Repurposing anticancer drugs for COVID-19-induced inflammation, immune dysfunction, and coagulopathy

Saini, Kamal S; Lucchesi, Carlo; Romano, Marco; Azambuja, Evandro de; Cortés, Javier; Heras, Begoña de las; Castro, Javier de; Saini, Monika; Loibl, Sibylle; Curigliano, Giuseppe; Twelves, Chris; Leone, Manuela; Patnaik, Mrinal M.

doi:10.1038/s41416-020-0948-x

Cited by 42 publications

(46 citation statements)

References 17 publications

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“…A global analysis found a 60% decrease in enrollment of new patients in oncology clinical trials in April 2020 compared with April 2019 [37]. On the other hand, a large number of COVID-19-related clinical trials have been launched, many of them testing repurposed anticancer drugs [38].…”

Section: Impact Of the Pandemic On Cancer Trialsmentioning

confidence: 99%

Cancer Treatment and Research During the COVID-19 Pandemic: Experience of the First 6 Months

et al. 2020

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The coronavirus disease-2019 (COVID-19) pandemic has had a significant impact on patients with underlying malignancy. In this article, we summarize emerging data related to patients with cancer and COVID-19. Among patients with COVID-19, a higher proportion have an underlying diagnosis of cancer than seen in the general population. Also, patients with malignancy are likely to be more vulnerable than the general population to contracting COVID-19. Mortality is significantly higher in patients with both cancer and COVID-19 compared with the Digital Features To view digital features for this article go to

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Section: Impact Of the Pandemic On Cancer Trialsmentioning

confidence: 99%

Cancer Treatment and Research During the COVID-19 Pandemic: Experience of the First 6 Months

et al. 2020

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“…Because of its profound impact on society and human health there is an urgent need to understand SARS-CoV-2 replication requirements and to identify therapeutic strategies 2 . Repurposing drugs developed for other purposes may provide a shortcut to therapeutic development [3][4][5][6] . The use of compounds known to target specific host factors may also elucidate key pathways needed for virus replication.…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

Silvas

Jureka

Nicolini

et al. 2020

Preprint

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Therapeutics targeting replication of SARS coronavirus 2 (SARS-CoV-2) are urgently needed. Coronaviruses rely on host membranes for entry, establishment of replication centers and egress. Compounds targeting cellular membrane biology and lipid biosynthetic pathways have previously shown promise as antivirals and are actively being pursued as treatments for other conditions. Here, we tested small molecule inhibitors that target membrane dynamics or lipid metabolism. Included were inhibitors of the PI3 kinase VPS34, which functions in autophagy, endocytosis and other processes; Orlistat, an inhibitor of lipases and fatty acid synthetase, is approved by the FDA as a treatment for obesity; and Triacsin C which inhibits long chain fatty acyl-CoA synthetases. VPS34 inhibitors, Orlistat and Triacsin C inhibited virus growth in Vero E6 cells and in the human airway epithelial cell line Calu-3, acting at a post-entry step in the virus replication cycle. Of these the VPS34 inhibitors exhibit the most potent activity.

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“…Studying these changes in this population may be particularly relevant because 'important manifestations of severe COVID-19 infection are shared with neoplasia, namely inflammation, immune dysfunction, and coagulopathy'. 16 In select patients with available data, we also evaluated associated changes in immune subsets by flow cytometry and serum cytokine levels.…”

Section: Introductionmentioning

confidence: 99%

Early changes in immune cell subsets with corticosteroids in patients with solid tumors: implications for COVID-19 management

Marté

Toney

Cordes

et al. 2020

J Immunother Cancer

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BackgroundThe risk–benefit calculation for corticosteroid administration in the management of COVID-19 is complex and urgently requires data to inform the decision. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation associated with poor prognosis in both COVID-19 and cancer. Investigating NLR as an inflammatory marker and lymphocyte levels as a critical component of antiviral immunity may inform the dilemma of reducing toxic hyperinflammation while still maintaining effective antiviral responses.MethodsWe performed a retrospective analysis of NLR, absolute neutrophil counts (ANCs) and absolute lymphocyte counts (ALCs) in patients with cancer enrolled in immunotherapy trials who received moderate-dose to high-dose corticosteroids. We compared paired presteroid and available poststeroid initiation values daily during week 1 and again on day 14 using the Wilcoxon signed-rank test. Associated immune subsets by flow cytometry were included where available.ResultsPatients (n=48) with a variety of solid tumors received prednisone, methylprednisolone, or dexamethasone alone or in combination in doses ranging from 20 to 190 mg/24 hours (prednisone equivalent). The median NLR prior to steroid administration was elevated at 5.0 (range: 0.9–61.2). The corresponding median ANC was 5.1 K/µL (range: 2.03–22.31 K/µL) and ALC was 1.03 K/µL (0.15–2.57 K/µL). One day after steroid administration, there was a significant transient drop in median ALC to 0.54 K/µL (p=0.0243), driving an increase in NLR (median 10.8, p=0.0306). Relative lymphopenia persisted through day 14 but was no longer statistically significant. ANC increased steadily over time, becoming significant at day 4 (median: 7.31 K/µL, p=0.0171) and remaining significantly elevated through day 14. NLR was consistently elevated after steroid initiation, significantly at days 1, 7 (median: 8.2, p=0.0272), and 14 (median: 15.0, p=0.0018). Flow cytometry data from 11 patients showed significant decreases in activated CD4 cells and effector memory CD8 cells.ConclusionsThe early drop in ALC with persistent lymphopenia as well as the prolonged ANC elevation seen in response to corticosteroid administration are similar to trends associated with increased mortality in several coronavirus studies to include the current SARS-CoV-2 pandemic. The affected subsets are essential for effective antiviral immunity. This may have implications for glucocorticoid therapy for COVID-19.

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Repurposing anticancer drugs for COVID-19-induced inflammation, immune dysfunction, and coagulopathy

Cited by 42 publications

References 17 publications

Cancer Treatment and Research During the COVID-19 Pandemic: Experience of the First 6 Months

Cancer Treatment and Research During the COVID-19 Pandemic: Experience of the First 6 Months

Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

Early changes in immune cell subsets with corticosteroids in patients with solid tumors: implications for COVID-19 management

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