A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors

Deming, Dustin A.; Ninan, Jacob; Bailey, Howard; Kolesar, Jill; Eickhoff, Jens; Reid, Joel M.; Ames, Matthew M.; McGovern, Renee M.; Alberti, Dona; Marnocha, Rebecca; Espinoza‐Delgado, Igor; Wright, John J.; Wilding, George; Schelman, William R.

doi:10.1007/s10637-013-0035-8

Cited by 39 publications

(22 citation statements)

References 16 publications

(14 reference statements)

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“…However, the strategy of inducing ER stress could be applied clinically by carefully undertaking a phase I trial. The vorinostat–bortezomib combination was shown to induce robust ER stress but has been proven to be safe to be given to patients …”

Section: Discussionmentioning

confidence: 99%

“…The vorinostat-bortezomib combination was shown to induce robust ER stress (7) but has been proven to be safe to be given to patients. (24)(25)(26)(27) In clinical settings, response to the combination of ritonavir and ixazomib may differ among the patients. Therefore, finding biomarkers that predict the combination's efficacy would be helpful in selecting the patients who would most benefit from its use.…”

Section: Discussionmentioning

confidence: 99%

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Ritonavir and ixazomib kill bladder cancer cells by causing ubiquitinated protein accumulation

et al. 2017

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There is no curative treatment for advanced bladder cancer. Causing ubiquitinated protein accumulation and endoplasmic reticulum stress is a novel approach to cancer treatment. The HIV protease inhibitor ritonavir has been reported to suppress heat shock protein 90 and increase the amount of unfolded proteins in the cell. If the proteasome functions normally, however, they are rapidly degraded. We postulated that the novel proteasome inhibitor ixazomib combined with ritonavir would kill bladder cancer cells effectively by inhibiting degradation of these unfolded proteins and thereby causing ubiquitinated proteins to accumulate. The combination of ritonavir and ixazomib induced drastic apoptosis and inhibited the growth of bladder cancer cells synergistically. The combination decreased the expression of cyclin D1 and cyclin‐dependent kinase 4, and increased the sub‐G1 fraction significantly. Mechanistically, the combination caused ubiquitinated protein accumulation and endoplasmic reticulum stress. The combination‐induced apoptosis was markedly attenuated by the protein synthesis inhibitor cycloheximide, suggesting that the accumulation of ubiquitinated proteins played an important role in the combination's antineoplastic activity. Furthermore, the combination induced histone acetylation cooperatively and the decreased expression of histone deacetylases was thought to be one mechanism of this histone acetylation. The present study provides a theoretical basis for future development of novel ubiquitinated‐protein‐accumulation‐based therapies effective against bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ritonavir and ixazomib kill bladder cancer cells by causing ubiquitinated protein accumulation

et al. 2017

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“…A later study from the same center was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Stable disease was found in two pre-treated sarcoma patients 120 .…”

Section: Clinical Trials Of Hdis In Sarcomamentioning

confidence: 95%

Therapeutic applications of histone deacetylase inhibitors in sarcoma

Tang

Choy

et al. 2017

Cancer Treatment Reviews

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Sarcomas are a rare group of malignant tumors originating from mesenchymal stem cells. Surgery, radiation and chemotherapy are currently the only standard treatments for sarcoma. However, their response rates to chemotherapy are quite low. Toxic side effects and multi-drug chemoresistance make treatment even more challenging. Therefore, better drugs to treat sarcomas are needed. Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are epigenetic modifying agents that can inhibit sarcoma growth in vitro and in vivo through a variety of pathways, including inducing tumor cell apoptosis, causing cell cycle arrest, impairing tumor invasion and preventing metastasis. Importantly, preclinical studies have revealed that HDIs can not only sensitize sarcomas to chemotherapy and radiotherapy, but also increase treatment responses when combined with other chemotherapeutic drugs. Several phase I and II clinical trials have been conducted to assess the efficacy of HDIs either as monotherapy or in combination with standard chemotherapeutic agents or targeted therapeutic drugs for sarcomas. Combination regimen for sarcomas appear to be more promising than monotherapy when using HDIs. This review summarizes our current understanding and therapeutic applications of HDIs in sarcomas.

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“…Moreover, bortezomib, which is an anti-NF-κB drug in clinical use, and HDAC inhibitor together have synergistic effect against cell lines of pancreatic cancer and HCC (12). Combination of SAHA and bortezomib has been tested in phase I clinical trials for advanced solid tumors (18,19).…”

Section: Introductionmentioning

confidence: 99%

Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling

Hsu¹,

Liu²,

Chiang

et al. 2014

International Journal of Oncology

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Sorafenib is effective for patients with advanced hepatocellular carcinoma (HCC) and particularly for those who are unsuitable to receive life-prolonging transarterial chemo-embolization. The survival benefit of sorafenib, however, is unsatisfactory. Vorinostat also known as suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor with anti-HCC efficacy in preclinical studies. SAHA induces nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in vitro, which may lead to cancer cell progression and jeopardize cytotoxic effect of SAHA in HCC. The goal of this study was to investigate whether sorafenib enhances SAHA cytotoxicity against HCC through inhibition of SAHA-induced NF-κB activity. The human HCC cell line Huh7 transfected with dual reporter genes, luciferase (luc) and thymidine kinase (tk) with NF-κB response elements, was co-transfected with red fluorescent protein (rfp) gene for non-invasive molecular imaging to assess NF-κB activity and living cells simultaneously. Cell viability assay, DNA fragmentation, western blotting, electrophoretic mobility shift assay (EMSA) and multiple modalities of molecular imaging were used to assess the combination efficacy and mechanism of sorafenib and SAHA. The administration of high-dose SAHA (10 µM) with long treatment time (48 h) in vitro, and 25 mg/kg/day by gavage in HCC-bearing nude mice to induce NF-κB activity were performed. Sorafenib inhibited SAHA-induced NF-κB activity and the expression of NF-κB-regulated effector proteins while it increased the efficacy of SAHA against HCC both in vitro and in vivo. The mechanism of sorafenib to enhance SAHA efficacy on HCC is through the suppression of ERK/NF-κB pathway, which induces extrinsic and intrinsic apoptosis. Combination of sorafenib and SAHA may have the potential as new strategy against HCC.

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A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors

Cited by 39 publications

References 16 publications

Ritonavir and ixazomib kill bladder cancer cells by causing ubiquitinated protein accumulation

Ritonavir and ixazomib kill bladder cancer cells by causing ubiquitinated protein accumulation

Therapeutic applications of histone deacetylase inhibitors in sarcoma

Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling

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