Blockade of Nonhormonal Fibroblast Growth Factors by FP-1039 Inhibits Growth of Multiple Types of Cancer

A soluble FGF receptor trap effectively inhibits tumor growth in the absence of toxicity. Treating Cancer by Design The Renaissance man (or woman) is held up as an ideal of someone with diverse knowledge. Yet, today, it is increasingly difficult to both be broad and have sufficient depth of knowledge to be successful in any one field. Unfortunately, this is also the case for cancer therapies. The most obvious outward signs of some cancers—severe weight loss, tiredness, hair loss, nausea—are actually caused by the nonspecific breadth of the treatments. One pathway that has proved particularly intractable is the fibroblast growth factor (FGF) pathway, which promotes tumor growth and angiogenesis but also contributes key metabolic hormones. Now, Harding et al. have designed a soluble FGF receptor Fc fusion protein (FP-1039) to overcome these difficulties. The authors tested the specificity of FP-1039 both in vitro and in vivo across a wide swath of cancer types. FP-1039 binds to mitogenic FGF ligands, blocking angiogenesis and inhibiting growth of tumors of many different types. Tumors with amplified expression of, or mutations in, FGF receptors (such as certain lung and endometrial cancers) were especially well targeted by this drug. In contrast, FP-1039 did not bind tightly to the hormonal FGFs, and treatment in animal models had minimal toxicity. Although this drug has only been tested in early-stage clinical trial in humans, these data support a specialized inhibition of mitogenic FGFs. Cancer drug design is truly entering the Age of Reason. The fibroblast growth factor (FGF) pathway promotes tumor growth and angiogenesis in many solid tumors. Although there has long been interest in FGF pathway inhibitors, development has been complicated: An effective FGF inhibitor must block the activity of multiple mitogenic FGF ligands but must spare the metabolic hormone FGFs (FGF-19, FGF-21, and FGF-23) to avoid unacceptable toxicity. To achieve these design requirements, we engineered a soluble FGF receptor 1 Fc fusion protein, FP-1039. FP-1039 binds tightly to all of the mitogenic FGF ligands, inhibits FGF-stimulated cell proliferation in vitro, blocks FGF- and vascular endothelial growth factor (VEGF)–induced angiogenesis in vivo, and inhibits in vivo growth of a broad range of tumor types. FP-1039 antitumor response is positively correlated with RNA levels of FGF2, FGF18, FGFR1c, FGFR3c, and ETV4; models with genetic aberrations in the FGF pathway, including FGFR1-amplified lung cancer and FGFR2-mutated endometrial cancer, are particularly sensitive to FP-1039–mediated tumor inhibition. FP-1039 does not appreciably bind the hormonal FGFs, because these ligands require a cell surface co-receptor, klotho or β-klotho, for high-affinity binding and signaling. Serum calcium and phosphate levels, which are regulated by FGF-23, are not altered by administration of FP-1039. By selectively blocking nonhormonal FGFs, FP-1039 treatment confers antitumor efficacy without the toxicities associated with other FGF pathway inhibitors.