A phase 1 trial of Vorinostat in combination with concurrent chemoradiation therapy in the treatment of advanced staged head and neck squamous cell carcinoma

Teknos, Theodoros N.; Grecula, J.C.; Agrawal, Amit; Old, Matthew; Özer, Enver; Carrau, R.; Kang, Seok-Young; Rocco, James W.; Blakaj, Duk M; Diavolitsis, V.M.; Kumar, Bhavna; Kumar, Pawan; Pan, Quintin; Palettas, Marilly; Wei, Lai; Baiocchi, Robert A.; Savvides, Panos

doi:10.1007/s10637-018-0696-4

Cited by 37 publications

(27 citation statements)

References 73 publications

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“…A major concept in EMT-targeting therapy is its reversal. This has been achieved by the histone deacetylase inhibitor, vorinostat [12,132]. In a novel phase I clinical trial by Teknos et al [132], in stage III IVa and IVb head and neck cancer, vorinostat with concurrent chemoradiation achieved a 96.2% complete response rate (Table 1).…”

Section: Therapeutic Targeting Of the Emt Fueling Radio/chemoresistancementioning

confidence: 99%

Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance

Dudás

Ladányi

Ingruber

et al. 2020

Cells

138

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Epithelial to mesenchymal transition (EMT) contributes to tumor progression, cancer cell invasion, and therapy resistance. EMT is regulated by transcription factors such as the protein products of the SNAI gene family, which inhibits the expression of epithelial genes. Several signaling pathways, such as TGF-beta1, IL-6, Akt, and Erk1/2, trigger EMT responses. Besides regulatory transcription factors, RNA molecules without protein translation, micro RNAs, and long non-coding RNAs also assist in the initialization of the EMT gene cluster. A challenging novel aspect of EMT research is the investigation of the interplay between tumor microenvironments and EMT. Several microenvironmental factors, including fibroblasts and myofibroblasts, as well as inflammatory, immune, and endothelial cells, induce EMT in tumor cells. EMT tumor cells change their adverse microenvironment into a tumor friendly neighborhood, loaded with stromal regulatory T cells, exhausted CD8+ T cells, and M2 (protumor) macrophages. Several EMT inhibitory mechanisms are instrumental in reversing EMT or targeting EMT cells. Currently, these mechanisms are also significant for clinical use.

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Section: Therapeutic Targeting Of the Emt Fueling Radio/chemoresistancementioning

confidence: 99%

Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance

Dudás

Ladányi

Ingruber

et al. 2020

Cells

138

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“…A study in phase I in patients with relapsed or refractory neuroblastoma showed that vorinostat combined with a radiosensitizer such as 131I-Metaiodobenzylguanidine (131I-MIBG) was well-tolerated by patients (NCT01019850) ( DuBois et al, 2015 ). Similarly, vorinostat in combination with chemoradiation therapy in phase I trial of neck squamous cell carcinoma patients was found to be safe and highly effective ( Teknos et al, 2019 ). Preclinical studies using SAHA combined with radiation have demonstrated an increase in tumor radiosensitivity in vitro and in vivo and a subsequent induction of apoptotic response in, for example, pancreatic adenocarcinoma cancer cell lines ( Moertl et al, 2019 ).…”

Section: Pan-hdacis In Combinationmentioning

confidence: 99%

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials

et al. 2020

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Chemotherapy is one of the most established and effective treatments for almost all types of cancer. However, the elevated toxicity due to the non-tumor-associated effects, development of secondary malignancies, infertility, radiation-induced fibrosis and resistance to treatment limit the effectiveness and safety of treatment. In addition, these multiple factors significantly impact quality of life. Over the last decades, our increased understanding of cancer epigenetics has led to new therapeutic approaches and the promise of improved patient outcomes. Epigenetic alterations are commonly found in cancer, especially the increased expression and activity of histone deacetylases (HDACs). Dysregulation of HDACs are critical to the development and progression of the majority of tumors. Hence, HDACs inhibitors (HDACis) were developed and now represent a very promising treatment strategy. The use of HDACis as monotherapy has shown very positive pre-clinical results, but clinical trials have had only limited success. However, combinatorial regimens with other cancer drugs have shown synergistic effects both in pre-clinical and clinical studies. At the same time, these combinations have enhanced the efficacy, reduced the toxicity and tumor resistance to therapy. In this review, we will examine examples of HDACis used in combination with other cancer drugs and highlight the synergistic effects observed in recent preclinical and clinical studies.

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“…Few clinical trials investigating the potential of HDACi in HNSCC have been reported or are currently ongoing, with limited activity as single agents, but with promising results in combination therapy ( Haigentz et al, 2012 ; Teknos et al, 2019 ). In detail, a recently concluded phase I trial reported the feasibility and the efficacy of vorinostat in combination with concurrent standard chemo-radiation in HNSCC patients, suggesting further investigations in phase II/III trials for this combination ( Teknos et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

Iannelli

Zotti

Roca

et al. 2020

Front. Cell Dev. Biol.

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Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with high toxicity and resistance, suggesting that new combinatorial strategies are needed to improve its therapeutic index. In our study, we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different 3D-self-assembled spheroid models, suggesting the ability of the combined approach to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced DNA damage in combination treatment by reducing the mRNA expression of ERCC Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular concentration via upregulation at transcriptional level of CDDP influx channel copper transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export. Valproic acid also induced a dose-dependent downregulation of epidermal growth factor receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also in vivo in both heterotopic and orthotopic models, demonstrating that the combined treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall, the introduction of a safe and generic drug such as VPA into the conventional treatment for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants further clinical evaluation. A phase II clinical trial exploring the combination of VPA and CDDP/CX in R/M HNSCC patients is currently ongoing in our institute.

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A phase 1 trial of Vorinostat in combination with concurrent chemoradiation therapy in the treatment of advanced staged head and neck squamous cell carcinoma

Cited by 37 publications

References 73 publications

Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance

Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

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