ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
Losartan Blocks Osteosarcoma-Elicited Monocyte Recruitment, and Combined With the Kinase Inhibitor Toceranib, Exerts Significant Clinical Benefit in Canine Metastatic Osteosarcoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 1 of them a synthesis that pooled it.
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64 citing papers in PubMed, 1 synthesis or guideline pooled it, 78 citations in OpenAlex.
- Impact of bone metastasis on prognosis in non-small cell lung cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.Frontiers in immunology · 2024Pooled it
- Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Trial
- Metabolites and cancer metastasis.Oncogene · 2026Review
- Article
- Percutaneous Cementoplasty as a Monotherapy in the Treatment of Appendicular Osteosarcoma in Ten Dogs.Animals : an open access journal from MDPI · 2026Article
- A review of spontaneous bone metastases in domestic and laboratory animals.Journal of bone oncology · 2026Review
- Review
- Spatial transcriptomic mapping of canine osteosarcoma reveals immune microenvironment features linked to survival.Communications biology · 2026Article
- Comprehensive analysis of non-tumor lung, liver, and kidney transcriptomes in canine metastatic osteosarcoma.Communications biology · 2026Article
- Losartan, toceranib, and carboplatin combination therapy for progressive pulmonary metastasis in canine osteosarcoma: a case report.Irish veterinary journal · 2026Article
- Monocyte-mediated mechanisms in idiopathic pulmonary fibrosis: opportunities for early intervention.Apoptosis : an international journal on programmed cell death · 2026Review
- Gene-based immunotherapy in osteosarcoma: from oncolytic vectors to engineered immune cells.Frontiers in immunology · 2026Review
- Current Status of Research on Losartan in Tumour Therapy.Journal of cellular and molecular medicine · 2026Review
- Immunotherapy and postoperative bone defect repair strategies based on osteosarcoma tumor microenvironment characteristics: balancing antitumor effects and promotion of bone regeneration.Regenerative biomaterials · 2026Review
- Dynamic immune state transitions and metastatic niche remodelling drive osteosarcoma evolution as a barrier-restricted immune-cold ecosystem.Frontiers in immunology · 2026Review
- Overcoming barriers in primary bone cancer: Nanomaterial-enabled immunotherapy.Materials today. Bio · 2025Review
- Drug Repurposing in Veterinary Oncology: Myth or Reality?Veterinary sciences · 2025Review
- Long-term management of mandibular osteosarcoma in a dog using toceranib after hemimandibulectomy.The Canadian veterinary journal = La revue veterinaire canadienne · 2025Article
- The tumor microenvironment of metastatic osteosarcoma in the human and canine lung.Communications biology · 2025Review
- Immunological responses and clinical outcomes in dogs with osteosarcoma receiving standard therapy and a Listeria vaccine expressing HER2.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
4 more citing papers are in PubMed but not listed here.
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11 authors at 1 institution in 1 country.
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Abstract
purposeThere is increasing recognition that progress in immuno-oncology could be accelerated by evaluating immune-based therapies in dogs with spontaneous cancers. Osteosarcoma (OS) is one tumor for which limited clinical benefit has been observed with the use of immune checkpoint inhibitors. We previously reported the angiotensin receptor blocker losartan suppressed metastasis in preclinical mouse models through blockade of CCL2-CCR2 monocyte recruitment. Here we leverage dogs with spontaneous OS to determine losartan's safety and pharmacokinetics associated with monocyte pharmacodynamic endpoints, and assess its antitumor activity, in combination with the kinase inhibitor toceranib. PATIENTS AND
methodsCCL2 expression, monocyte infiltration, and monocyte recruitment by human and canine OS tumors and cell lines were assessed by gene expression, ELISA, and transwell migration assays. Safety and efficacy of losartan-toceranib therapy were evaluated in 28 dogs with lung metastatic OS. Losartan PK and monocyte PD responses were assessed in three dose cohorts of dogs by chemotaxis, plasma CCL2, and multiplex cytokine assays, and RNA-seq of losartan-treated human peripheral blood mononuclear cells.
resultsHuman and canine OS cells secrete CCL2 and elicit monocyte migration, which is inhibited by losartan. Losartan PK/PD studies in dogs revealed that a 10-fold-higher dose than typical antihypertensive dosing was required for blockade of monocyte migration. Treatment with high-dose losartan and toceranib was well-tolerated and induced a clinical benefit rate of 50% in dogs with lung metastases.
conclusionsLosartan inhibits the CCL2-CCR2 axis, and in combination with toceranib, exerts significant biological activity in dogs with metastatic osteosarcoma, supporting evaluation of this drug combination in patients with pediatric osteosarcoma. See related commentary by Weiss et al., p. 571.
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