The HDAC Inhibitor Domatinostat Promotes Cell-Cycle Arrest, Induces Apoptosis, and Increases Immunogenicity of Merkel Cell Carcinoma Cells

Song, Lina; Bretz, Anne Catherine; Gravemeyer, Jan; Spassova, Ivelina; Muminova, Shakhlo; Gambichler, Thilo; Sriram, Ashwin; Ferrone, Soldano; Becker, Jürgen C.

doi:10.1016/j.jid.2020.08.023

Cited by 35 publications

(42 citation statements)

References 52 publications

(63 reference statements)

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“…Beyond available immunotherapies and chemotherapies for advanced MCC, innovative clinical trial development is needed to address or prevent anti-PD-(L)1-refractory disease. Diverse approaches to address this problem include the addition of anti-CTLA-4 to anti-PD-(L)1, 45 toll-like receptor agonists, 46 histone deacetylase inhibitors 47 and oncolytic virotherapy. 48 In particular, infusion of MCPyV-specific T cells combined with immune checkpoint inhibitors may reduce the chance of tumor escape by boosting T cell numbers, increasing diversity of T cell responses and augmenting terminally exhausted T cells (NCT03747484).…”

Section: Discussionmentioning

confidence: 99%

Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma

Nghiem

Bhatia

Lipson

et al. 2021

J Immunother Cancer

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BackgroundMerkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017.MethodsIn this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months.ResultsOverall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies.ConclusionsThis study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority.Trial registration numberNCT02267603.

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Section: Discussionmentioning

confidence: 99%

Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma

Nghiem

Bhatia

Lipson

et al. 2021

J Immunother Cancer

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“…Song and colleagues performed a preclinical analysis of the efficacy and mode of action of dominostat for MCC [ 128 ]. Their results suggest dominostat can upregulate antigen-processing machinery, resulting in increased MHC1 expression.…”

Section: Treatmentmentioning

confidence: 99%

Merkel Cell Carcinoma of the Head and Neck: Epidemiology, Pathogenesis, Current State of Treatment and Future Directions

Yusuf

McKenzie

Rattani

et al. 2021

Cancers

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Merkel cell carcinoma (MCC) is a rare, cutaneous neuroendocrine malignancy with increasing incidence. The skin of the head and neck is a common subsite for MCC with distinctions in management from other anatomic areas. Given the rapid pace of developments regarding MCC pathogenesis (Merkel cell polyoma virus (MCPyV)-positive or virus-negative, cell of origin), diagnosis, staging and treatment, and up to date recommendations are critical for optimizing outcomes. This review aims to summarize currently available literature for MCC of the head and neck. The authors reviewed current literature, including international guidelines regarding MCC pathogenesis, epidemiology, diagnosis, staging, and treatment. Subsequently recommendations were derived including the importance of baseline imaging, MCPyV serology testing, primary site surgery, nodal evaluation, radiotherapy, and the increasing role of immune modulating agents in MCC. MCPyV serology testing is increasingly important with potential distinctions in treatment response and surveillance between virus-positive and virus-negative MCC. Surgical management continues to balance optimizing local control with minimal morbidity. Similarly, radiotherapy continues to have importance in the adjuvant, definitive, and palliative setting for MCC of the head and neck. Immunotherapy has changed the paradigm for advanced MCC, with increasing work focusing on optimizing outcomes for non-responders and high-risk patients, including those with immunosuppression.

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“…Published reports hint that cell cycle regulators are potential therapeutic targets in MCC [23]. However, the therapeutic efficacy of FDA-approved CDK4/6 inhibitors in MCC is limited due to frequent loss of RB1 function in MCC either by an inactivating mutation or MCPyV large antigen integration.…”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

Das

Kannan

Nguyen

et al. 2021

Cancers

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Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.

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The HDAC Inhibitor Domatinostat Promotes Cell-Cycle Arrest, Induces Apoptosis, and Increases Immunogenicity of Merkel Cell Carcinoma Cells

Cited by 35 publications

References 52 publications

Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma

Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma

Merkel Cell Carcinoma of the Head and Neck: Epidemiology, Pathogenesis, Current State of Treatment and Future Directions

Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

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