDX-275. The Vorinostat-resistant HH/VOR cells had reduced accumulation of acetylated histones (H3 & H4) and decreased expression of class I and class II HDACs (1-11), and no expression of multi-drug resistant (MDR) efflux transporters. Moreover, the Vorinostat-resistant HH/VOR cells had elevated DNA binding of NF-κB and increased expression of phospho-NF-κB p65 and phospho-STAT-1 compared with the parent sensitive HH cells. Co-treatment with the RXR-selective retinoid bexarotene selectively enhanced Vorinostat-induced apoptosis in the Vorinostat-sensitive HH and -resistant HH/VOR CTCL cell lines as well as in patients9 Sezary cells compared to normal CD4+ T-cells. Taken together, our findings provide further evidence for the potential of Vorinostat to cause acquisition of HDAC inhibitor resistance in CTCL. This acquired HDAC inhibitor resistance neither correlates with over-expression of HDACs nor with expression of MDR but correlates with abnormal activation of the NF-κB and STAT-1. Bexarotene may override this acquired resistance of CTCL cells to Vorinostat and other HDAC inhibitors. Disclosures Zhang:Merck: Research Funding. Duvic:Merck: Honoraria, Research Funding, Speakers Bureau.

  • Benefits of Vorinostat in Treating Advanced Cutaneous T-cell Lymphoma
    Oral History Review, 2009
    Co-Authors: Chunlei Zhang, Madeleine Duvic
    Abstract:

    Vorinostat (suberoylanilide hydroxamic acid) is the first US Food and Drug Administration (FDA)-approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphomas (CTCLs) who have progressive, persistent, or recurrent disease on or following two systemic therapies. In two phase II trials, Vorinostat was safe and effective at an oral dose of 400mg/day, with an overall response rate of 24‐30% in refractory advanced patients with CTCL including large cell transformation and Sezary syndrome. Most patients with CTCL also experience significant itching relief with Vorinostat therapy. The most frequent side effects of Vorinostat include gastrointestinal symptoms, fatigue, and thrombocytopenia. These side effects are dose-related and reversible upon cessation of therapy. Translational studies have shown that Vorinostat has in vitro and in vivo antitumor activities against CTCL, including selective induction of tumor T-cells, inhibition of angiogenesis, suppression of STATs, and upregulation of proapoptotic proteins. Constitutive activation of STATs may predict Vorinostat resistance in CTCL, and inhibitors of JAK/STAT combined with Vorinostat may help to overcome resistance and improve the clinical response of Vorinostat. Further identification of predictive biomarkers of Vorinostat will help to select patients most likely to benefit from treatment and to develop better combination therapies for patients with CTCL.

  • Benefits of Vorinostat in Treating Advanced Cutaneous T-cell Lymphoma
    Oncology & Hematology Review (US), 2009
    Co-Authors: Chunlei Zhang, Madeleine Duvic
    Abstract:

    Vorinostat (suberoylanilide hydroxamic acid) is the first US Food and Drug Administration (FDA)-approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphomas (CTCLs) who have progressive, persistent, or recurrent disease on or following two systemic therapies. In two phase II trials, Vorinostat was safe and effective at an oral dose of 400mg/day, with an overall response rate of 24–30% in refractory advanced patients with CTCL including large cell transformation and Sézary syndrome. Most patients with CTCL also experience significant itching relief with Vorinostat therapy. The most frequent side effects of Vorinostat include gastrointestinal symptoms, fatigue, and thrombocytopenia. These side effects are dose-related and reversible upon cessation of therapy. Translational studies have shown that Vorinostat hasin vitroandin vivoantitumor activities against CTCL, including selective induction of tumor T-cells, inhibition of angiogenesis, suppression of STATs, and upregulation of proapoptotic proteins. Constitutive activation of STATs may predict Vorinostat resistance in CTCL, and inhibitors of JAK/STAT combined with Vorinostat may help to overcome resistance and improve the clinical response of Vorinostat. Further identification of predictive biomarkers of Vorinostat will help to select patients most likely to benefit from treatment and to develop better combination therapies for patients with CTCL.

