2. Academic Validation
  3. Modified C-type natriuretic peptide normalizes tumor vasculature, reinvigorates antitumor immunity, and improves solid tumor therapies

Modified C-type natriuretic peptide normalizes tumor vasculature, reinvigorates antitumor immunity, and improves solid tumor therapies

  • Sci Transl Med. 2024 Aug 21;16(761):eadn0904. doi: 10.1126/scitranslmed.adn0904.
Zhen Lu 1,  Ioannis Verginadis 2,  Motofumi Kumazoe 3,  Gerardo M Castillo 4,  Yao Yao 4,  Rebecca E Guerra 4,  Sandra Bicher 2,  Menghao You 1,  George McClung 5,  Rong Qiu 1,  Zebin Xiao 1,  Zhen Miao 6,  Subin S George 7,  Daniel P Beiting 8,  Takashi Nojiri 9,  Yasutake Tanaka 3,  Yoshinori Fujimura 3,  Hiroaki Onda 3,  Yui Hatakeyama 3,  Akiko Nishimoto-Ashfield 4,  Katrina Bykova 4,  Wei Guo 6,  Yi Fan 2,  Nikolay M Buynov 4,  J Alan Diehl 10,  Ben Z Stanger 11,  Hirofumi Tachibana 3,  Terence P Gade 5,  Ellen Puré 1,  Constantinos Koumenis 2,  Elijah M Bolotin 4,  Serge Y Fuchs 1
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2 Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan.
  • 4 PharmaIN Corp., Bothell, WA 98011, USA.
  • 5 Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6 Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7 Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 9 Department of General Thoracic Surgery, Higashiosaka City Medical Center, Higashiosaka 578-8588, Japan.
  • 10 Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
  • 11 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
PMID: 39167664 DOI: 10.1126/scitranslmed.adn0904
Abstract

Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of Anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.

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