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Inhibition of placental growth factor in renal cell carcinoma
Hideharu Bessho1, Bernice Wong2, Dan Huang3
1Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore, Singapore Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore Department of Urology, Kitasato University School of Medicine, Kanagawa, Japan hideji56@gmail.com.
Background/Aim:
Placental growth factor (PlGF) is up-regulated in major malignant diseases or following antiangiogenic therapy, although it is present in low levels under normal physiological conditions. TB403, a monoclonal antibody against PlGF, was investigated in clear cell renal cell carcinoma (ccRCC) xenografts since it has been proposed as a potential target in oncology.
Materials And Methods:
Human ccRCCs were implanted in athymic nude mice to evaluate the efficacy of TB403 and to excise xenograft tumors for molecular experiments.
Results:
TB403 did not significantly inhibit tumor growth in treatment-naïve or sunitinib-resistant ccRCC xenografts. Gene expression profiling resulted in over-expression of the C1orf38 gene, which induced immunoreactivity in macrophages. Angiogenesis PCR arrays showed that VEGFR-1 was not expressed in ccRCC xenografts.
Conclusion:
PlGF blockade did not have a broad antiangiogenic efficacy; however, it might be effective on-target in VEGFR1-expressing tumors. The inhibition of VEGF pathway may induce the activity of tumor-associated-macrophages for angiogenesis escape.
Insights
Placental growth factor (PlGF) blockade with TB403 did not inhibit clear cell renal cell carcinoma (ccRCC) xenograft growth. However, PlGF targeting may be effective in specific tumors, as VEGF pathway inhibition can promote tumor angiogenesis escape.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Placental growth factor (PlGF) is elevated in cancers and after antiangiogenic therapy.
- TB403, an antibody targeting PlGF, was evaluated for its potential in oncology.
- Clear cell renal cell carcinoma (ccRCC) is a major malignancy where PlGF may play a role.
Purpose of the Study:
- To investigate the efficacy of TB403, a PlGF-targeting monoclonal antibody, in ccRCC xenografts.
- To explore the molecular mechanisms underlying ccRCC response to PlGF blockade.
- To assess the potential of PlGF as a therapeutic target in ccRCC.
Main Methods:
- Human ccRCC tumors were xenografted into athymic nude mice.
- Tumor growth was monitored following TB403 treatment in treatment-naïve and sunitinib-resistant models.
- Gene expression profiling and angiogenesis PCR arrays were performed on excised tumors.
Main Results:
- TB403 did not significantly inhibit tumor growth in either treatment-naïve or sunitinib-resistant ccRCC xenografts.
- Gene expression analysis revealed C1orf38 overexpression and induced macrophage immunoreactivity.
- VEGFR-1 was not detected in the ccRCC xenografts, suggesting limited direct antiangiogenic effect via this pathway.
Conclusions:
- PlGF blockade demonstrated limited broad antiangiogenic efficacy in this ccRCC model.
- Targeting PlGF may be effective in tumors expressing VEGFR-1.
- Inhibition of the VEGF pathway could potentially enhance tumor angiogenesis through mechanisms involving tumor-associated macrophages.
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