  • Vorinostat a new oral histone deacetylase inhibitor approved for cutaneous t cell lymphoma
    Expert Opinion on Investigational Drugs, 2007
    Co-Authors: Madeleine Duvic
    Abstract:

    Epigenetic regulation of gene transcription by small-molecule inhibitors of histone deacetylases (HDACs) is a novel cancer therapy. Vorinostat (suberoylanilide hydroxamic acid) is the first FDA-approved HDAC inhibitor for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL). Vorinostat was active against solid tumors and hematologic malignancies as intravenous and oral preparations in Phase I development. In two Phase II trials, Vorinostat 400 mg/day was safe and effective with an overall response rate of 24 – 30% in refractory advanced patients with CTCL including large cell transformation and Sezary syndrome. The common side effects of Vorinostat, which are similar in all studies, include gastrointestinal symptoms, fatigue and thrombocytopenia and the most common serious event was thrombosis.

Pamela A. Hershberger - One of the best experts on this subject based on the ideXlab platform.

  • Vorinostat increases carboplatin and paclitaxel activity in non‐small cell lung cancer cells
    International journal of cancer, 2010
    Co-Authors: Taofeek K. Owonikoko, Suresh S. Ramalingam, Beatriz Kanterewicz, Trent E. Balius, Chandra P. Belani, Pamela A. Hershberger
    Abstract:

    We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with Vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed in NSCLC cells by MTT assay after 72 h of continuous drug exposure. Vorinostat (1 µM) inhibited growth by: 17±7% in A549, 28±6% in 128-88T, 39±8% in Calu1, and 41±7% in 201T cells. Vorinostat addition to carboplatin or paclitaxel led to significantly greater growth inhibition than chemotherapy alone in all 4 cell lines. Vorinostat (1 µM) synergistically increased the growth inhibitory effects of carboplatin/paclitaxel in 128-88T cells. When colony formation was measured after drug withdrawal, Vorinostat significantly increased the effects of carboplatin but not paclitaxel. The % colony formation was: control 100%; 1 µM Vorinostat 83% ± 10%; 5 µM carboplatin, 41% ± 11%; carboplatin/Vorinostat, 8% ± 4%; 2 nM paclitaxel, 53% ± 11%; paclitaxel/Vorinostat 46% ± 21%. In A549 and 128-88T, Vorinostat potentiated carboplatin induction of gamma-H2AX (a DNA damage marker) and increased α-tubulin acetylation (a marker for stabilized mictrotubules). In A549, combination of Vorinostat with paclitaxel resulted in a synergistic increase in α-tubulin acetylation, which reversed upon drug wash-out. We conclude that Vorinostat interacts favorably with carboplatin and paclitaxel in NSCLC cells, which may explain the provocative response observed in our clinical trial. This likely involves a Vorinostat-mediated irreversible increase in DNA damage in the case of carboplatin and a reversible increase in microtubule stability in the case of paclitaxel.

  • Vorinostat increases carboplatin and paclitaxel activity in non small cell lung cancer cells
    International Journal of Cancer, 2010
    Co-Authors: Taofeek K. Owonikoko, Suresh S. Ramalingam, Beatriz Kanterewicz, Trent E. Balius, Chandra P. Belani, Pamela A. Hershberger
    Abstract:

    We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with Vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed in NSCLC cells by MTT assay after 72 h of continuous drug exposure. Vorinostat (1 µM) inhibited growth by: 17±7% in A549, 28±6% in 128-88T, 39±8% in Calu1, and 41±7% in 201T cells. Vorinostat addition to carboplatin or paclitaxel led to significantly greater growth inhibition than chemotherapy alone in all 4 cell lines. Vorinostat (1 µM) synergistically increased the growth inhibitory effects of carboplatin/paclitaxel in 128-88T cells. When colony formation was measured after drug withdrawal, Vorinostat significantly increased the effects of carboplatin but not paclitaxel. The % colony formation was: control 100%; 1 µM Vorinostat 83% ± 10%; 5 µM carboplatin, 41% ± 11%; carboplatin/Vorinostat, 8% ± 4%; 2 nM paclitaxel, 53% ± 11%; paclitaxel/Vorinostat 46% ± 21%. In A549 and 128-88T, Vorinostat potentiated carboplatin induction of gamma-H2AX (a DNA damage marker) and increased α-tubulin acetylation (a marker for stabilized mictrotubules). In A549, combination of Vorinostat with paclitaxel resulted in a synergistic increase in α-tubulin acetylation, which reversed upon drug wash-out. We conclude that Vorinostat interacts favorably with carboplatin and paclitaxel in NSCLC cells, which may explain the provocative response observed in our clinical trial. This likely involves a Vorinostat-mediated irreversible increase in DNA damage in the case of carboplatin and a reversible increase in microtubule stability in the case of paclitaxel.

Valeria R Fantin - One of the best experts on this subject based on the ideXlab platform.

  • constitutive activation of signal transducers and activators of transcription predicts Vorinostat resistance in cutaneous t cell lymphoma
    Cancer Research, 2008
    Co-Authors: Valeria R Fantin, Andrey Loboda, Cloud P Paweletz, Ronald C Hendrickson, Jacqueline W Pierce, Jennifer Roth, Frank Gooden, Susan Korenchuk, Xiaoli S Hou, Elizabeth A Harrington
    Abstract:

    Vorinostat is a histone deacetylase inhibitor that induces differentiation, growth arrest, and/or apoptosis of malignant cells both in vitro and in vivo and has shown clinical responses in approximately 30% of patients with advanced mycosis fungoides and Sezary syndrome cutaneous T-cell lymphoma (CTCL). The purpose of this study was to identify biomarkers predictive of Vorinostat response in CTCL using preclinical model systems and to assess these biomarkers in clinical samples. The signal transducer and activator of transcription (STAT) signaling pathway was evaluated. The data indicate that persistent activation of STAT1, STAT3, and STAT5 correlate with resistance to Vorinostat in lymphoma cell lines. Simultaneous treatment with a pan-Janus-activated kinase inhibitor resulted in synergistic antiproliferative effect and down-regulation of the expression of several antiapoptotic genes. Immunohistochemical analysis of STAT1 and phosphorylated tyrosine STAT3 (pSTAT3) in skin biopsies obtained from CTCL patients enrolled in the Vorinostat phase IIb trial showed that nuclear accumulation of STAT1 and high levels of nuclear pSTAT3 in malignant T cells correlate with a lack of clinical response. These results suggest that deregulation of STAT activity plays a role in Vorinostat resistance in CTCL, and strategies that block this pathway may improve Vorinostat response. Furthermore, these findings may be of prognostic value in predicting the response of CTCL patients to Vorinostat.

  • Mechanisms of in vitro acquired resistance to Vorinostat (suberoylanilide hydroxamic acid, SAHA)
    Cancer Research, 2007
    Co-Authors: Jennifer Roth, Victoria M Richon, Andrey Loboda, Susan Korenchuk, Theresa Zhang, James Hardwick, Elizabeth Harrington, Valeria R Fantin
    Abstract:

    AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 694 Vorinostat is a histone deacetylase (HDAC) inhibitor that induces differentiation, growth arrest and/or apoptosis of malignant cells both in vitro and in vivo . Vorinostat has demonstrated antitumor activity in both hematological malignancies and solid tumors, including an overall response rate of approximately 30% in cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following 2 systemic therapies. As not all clinical responses are permanent, we developed model systems to investigate the mechanisms of acquired resistance to Vorinostat and used these results to identify rational combination strategies to overcome this clinical issue. Using a dose escalation protocol Vorinostat resistant clones were derived from sensitive HCT116 colon carcinoma cells and A549 non-small cell lung cancer (NSCLC) cells. This method established cell lines that can be maintained in media containing Vorinostat at 2 μM (A549-VR2), 3μM (A549-VR3), 5 μM (A549-VR5) and 8 μM (HCT116-VR8) for a prolonged period of time (3 weeks) without signs of apoptosis. Gene expression profiling was performed on the parental HCT116 cells and Vorinostat-resistant cells. In addition to an unbiased analysis of the data, the status of several pathways possibly related to Vorinostat's mechanism of action were examined. Preliminary analyses revealed alterations in the expression of genes that participate in the apoptotic cascade (e.g. Bcl-2, survivin), protein acetylation (CBP/p300), redox homeostasis (SOD2, metallothionein) and Wnt/ β-catenin signaling pathway (frizzle, β-catenin and cyclin D1). The expression of candidate genes from this analysis was assessed across the panel of Vorinostat-resistant A549 clones. The results indicate that acquired resistance to Vorinostat appears to comprise mechanisms that inhibit the induction of apoptosis, including an increase in antioxidants and in anti-apoptotic Bcl-2 levels. In particular, upregulation of antioxidant enzymes and thiol modulating proteins including SOD2 and metallothioneins have been associated with clinical resistance to cytotoxic drugs and radiation therapy as well as poor prognosis. Future studies will help to address the clinical relevance of these findings. One prediction from this analysis is that compounds that inhibit the glutathione system like buthionine sulfoximine or agents that downregulate or block Bcl-2 could be used to revert these mechanisms of resistance. Combination strategies with emerging treatment modalities may help to increase Vorinostat efficacy in specific genetic contexts.

W. R. Schelman - One of the best experts on this subject based on the ideXlab platform.

  • A phase I study of Vorinostat in combination with bortezomib in refractory solid tumors
    Journal of Clinical Oncology, 2009
    Co-Authors: J. A. Ninan, J. Kolesar, R. Marnocha, J. Eickhoff, D. Alberti, G. Wilding, H. Bailey, J. Wright, I. Espinoza-delgado, W. R. Schelman
    Abstract:

    2531 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an oral histone deacytlase (HDAC) inhibitor that has anti-tumor activity in hematologic malignancies and advanced solid tumors. Vorinostat has been postulated to act synergistically with bortezomib at the level of aggresome inhibition with creation of reactive oxygen species. We previously conducted a study of this combination with once-daily dosing of Vorinostat with bortezomib (Step A). This study (Step B) was conducted to evaluate twice daily dosing of Vorinostat during administration of bortezomib to determine safety and efficacy, pharmacokinetics, and activity this combination. Methods: This study used standard eligibility criteria except patients must have had no prior bortezomib. The treatment plan initially consisted of Vorinostat given orally twice daily on days 1–14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at level 1, and the protocol was amended to administer Vorinostat twice daily on days 1–4 and 8–11. Starting dose was Vorinostat 200 mg and bortezomib 1 mg/m2. RECIST was used to measure response. Results: 29 pts have been enrolled; 13 men and 16 women. Tumor types include: Prostate (1), Colorectal (3), Pancreatic (6), Sarcoma (7), Biliary (1), Thymus (1), GIST (2), Mesothelioma (1), ovarian (1), Neuroendocrine (1), Lung (1), Head and Neck (1), Breast (2), and Cervical (1). Grade 3–4 toxicities possibly related to SAHA at any dose level were as follows: thrombocytopenia (5), fatigue (3), increased ALT (1), elevated INR (1), anemia, (1), hypotension (1), diarrhea (3), anorexia (1), dizziness (1), nausea/vomiting (1), and hypoalbuminemia (1). The only dose limiting toxicities included elevated ALT (1), fatigue (1). There were two deaths but neither was felt to be related to the drug. The MTD for Step B was established at Vorinostat 300 mg BID and bortezomib 1.3 mg/m2. Conclusions: The MTD for Step B was established at Vorinostat 300 mg BID and bortezomib 1.3 mg/m2. Subjective evidence of clinical activity has been observed in patients with refractory solid tumors. These studies were supported by NCI, UO1, CA062491, SAIC 25XS097, and 1ULRR025011. No significant financial relationships to disclose.

