Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy
Joint Authors
Hayashi, Tomoko
Yao, Shiyin
Chan, Michael
Cottam, Howard B.
Lao, Fitzgerald
Carson, Dennis A.
Sato-Kaneko, Fumi
Wang, Xiaodong
Hosoya, Tadashi
Shukla, Nikunj M.
Corr, Maripat
Messer, K.
Pu, M.
Source
Issue
Vol. 2018, Issue 2018 (31 Dec. 2018), pp.1-13, 13 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2018-10-10
Country of Publication
Egypt
No. of Pages
13
Main Subjects
Abstract EN
For an activating immunotherapy such as adjuvants, a compound that can prolong immune stimulation may enhance efficacy.
We leveraged data from two prior high throughput screens with NF-κB and interferon reporter cell lines to identify 4H-chromene-3-carbonitriles as a class of compounds that prolonged activation in both screens.
We repurchased 23 of the most promising candidates.
Out of these compounds we found #1 to be the most effective agent in stimulating the release of cytokines and chemokines from immune cells, including murine primary bone marrow derived dendritic cells.
Mechanistically, #1 inhibited tubulin polymerization, and its effect on immune cell activation was abolished in cells mutated in the beta-tubulin gene (TUBB) encoding the site where colchicine binds.
Treatment with #1 resulted in mitochondrial depolarization followed by mitogen-activated protein kinase activation.
Because tubulin polymerization modulating agents have been used for chemotherapy to treat malignancy and #1 activated cytokine responses, we hypothesized that #1 could be effective for cancer immunotherapy.
Intratumoral injection of #1 delayed tumor growth in a murine syngeneic model of head and neck cancer.
When combined with PD-1 blockade, tumor growth slowed in the injected tumor nodule and there was an abscopal effect in an uninjected nodule on the contralateral flank, suggesting central antitumor immune activation.
Thus, we identified a new class of tubulin depolymerizing agent that acts as both an innate and an adaptive immune activating agent and that limits solid tumor growth when used concurrently with a checkpoint inhibitor.
American Psychological Association (APA)
Sato-Kaneko, Fumi& Wang, Xiaodong& Yao, Shiyin& Hosoya, Tadashi& Lao, Fitzgerald& Messer, K.…[et al.]. 2018. Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy. BioMed Research International،Vol. 2018, no. 2018, pp.1-13.
https://search.emarefa.net/detail/BIM-1128883
Modern Language Association (MLA)
Sato-Kaneko, Fumi…[et al.]. Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy. BioMed Research International No. 2018 (2018), pp.1-13.
https://search.emarefa.net/detail/BIM-1128883
American Medical Association (AMA)
Sato-Kaneko, Fumi& Wang, Xiaodong& Yao, Shiyin& Hosoya, Tadashi& Lao, Fitzgerald& Messer, K.…[et al.]. Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy. BioMed Research International. 2018. Vol. 2018, no. 2018, pp.1-13.
https://search.emarefa.net/detail/BIM-1128883
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1128883