Far beyond anti-angiogenesis: Benefits for anti-basicFGF therapy in cancer

Basic FGF (bFGF) was discovered as a typical inducer of angiogenesis and has already been studied for 3 decades. Recent evidence indicates that bFGF plays different roles and controls signaling pathways that participate in the hallmarks of cancer, underscoring bFGF an appealing target for anti-cancer therapy. However, the early clinical trials designed to block bFGF signaling showed safety without satisfiable benefits for cancer patients. In this review, we firstly discuss bFGF's canonical signaling pathways and later review newly identified bFGF's functions that contribute to the cancer hallmarks besides its typical role in angiogenesis. After, we summarize the role of bFGF as a therapeutic target in response to different cancer therapies including radiotherapy, chemotherapy, targeted therapy, immunotherapy, and highlight the difficulties we must solve regarding the design of drugs targeting specifically bFGF. We also emphasize the need, especially for natural bFGF traps, to deepen their molecular mechanisms of action considering the specific context of cancer with different FGFR status, as well as the urgence of stratifying patients for both anti-bFGF first line and second line anti-cancer therapy. Finally, a perspective on potential feed-forward oncogenic signaling pathways mediated by bFGF is made. We discuss the importance of developing additional robust biomarkers to select patients who will benefit from bFGF-targeted therapy, as well as the rationale of developing combinatory therapies targeting either bFGF and/or its intracellular (co)effectors. This would ultimately provide novel therapeutic strategies to fight cancer.