Importance: Novel therapies for SARS-CoV-2 infection are urgently needed. Antineoplastic compounds that target cellular machinery used by SARS-CoV-2 for entry and replication, including angiotensin-converting enzyme 2 (ACE2), may disrupt SARS-CoV-2 activity. Objectives: To determine whether patients with cancer treated with potential ACE2-lowering antineoplastic compounds exhibit lower SARS-CoV-2 infection rates. Design, Setting, and Participants: We used the Library of Integrated Network-Based Cellular Signatures database to identify antineoplastic compounds associated with decreased ACE2 gene expression across cell lines. We then evaluated a retrospective cohort of 1701 patients who were undergoing antineoplastic therapy at Memorial Sloan Kettering Cancer Center in New York, New York, during the COVID-19 pandemic to determine if treatment with an ACE2-lowering antineoplastic was associated with a decreased odds ratio (OR) of SARS-CoV-2 infection. Patients included in the analysis underwent active treatment for cancer and received a SARS-CoV-2 test between March 10 and May 28, 2020. Main Outcome and Measure: The association between potential ACE2-lowering antineoplastic treatment and a positive SARS-CoV-2 test. Results: In the cohort of 1701 patients, SARS-CoV-2 infection rates were determined for 949 (55.8%) female and 752 (44.2%) male patients (mean [SD] age, 63.1 [13.1] years) with diverse cancers receiving antineoplastic therapy. In silico analysis of gene expression signatures after drug treatment identified 91 compounds associated with downregulation of ACE2 across cell lines. Of the total cohort, 215 (12.6%) patients were treated with 8 of these compounds, including 3 mTOR/PI3K inhibitors and 2 antimetabolites. In a multivariable analysis of patients who received an ACE2-lowering antineoplastic adjusting for confounders, 15 of 215 (7.0%) patients had a positive SARS-CoV-2 test compared with 191 of 1486 (12.9%) patients who received other antineoplastic therapies (OR, 0.53; 95% CI, 0.29-0.88). Findings were confirmed in additional sensitivity analyses including cancer type, steroid use, and a propensity-matched subcohort. Gemcitabine treatment was associated with reduced SARS-CoV-2 infection (OR, 0.42; 95% CI, 0.17-0.87). Conclusions and Relevance: In this cohort study, in silico analysis of drug-associated gene expression signatures identified potential ACE2-lowering antineoplastic compounds, including mTOR/PI3K inhibitors and antimetabolites. Patients who received these compounds exhibited statistically significantly lower rates of SARS-CoV-2 infection compared with patients given other antineoplastics. Further evaluation of the biological and clinical anti-SARS-CoV-2 properties of identified antineoplastic compounds is warranted.
Importance: Novel therapies for SARS-CoV-2 infection are urgently needed. Antineoplastic compounds that target cellular machinery used by SARS-CoV-2 for entry and replication, including angiotensin-converting enzyme 2 (ACE2), may disrupt SARS-CoV-2 activity. Objectives: To determine whether patients with cancer treated with potential ACE2-lowering antineoplastic compounds exhibit lower SARS-CoV-2 infection rates. Design, Setting, and Participants: We used the Library of Integrated Network-Based Cellular Signatures database to identify antineoplastic compounds associated with decreased ACE2 gene expression across cell lines. We then evaluated a retrospective cohort of 1701 patients who were undergoing antineoplastic therapy at Memorial Sloan Kettering Cancer Center in New York, New York, during the COVID-19 pandemic to determine if treatment with an ACE2-lowering antineoplastic was associated with a decreased odds ratio (OR) of SARS-CoV-2 infection. Patients included in the analysis underwent active treatment for cancer and received a SARS-CoV-2 test between March 10 and May 28, 2020. Main Outcome and Measure: The association between potential ACE2-lowering antineoplastic treatment and a positive SARS-CoV-2 test. Results: In the cohort of 1701 patients, SARS-CoV-2 infection rates were determined for 949 (55.8%) female and 752 (44.2%) male patients (mean [SD] age, 63.1 [13.1] years) with diverse cancers receiving antineoplastic therapy. In silico analysis of gene expression signatures after drug treatment identified 91 compounds associated with downregulation of ACE2 across cell lines. Of the total cohort, 215 (12.6%) patients were treated with 8 of these compounds, including 3 mTOR/PI3K inhibitors and 2 antimetabolites. In a multivariable analysis of patients who received an ACE2-lowering antineoplastic adjusting for confounders, 15 of 215 (7.0%) patients had a positive SARS-CoV-2 test compared with 191 of 1486 (12.9%) patients who received other antineoplastic therapies (OR, 0.53; 95% CI, 0.29-0.88). Findings were confirmed in additional sensitivity analyses including cancer type, steroid use, and a propensity-matched subcohort. Gemcitabine treatment was associated with reduced SARS-CoV-2 infection (OR, 0.42; 95% CI, 0.17-0.87). Conclusions and Relevance: In this cohort study, in silico analysis of drug-associated gene expression signatures identified potential ACE2-lowering antineoplastic compounds, including mTOR/PI3K inhibitors and antimetabolites. Patients who received these compounds exhibited statistically significantly lower rates of SARS-CoV-2 infection compared with patients given other antineoplastics. Further evaluation of the biological and clinical anti-SARS-CoV-2 properties of identified antineoplastic compounds is warranted.