  • A phase I study of Vorinostat in combination with bortezomib in refractory solid tumors
    Journal of Clinical Oncology, 2007
    Co-Authors: W. R. Schelman, J. Kolesar, K. Schell, R. Marnocha, J. Eickhoff, D. Alberti, G. Wilding, H. Bailey
    Abstract:

    3573 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase (HDAC) inhibitor that has anti- tumor activity in hematologic malignancies and advanced solid tumors. Based on studies showing that HDAC inhibitors increase the activity of the 26S proteasome, Vorinostat has been postulated to act synergistically with bortezomib. This study was conducted to determine the toxicities and efficacy of Vorinostat with bortezomib. Correlative studies included pharmacokinetics and the effects of Vorinostat/bortezomib on cell cycle, proteasome inhibition, histone acetylation, gene expression and apoptosis. Methods: This study used standard eligibility criteria except pts must have had no prior bortezomib. The treatment plan consisted of Vorinostat given orally on days 1–14 with bortezomib IV on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (Step A, level 1) was once-daily Vorinostat (400 mg) and bortezomib (0.7 mg/m2). Step B consisted of twice-daily dosing of Vorinostat (200mg) with bortezomib at MTD established in Step A. RECIST was used to measure response. Effects on G2/M-phase arrest in buccal mucosa cells (BMC) were measured using flow cytometry. Samples were collected on days 1 and 9, at 0, 2 and 4 hr following treatment. Results: 22 pts have been enrolled; 14 men, 8 women. Tumor types: 5 sarcoma, 5 colorectal, 3 pancreatic, 2 lung, 1 breast, 1 ovarian, 1 bladder, 1 gastric, 1 germ cell, 1 mesothelioma, 1 GIST. Grade 3–4 toxicities at least possibly related to Vorinostat at any dose level were as follows: fatigue (3), n/v (1), thrombocytopenia (1), and hyponatremia (1). One pt was unevaluable. DLTs included fatigue (3), hyponatremia (1) and elevated ALT (1). The MTD for Step A was established at Vorinostat 400mg daily and bortezomib 1.3 mg/m2. One pt with refractory soft tissue sarcoma had a PR > 9 mo. There was no effect on cell cycle arrest observed with Vorinostat in BMCs. Conclusions: The MTD for Step A was established at Vorinostat 400mg daily and bortezomib 1.3 mg/m2. Accrual continues at Step B, dose level 1. Subjective and objective evidence of clinical activity has been observed in pts with refractory solid tumors. (Supported by NCI grant UO1 CA062491, NCI SAIC contract 25XS097 and GCRC M01 RR03186.) No significant financial relationships to disclose.

  • A phase I study of Vorinostat in combination with bortezomib in refractory solid tumors
    Journal of Clinical Oncology, 2007
    Co-Authors: J. A. Ninan, Jill M. Kolesar, R. Marnocha, D. Alberti, G. Wilding, Howard H. Bailey, Jens C. Eickhoff, J. Wright, I. Espinoza-delgado, W. R. Schelman
    Abstract:

    2531 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an oral histone deacytlase (HDAC) inhibitor that has anti-tumor activity in hematologic malignancies and advanced solid tumors. Vorinostat has been postulated to act synergistically with bortezomib at the level of aggresome inhibition with creation of reactive oxygen species. We previously conducted a study of this combination with once-daily dosing of Vorinostat with bortezomib (Step A). This study (Step B) was conducted to evaluate twice daily dosing of Vorinostat during administration of bortezomib to determine safety and efficacy, pharmacokinetics, and activity this combination. Methods: This study used standard eligibility criteria except patients must have had no prior bortezomib. The treatment plan initially consisted of Vorinostat given orally twice daily on days 1–14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at level 1, and the protocol was amended to admini...