Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non–Small Cell Lung Cancer

Gray, Jhanelle E.; Saltos, Andreas; Tanvetyanon, Tawee; Haura, Eric B.; Creelan, Ben; Antonia, Scott; Shafique, Michael; Zheng, Hong; Dai, Wenjie; Saller, James J.; Chen, Zhihua; Tchekmedyian, Nishan; Goas, Kristen; Thapa, Ram; Boyle, Theresa A.; Chen, Dung-Tsa; Beg, Amer A.

doi:10.1158/1078-0432.ccr-19-1305

Cited by 107 publications

(67 citation statements)

References 40 publications

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“…Given that the HDAC inhibitor (HDACi) pembrolizumab is currently in clinical trials for use in lung cancer patients (35), our findings will be helpful to establish clinical study protocols. What is more, our results suggested that HDAC is might act on the immune networks of lung cancer cells, including changes in the profiles of co-stimulatory molecules, costimulatory antigens and cytokines of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

HDAC10 Is Positively Associated With PD-L1 Expression and Poor Prognosis in Patients With NSCLC

Liu¹,

Wang

Zhang

et al. 2020

Front. Oncol.

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Currently, non-small cell lung carcinoma (NSCLC) is a major worldwide health problem. Meanwhile accumulating evidence indicates that histone deacetylase (HDAC) activation could induce PD-L1 expression in various types of cancer, especially in myeloma and B-cell lymphomas. Therefore, we hypothesized that high-level expression of HDAC10 is associated with PD-L1 induction and poor prognosis in patients with NSCLC. In total 180 NSCLC patients receiving complete pulmonary resection and systematic lymph node dissection were enrolled from April 2004 to August 2009. The patients with integrated clinicopathological records were followed up. The expression level of HDAC10 and PD-L1 in tissue samples was determined by immunohistochemistry. We observed that HDAC10 expression in lung cancer tissue is significantly higher than that in corresponding paracancer tissue. Moreover, HDAC10 expression positively correlated with the expression level of PD-L1 (r = 0.213, P < 0.05) in NSCLC patients. Subgroup, multivariate analysis showed that the expression level of HDAC10 can be an independent prognostic factor and high-level expression of HDAC10 indicated poor overall survival for pulmonary carcinoma (r = 0.540, P < 0.001). Our findings suggest that the expression level of HDAC10 is positively associated with PD-L1 expression and may predict the outcome of patients with NSCLC.

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Section: Discussionmentioning

confidence: 99%

HDAC10 Is Positively Associated With PD-L1 Expression and Poor Prognosis in Patients With NSCLC

Liu¹,

Wang

Zhang

et al. 2020

Front. Oncol.

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“…No significant correlation was found between peripheral blood MDSCs and response rates upon treatment, probably because of the small sample number. Patients with NSCLC showed higher levels of MDSCs than heathy donors [ 238 ].…”

Section: Combination Strategiesmentioning

confidence: 99%

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

124

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The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

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“…Due to the relevance of HDAC/HAT pathways in regulating the immune system, HDACis have been considered as immunomodulatory agents (Banik et al, 2019), thus they have been combined with ICIs. Pembrolizumab (an anti-PD1 inhibitor) with vorinostat was well-tolerated in advanced/metastatic non-small cell lung cancer and anti-tumor activity was demonstrated (Gray et al, 2019). Another combination strategy is the use of antibodies, anti-PD-1 or anti-CTLA-4.…”

Section: Pan-hdacis In Combination With Immunotherapymentioning

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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Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non–Small Cell Lung Cancer

Cited by 107 publications

References 40 publications

HDAC10 Is Positively Associated With PD-L1 Expression and Poor Prognosis in Patients With NSCLC

HDAC10 Is Positively Associated With PD-L1 Expression and Poor Prognosis in Patients With NSCLC

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

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

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