Authors: Julie Dyall; Christopher M Coleman; Brit J Hart; Thiagarajan Venkataraman; Michael R Holbrook; Jason Kindrachuk; Reed F Johnson; Gene G Olinger; Peter B Jahrling; Monique Laidlaw; Lisa M Johansen; Calli M Lear-Rooney; Pamela J Glass; Lisa E Hensley; Matthew B Frieman Journal: Antimicrob Agents Chemother Date: 2014-05-19 Impact factor: 5.191
Authors: Basil S Karam; Rachel S Morris; Carolyn T Bramante; Michael Puskarich; Emily J Zolfaghari; Sahar Lotfi-Emran; Nicholas E Ingraham; Anthony Charles; David J Odde; Christopher J Tignanelli Journal: J Med Virol Date: 2020-12-17 Impact factor: 2.327
Authors: Alexandra B Keenan; Sherry L Jenkins; Kathleen M Jagodnik; Simon Koplev; Edward He; Denis Torre; Zichen Wang; Anders B Dohlman; Moshe C Silverstein; Alexander Lachmann; Maxim V Kuleshov; Avi Ma'ayan; Vasileios Stathias; Raymond Terryn; Daniel Cooper; Michele Forlin; Amar Koleti; Dusica Vidovic; Caty Chung; Stephan C Schürer; Jouzas Vasiliauskas; Marcin Pilarczyk; Behrouz Shamsaei; Mehdi Fazel; Yan Ren; Wen Niu; Nicholas A Clark; Shana White; Naim Mahi; Lixia Zhang; Michal Kouril; John F Reichard; Siva Sivaganesan; Mario Medvedovic; Jaroslaw Meller; Rick J Koch; Marc R Birtwistle; Ravi Iyengar; Eric A Sobie; Evren U Azeloglu; Julia Kaye; Jeannette Osterloh; Kelly Haston; Jaslin Kalra; Steve Finkbiener; Jonathan Li; Pamela Milani; Miriam Adam; Renan Escalante-Chong; Karen Sachs; Alex Lenail; Divya Ramamoorthy; Ernest Fraenkel; Gavin Daigle; Uzma Hussain; Alyssa Coye; Jeffrey Rothstein; Dhruv Sareen; Loren Ornelas; Maria Banuelos; Berhan Mandefro; Ritchie Ho; Clive N Svendsen; Ryan G Lim; Jennifer Stocksdale; Malcolm S Casale; Terri G Thompson; Jie Wu; Leslie M Thompson; Victoria Dardov; Vidya Venkatraman; Andrea Matlock; Jennifer E Van Eyk; Jacob D Jaffe; Malvina Papanastasiou; Aravind Subramanian; Todd R Golub; Sean D Erickson; Mohammad Fallahi-Sichani; Marc Hafner; Nathanael S Gray; Jia-Ren Lin; Caitlin E Mills; Jeremy L Muhlich; Mario Niepel; Caroline E Shamu; Elizabeth H Williams; David Wrobel; Peter K Sorger; Laura M Heiser; Joe W Gray; James E Korkola; Gordon B Mills; Mark LaBarge; Heidi S Feiler; Mark A Dane; Elmar Bucher; Michel Nederlof; Damir Sudar; Sean Gross; David F Kilburn; Rebecca Smith; Kaylyn Devlin; Ron Margolis; Leslie Derr; Albert Lee; Ajay Pillai Journal: Cell Syst Date: 2017-11-29 Impact factor: 10.304
