Blocking the FGF/FGFR system as a "two-compartment" antiangiogenic/antitumor approach in cancer therapy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Fibroblast growth factors (FGFs) are pleiotropic factors produced by tumor cells, influencing both tumor and stromal compartments.
• The FGF/FGF receptor (FGFR) pathway plays a critical role in tumor growth, angiogenesis, and resistance to anti-VEGF therapies.
• FGF/FGFR pathway activation occurs through various mechanisms including gene upregulation, mutation, and amplification in diverse human cancers.

Purpose of the Study:

• To review preclinical and clinical strategies for targeting the FGF/FGFR system in human cancer.
• To explore the challenges and potential of developing anti-FGF/FGFR therapeutics.
• To highlight the promise of dual-action agents with both antiangiogenic and antitumor effects.

Main Methods:

• Review of existing preclinical data on FGF/FGFR pathway inhibitors.
• Analysis of clinical trial outcomes for agents targeting FGF/FGFR.
• Examination of the biological rationale for FGF/FGFR blockade in cancer.

Main Results:

• FGF/FGFR pathway activation is implicated in tumor growth, progression, and escape from antiangiogenic treatments.
• Development of FGF/FGFR inhibitors is challenging due to pathway redundancy and pleiotropic effects.
• The development of "two-compartment" agents with combined antiangiogenic and antitumor activities is a promising therapeutic avenue.

Conclusions:

• The FGF/FGFR pathway is a validated target in oncology, necessitating further therapeutic development.
• Overcoming challenges related to drug specificity and efficacy is crucial for successful FGF/FGFR-targeted therapies.
• Dual-acting agents represent a potential strategy to effectively inhibit tumor growth and overcome resistance mechanisms.