Semaphoring to tumor vasculature
Solid tumors typically have blood vessels that are not only increased in number but also exhibit various structural and functional abnormalities. Thus, vascular normalization is frequently proposed as an antitumor strategy, with the goal of improving intratumoral oxygenation and drug delivery. SEMA3A, a protein from the semaphorin family, is a known vascular normalizing agent but not a good therapeutic candidate due to adverse effects. To address this concern, Gioelli et al. engineered a mutant version of SEMA3A that retained its vascular normalizing function but did not activate the pathway responsible for the main side effects. The authors then confirmed the ability of mutant SEMA3A to normalize tumor vasculature and demonstrated its anticancer effects alone and combined with chemotherapy.
Vascular normalizing strategies, aimed at ameliorating blood vessel perfusion and lessening tissue hypoxia, are treatments that may improve the outcome of cancer patients. Secreted class 3 semaphorins (SEMA3), which are thought to directly bind neuropilin (NRP) co-receptors that, in turn, associate with and elicit plexin (PLXN) receptor signaling, are effective normalizing agents of the cancer vasculature. Yet, SEMA3A was also reported to trigger adverse side effects via NRP1. We rationally designed and generated a safe, parenterally deliverable, and NRP1-independent SEMA3A point mutant isoform that, unlike its wild-type counterpart, binds PLXNA4 with nanomolar affinity and has much greater biochemical and biological activities in cultured endothelial cells. In vivo, when parenterally administered in mouse models of pancreatic cancer, the NRP1-independent SEMA3A point mutant successfully normalized the vasculature, inhibited tumor growth, curbed metastatic dissemination, and effectively improved the supply and anticancer activity of chemotherapy. Mutant SEMA3A also inhibited retinal neovascularization in a mouse model of age-related macular degeneration. In summary, mutant SEMA3A is a vascular normalizing agent that can be exploited to treat cancer and, potentially, other diseases characterized by pathological angiogenesis.