Authors: Justin Jee; Michael B Foote; Melissa Lumish; Aaron J Stonestrom; Beatriz Wills; Varun Narendra; Viswatej Avutu; Yonina R Murciano-Goroff; Jason E Chan; Andriy Derkach; John Philip; Rimma Belenkaya; Marina Kerpelev; Molly Maloy; Adam Watson; Chris Fong; Yelena Janjigian; Luis A Diaz; Kelly L Bolton; Melissa S Pessin Journal: J Clin Oncol Date: 2020-08-14 Impact factor: 44.544
Authors: Mark Roschewski; Michail S Lionakis; Jeff P Sharman; Joseph Roswarski; Andre Goy; M Andrew Monticelli; Michael Roshon; Stephen H Wrzesinski; Jigar V Desai; Marissa A Zarakas; Jacob Collen; Keith Rose; Ahmed Hamdy; Raquel Izumi; George W Wright; Kevin K Chung; Jose Baselga; Louis M Staudt; Wyndham H Wilson Journal: Sci Immunol Date: 2020-06-05
Authors: Alexandra C Walls; Young-Jun Park; M Alejandra Tortorici; Abigail Wall; Andrew T McGuire; David Veesler Journal: Cell Date: 2020-03-09 Impact factor: 41.582
Authors: Jin Wei; Mia Madel Alfajaro; Peter C DeWeirdt; Ruth E Hanna; William J Lu-Culligan; Wesley L Cai; Madison S Strine; Shang-Min Zhang; Vincent R Graziano; Cameron O Schmitz; Jennifer S Chen; Madeleine C Mankowski; Renata B Filler; Neal G Ravindra; Victor Gasque; Fernando J de Miguel; Ajinkya Patil; Huacui Chen; Kasopefoluwa Y Oguntuyo; Laura Abriola; Yulia V Surovtseva; Robert C Orchard; Benhur Lee; Brett D Lindenbach; Katerina Politi; David van Dijk; Cigall Kadoch; Matthew D Simon; Qin Yan; John G Doench; Craig B Wilen Journal: Cell Date: 2020-10-20 Impact factor: 66.850
Authors: Michael P Wilczek; Francesca J Armstrong; Colleen L Mayberry; Benjamin L King; Melissa S Maginnis Journal: Cells Date: 2021-11-18 Impact factor: 6.600
Authors: Christophe Deben; Maxim Le Compte; Vasiliki Siozopoulou; Hilde Lambrechts; Christophe Hermans; Ho Wa Lau; Manon Huizing; Kevin Lamote; Jeroen M H Hendriks; Peter Van Dam; Patrick Pauwels; Evelien L J Smits; Marc Peeters; Filip Lardon Journal: Cancers (Basel) Date: 2022-08-23 Impact factor: 6.575
Authors: Halie M Rando; Adam L MacLean; Alexandra J Lee; Ronan Lordan; Sandipan Ray; Vikas Bansal; Ashwin N Skelly; Elizabeth Sell; John J Dziak; Lamonica Shinholster; Lucy D'Agostino McGowan; Marouen Ben Guebila; Nils Wellhausen; Sergey Knyazev; Simina M Boca; Stephen Capone; Yanjun Qi; YoSon Park; David Mai; Yuchen Sun; Joel D Boerckel; Christian Brueffer; James Brian Byrd; Jeremy P Kamil; Jinhui Wang; Ryan Velazquez; Gregory L Szeto; John P Barton; Rishi Raj Goel; Serghei Mangul; Tiago Lubiana; Anthony Gitter; Casey S Greene Journal: mSystems Date: 2021-10-26 Impact factor: 6.496