S2 Targeting the Achilles Heel of Cancer: Nutrient Transporters

Vadivel Ganapathy , Texas Tech University Health Sciences Center, Lubbock, TX
Uncontrolled proliferation is a hallmark of cancer, which necessitates an increased demand for nutrients by cancer cells. Indeed, cancer cells exhibit “addiction” to certain nutrients (e.g., glucose, glutamine). As the majority of nutrients are water-soluble and cannot diffuse across the plasma membrane, cancer cells have to depend on specific transporters to satisfy their increased demand for these nutrients. They do so by up-regulating selective transporters that become obligatory for their growth and proliferation. This makes them the Achilles heel of cancer as the cancer cells would become vulnerable to death by starvation if these transporters are rendered non-functional. As these transporters are expressed at higher than normal levels in cancer cells, their blockade would have a differential detrimental effect on the cancer cells with less impact on normal cells. Small molecules as specific inhibitors could be used as blockers of these transporters; alternatively, monoclonal antibodies can also be used given the fact that these transporters are cell-surface proteins with external epitopes, thereby making it feasible to exploit these epitopes for functional blockade with monoclonals. These transporters thus provide a novel, hitherto unexplored, drug targets for cancer therapy. Potential candidates include the glucose transporters SLC2A1 and SLC5A1, amino acid transporters SLC1A5, SLC6A14, SLC7A5, SLC7A11, and SLC38A5, lactate transporters SLC16A1 and SLC16A3, peptide transporter SLC15A1, and the vitamin transporters SLC19A3 (thiamine), and SLC19A1 and SLC46A1 (folate). Focused efforts are currently underway in academia and pharmaceutical companies to develop small molecules and biologics targeting some of these transporters as an innovative strategy for cancer treatment.

While the potential of nutrient transporters in cancer as drug targets undoubtedly holds promise, there are other therapeutic aspects as well. These transporters are amenable for use in tumor imaging with appropriate probes. Because of the increased expression, cancer cells would accumulate via these transporters suitable substrate probes to aid in in vivo imaging of tumors. This strategy is already successful with the facilitative glucose transporter SLC2A1 for PET (positron emission tomography) scanning of tumors using 18F-2-deoxy-D-glucose. Published reports indicate similar potential for the Na+/glucose co-transporter SLC5A1, Na+/Cl- -coupled amino acid transporter SLC6A14, and amino acid exchanger SLC7A5. These transporters could also be exploited for tumor-targeted delivery of cancer therapeutics as many of these transporters recognize structurally related pharmaceuticals as substrates. If anticancer drugs could be designed such that they are accepted as substrates by these transporters, these drugs would accumulate preferentially in cancer cells. Delivery of anticancer drugs as prodrugs offers another possibility; resistance to certain chemotherapeutic agents in cancer cells could be overcome by chemically modifying these agents in the form of prodrugs to make them recognizable by the transporters that are up-regulated in cancer. There is evidence for the potential utility of the peptide transporter SLC15A1 and the amino acid transporter SLC6A14 for this purpose. The same strategy could also apply for tumor-specific targeting of nanoparticles. The surface of the drug-encapsulated nanoparticles could be modified with appropriate ligands such that the transporters bind these ligands and facilitate the entry of the nanoparticles into cancer cells.