Defining the Glycan-Specificity and Mechanisms of Action for Antitumor Lectin
Abstract: Glycans are multi-branched sugars attached to proteins and lipids, particularly on cell surfaces, whose diverse structures affect healthy cellular functions ranging from subtle changes in cell behavior to critical roles in development, growth and survival. Disruption of glycan synthesis is fundamental to various human diseases, including cancer, where aberrant glycosylation drives the initiation and malignancy of many tumor types. Despite this link, the glycome of different cancers remains largely unknown and, along with it, a wealth of potentially novel targets for therapies. Lectins are a family of proteins that recognize and bind to glycans with sugar-type specificity, and thus represent powerful biochemical tools to precisely distinguish altered expression of cell-surface glycans. This glycan-specifictiy of lectins makes them useful for probing pathways important in cancer biology, while in some cases also disrupting cell function. We have recently discovered a novel lectin that kills cancer cells with thousand-fold greater potency than standard chemotherapeutics, while being remarkably biocompatible toward healthy cells. Here we propose research to understand the mechanism by which it differentiates cancer-associated glycans and define its mechanisms of cytotoxicity. This lectin was engineered from a gene identified in an environmental sample from a tropical rainforest, from which we have identified another >80 additional novel lectins with diverse functional domains. We have some evidence that these lectins mediate species interactions and hence suspect that they evolved in the context of cross-species arms races. Strategic use of proteins such as these, involved in interactions among competing microorganisms, may already counteract common mutations that cause resistance and hence provide a fundamentally new strategy to combat the evolution of resistance leading to remission of cancers. In summary, this research will advance the understanding of potent new anti-cancer lectins while simultaneously exploring new ways to avoid rapid evolution of resistance that remains a challenge and shortcoming for other approaches to treating cancers.