GlycoMimetics, Inc. has recognized the importance of carbohydrate interactions in different diseases, including cancer, and have become pioneers in the development of drugs to target these key carbohydrate molecules and potentially offer hope to patients with cancer and other diseases. GlycoMimetics, Inc. has several investigational drugs in its pipeline, including uproleselan, an E-selectin antagonist in Phase 3 development for people living with acute myeloid leukemia, and GMI-1687, in development for people living with sickle cell disease.
Carbohydrates, commonly known as sugars, are found everywhere in nature and are expressed in all forms of life, from viruses and bacteria to plants, invertebrates, and mammals -- including humans. They are involved in many fundamental processes that contribute to life. Given their critical involvement to living organisms, they are also intricately connected to the development of disease and infection. While the importance of carbohydrates has been known for decades, scientists are only recently understanding how these carbohydrate molecules can be targeted to impact disease.
Figure 1. All living cells are coated with complex carbohydrates that are recognized by carbohydrate-binding proteins and contribute to all aspects of normal and disease processes, such as cell-to-cell binding, cell maturation and specialization, survival, and migration.
Carbohydrates can be simple (monosaccharide) or complex (oligosaccharide) and have many different roles inside and outside of cells. They can be sources of energy and metabolism (i.e., glucose), form cell structures (i.e., cell walls of plants), and enable cells to recognize and interact with each other. All cells in nature are coated with complex carbohydrates that act as recognition molecules, thus enabling interactions with different cells, other molecules, and pathogens. These interactions (referred to as recognition events) can occur between the complex carbohydrate molecules and protein molecules on cells (called carbohydrate-binding proteins [lectins]). When the complex carbohydrate molecules bind to these protein molecules, numerous different processes of cells occur, including cell-to-cell binding, cell activation, differentiation, survival, and migration (the specialized movement of cells to specific locations) (Figure 1).
Figure 2: Immune cells travel through the blood circulatory system. E-selectin acts as a brake to catch the immune cells, which roll on the blood vessel wall. Rolling causes integrins to stop the immune cells and helps them adhere strongly to the blood vessel wall. The immune cells migrate in between the endothelial cells to reach sites of infection or injury.
One carbohydrate-binding protein family is called the selectins, and they are composed of three members: E-selectin found on vascular endothelial cells (tissue that lines blood vessels), P-selectin also found on vascular endothelial cells as well as on platelets (blood cells that cause clotting), and L-selectin found on leukocytes (white blood cells involved in immune responses). Each of the selectins bind to a specific complex carbohydrate domain shared by sialyl Lewisx and sialyl Lewisa.
One of the primary roles of the selectin family of proteins is to help in the overall process of mobilizing immune cells to exit the bloodstream to sites where they are needed to fight infection or disease. The selectins are involved in the early steps of this process, which are the adhesion, tethering, and rolling of immune cells on the vascular endothelium.
In addition to their important role in mobilizing immune cells, carbohydrates and selectins help control other cell processes inherent in normal life. Therefore, any small change in these molecules or the events they control can lead to the development of diseases, such as cancer.
Cancer cells hijack the normal function of carbohydrates and E-selectin to promote their own metastasis and survival. For example, in acute myeloid leukemia, the interaction between E-selectin and carbohydrates contributes to the migration of leukemia cells to areas in the bone marrow where they are able to bind, sequester and become less susceptible to cytotoxic therapy (e.g., chemotherapy). Similarly, cells from other tumor types, including breast cancer and pancreatic cancer, also bind to E-selectin on endothelial cells to promote their survival and metastatic spread to the lung, liver and bone. These interactions also contribute to resistance to chemotherapy and other drugs.