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Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Anti-Tumor Innate Immunity.

Date Posted: May 12, 2017

TitleCabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Anti-Tumor Innate Immunity.
Publication TypeJournal Article
Year of Publication2017
AuthorsPatnaik A, Swanson KD, Csizmadia E, Solanki A, Landon-Brace N, Gehring MP, Helenius K, Olson BM, Pyzer AR, Wang LC, Elemento O, Novak J, Thornley TB, Asara JM, Montaser L, Timmons JJ, Morgan TM, Wang Y, Levantini E, Clohessy JG, Kelly K, Pandolfi PPaolo, Rosenblatt JM, Avigan DE, Ye H, Karp JM, Signoretti S, Balk SP, Cantley LC
JournalCancer Discov
Date Published2017 Mar 08
ISSN2159-8290
Abstract

Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor, plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anti-cancer innate immune response, resulting in tumor clearance.

DOI10.1158/2159-8290.CD-16-0778
Alternate JournalCancer Discov
PubMed ID28274958
Grant ListP01 CA089021 / CA / NCI NIH HHS / United States
R01 GM041890 / GM / NIGMS NIH HHS / United States