CD44 as a drug delivery target in human cancers: where are we now?

In the treatment of cancers, the dual goals of drug targeting are to deliver therapeutic agents more selectively to tumor tissue and to minimize exposure of normal tissues and organs to those agents, the latter causing toxicities that limit treatment and thereby attenuate clinical efficacy. CD44, a transmembrane proteoglycan, has been considered as a targetable candidate to generate a cancer-specific drug delivery axis. Although numerous preclinical studies showed promising results exploiting CD44 as such a target, results of two clinical trials, including a Phase III registration trial, have been very disappointing. Herein, we discuss the potential underlying causes that might have led to such failures, as well as the future of CD44-targeted cancer treatment.