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

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.

Authors

Institutions

Publication Details

Journal
Science Translational Medicine
Published
2024-08-21
DOI
https://doi.org/10.1126/scitranslmed.adn0904
Citations
13
Primary Topic
Peptidase Inhibition and Analysis
Type
article
Field-Weighted Citation Impact
3.67

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Ellen Puré, Motofumi Kumazoe, Yi Fan, Elijah M. Bolotin et al.
13 citations
Science Translational Medicine
Peptidase Inhibition and Analysis
3.67
article

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

Ellen Puré, Motofumi Kumazoe, Yi Fan, Elijah M. Bolotin, Serge Y. Fuchs, Takashi Nojiri, Wei Guo, Menghao You, Sandra Bicher, Ioannis I. Verginadis, Rong Qiu, Zhen Miao, John Alan Diehl, Akiko Nishimoto-Ashfield, G. Castillo, Yasutake Tanaka, Hirofumi Tachibana, Ben Z. Stanger, Hiroaki Onda, Rebecca Guerra, Yao Yao, Yoshinori Fujimura, Subin S. George, Katrina Bykova, Zebin Xiao, Constantinos Koumenis, T. Gade, Daniel P. Beiting, Nikolay M. Buynov, Zhen Lu, George McClung, Yui Hatakeyama
article en
13 citations

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.

Science Translational MedicineVol. 16(761)
Kyushu University (JP), University of the Arts (US), Higashiosaka College & Higashiosaka Junior College (JP), EKOS Corporation (US), Higashi Osaka City General Hospital (JP), University School (US), Case Western Reserve University (US), University of Pennsylvania (US)
Pfizer, University of Pennsylvania, Queen Mary University of London, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 5%
Peptidase Inhibition and Analysis
3.67
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.