Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL)

Duvic, Madeleine; Talpur, Rakshandra; Ni, Xiao; Zhang, Chunlei; Hazarika, Parul; Kelly, Cecelia; Chiao, Judy; Reilly, John F.; Ricker, Justin L.; Richon, Victoria M.; Frankel, Stanley R.

doi:10.1182/blood-2006-06-025999

Cited by 1,024 publications

(760 citation statements)

References 26 publications

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“…Vorinostat is the first of the new HDACi to be approved by Food and Drug Administration for the clinical use in cancer patients, namely the treatment of cutaneous T-cell lymphoma (CTCL) (Duvic et al, 2007;Garber, 2007). In a phase II study with orally administered vorinostat on 33 previously treated patients with refractory cutaneous T-cell lymphoma, partial response were observed in eight patients (24.2%) and 14 of 31 evaluable patients (45.2%) had pruritis relief (Duvic et al, 2007).…”

Section: Clinical Development Of Hdacimentioning

confidence: 99%

“…In preclinical studies, resistance to HDACi-induced transformed cell death was observed in human bladder carcinoma cells (T24) and prostate cancer cells (PC3) (Butler et al, 2000;Richon et al, 2000;Xu et al, 2006). Although vorinostat achieved 24.2% response rate in a phase II trial on CTCL, a considerable proportion of patients with CTCL did not respond well (Duvic et al, 2007). Resistance has been observed in clinical trials with other HDACi in different tumors.…”

Section: The Resistance To Hdacimentioning

confidence: 99%

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Histone deacetylase inhibitors: molecular mechanisms of action

2007

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Section: Clinical Development Of Hdacimentioning

confidence: 99%

Section: The Resistance To Hdacimentioning

confidence: 99%

Histone deacetylase inhibitors: molecular mechanisms of action

2007

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“…Early phase I studies of both vorinostat and romidepsin established their safety and potential efficacy in lymphoproliferative disorders, including CTCL [269], thus paving the way for larger phase II studies. An earlier phase II study established 400 mg of oral vorinostat once daily as the optimal dose that was investigated further in 74 previously treated patients with CTCL, most of whom (>80%) had advanced-stage disease [270,271]. The overall response rate was 30% for patients with advanced-stage disease and was associated with a median duration of response estimated to exceed 185 days.…”

Section: Hdac Inhibitorsmentioning

confidence: 99%

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Wilcox

2011

American J Hematol

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Disease overview: Cutaneous T‐cell lymphomas are a heterogenous group of T‐cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS).Diagnosis: The diagnosis of MF or SS requires the integration of clinical and histopathologic data.Risk‐adapted therapy: Tumor, node, metastasis, and blood (TNMB) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin‐directed therapies is preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic‐response modifiers, denileukin diftitox, and histone deacetylase inhibitors before escalating therapy to include systemic, single‐agent chemotherapy. Multiagent chemotherapy may be used for those patients with extensive visceral involvement requiring rapid disease control. In highly‐selected patients with disease refractory to standard treatments, allogeneic stem‐cell transplantation may be considered. Am. J. Hematol., 2011. © 2011 Wiley‐Liss, Inc.

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“…Several HDAC inhibitors are in clinical development where activity has been observed mainly in haematological malignancies. This has led to the recent approval of vorinostat (SAHA) for the treatment of cutaneous T-cell lymphoma (Duvic et al, 2007).…”

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confidence: 99%

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Arts¹,

Angibaud²,

Marien³

et al. 2007

Br J Cancer

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R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21 waf1,cip1 , a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC 50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.

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Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL)

Cited by 1,024 publications

References 26 publications

Histone deacetylase inhibitors: molecular mechanisms of action

Histone deacetylase inhibitors: molecular mechanisms of action

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

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