2. Academic Validation
  3. Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

  • Cancer Res Commun. 2022 Nov 29;2(11):1504-1519. doi: 10.1158/2767-9764.CRC-22-0151.
Michael R Paillasse 1,  Michael Esquerré 1,  Florie A Bertrand 1,  Céline Poussereau-Pomié 1,  Mélanie Pichery 1,  Virgile Visentin 1,  Geneviève Gueguen-Dorbes 1,  Florence Gaujarengues 1,  Pauline Barron 1,  Gaelle Badet 1,  Anne Briaux 1,  Pierre-Benoit Ancey 1,  David Sibrac 1,  Eric Erdociain 1,  Dennis Özcelik 2,  Jérôme Meneyrol 1,  Valérie Martin 3,  Anne Gomez-Brouchet 4,  Janik Selves 4,  Philippe Rochaix 4,  Maxime Battistella 5,  Céleste Lebbé 6,  Jean-Pierre Delord 4,  Frédérique Dol-Gleizes 1,  Françoise Bono 1,  Isabelle Blanc 1,  Antoine Alam 7,  Ian Hunneyball 8,  Mark Whittaker 8,  Pierre Fons 1
Affiliations

Affiliations

  • 1 Evotec France, Campus Curie, Toulouse CEDEX, France.
  • 2 Evotec SE, Manfred Eigen Campus, Hamburg, Germany.
  • 3 Sanofi, Chilly-Mazarin, France.
  • 4 Institut Universitaire du Cancer Toulouse Oncopole (IUCT-O), Toulouse, Occitanie, France.
  • 5 Université de Paris, Department of Pathology, AP-HP Hôpital Saint Louis, INSERM U976, Paris, France.
  • 6 Université de Paris, Department of Dermatology, AP-HP Hôpital Saint Louis, INSERM U976, Paris, France.
  • 7 Evotec ID, Lyon, France.
  • 8 Evotec Ltd, Oxfordshire, United Kingdom.
PMID: 36970050 DOI: 10.1158/2767-9764.CRC-22-0151
Abstract

The receptor tyrosine kinase VEGFR-3 plays a crucial role in cancer-induced angiogenesis and lymphangiogenesis, promoting tumor development and metastasis. Here, we report the novel VEGFR-3 inhibitor EVT801 that presents a more selective and less toxic profile than two major inhibitors of VEGFRs (i.e., sorafenib and pazopanib). As monotherapy, EVT801 showed a potent antitumor effect in VEGFR-3-positive tumors, and in tumors with VEGFR-3-positive microenvironments. EVT801 suppressed VEGF-C-induced human endothelial cell proliferation in vitro and tumor (lymph)angiogenesis in different tumor mouse models. In addition to reduced tumor growth, EVT801 decreased tumor hypoxia, favored sustained tumor blood vessel homogenization (i.e., leaving fewer and overall larger vessels), and reduced important immunosuppressive cytokines (CCL4, CCL5) and myeloid-derived suppressor cells (MDSC) in circulation. Furthermore, in carcinoma mouse models, the combination of EVT801 with immune checkpoint therapy (ICT) yielded superior outcomes to either single treatment. Moreover, tumor growth inhibition was inversely correlated with levels of CCL4, CCL5, and MDSCs after treatment with EVT801, either alone or combined with ICT. Taken together, EVT801 represents a promising anti(lymph)angiogenic drug for improving ICT response rates in patients with VEGFR-3 positive tumors.

Significance: The VEGFR-3 inhibitor EVT801 demonstrates superior selectivity and toxicity profile than other VEGFR-3 tyrosine kinase inhibitors. EVT801 showed potent antitumor effects in VEGFR-3-positive tumors, and tumors with VEGFR-3-positive microenvironments through blood vessel homogenization, and reduction of tumor hypoxia and limited immunosuppression. EVT801 increases immune checkpoint inhibitors' antitumor effects.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15458
    99.76%, VEGFR3抑制剂
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