Starve the tumor cells to death – A novel therapeutic approach with a logical basis: Rapid growth is a hallmark of cancer, a feature that places increased demand for nutrients. Entry of nutrients into tumor cells is enhanced by upregulation of specific transporters; these transporters have potential as drug targets for cancer therapy. If we can interfere with the entry of essential nutrients into tumor cells, we should be able to starve these cells to death. If the transporters that are specifically induced in tumor cells compared to normal cells are identified, blocking the function of the induced transporters would have potential as a logical therapeutic strategy for cancer treatment. Since normal cells don’t depend on these transporters for survival, cell death induced by such a strategy would be tumor-specific, with little off-target effects. Amino acid nutrition in cancer: Tumor cells have an increased need for amino acids to support protein/nucleotide synthesis. Mammalian cells cannot synthesize essential amino acids; they must obtain these amino acids via specific transporters. Glutamine, though a non-essential amino acid, is critical for tumor cells. Tumor cells are addicted to glutamine (“glutamine addiction”) and metabolize glutamine through a novel pathway known as “glutaminolysis” (1). Amino acids are also coupled to cell signaling via the mammalian target of rapamycin (mTOR), which integrates signals from growth factors, energy status, and amino acid nutritional status, and coordinates these signals with cell growth (2). Inhibitors of mTOR are in clinics for cancer treatment. Amino acid deprivation in tumor cells would also be expected to interfere with mTOR signaling. SLC6A14 as a novel drug target for treatment of cancer: Mammalian cells express ~40 amino acid transporters that are expressed in different combinations in a cell type-specific manner. Among them, one transporter stands out as unique based on its functional features. It is SLC6A14 (3). It transports all essential amino acids as well as glutamine. It is exceptionally concentrative, coupled to a Na+ gradient, a Cl- gradient, and membrane potential. It is expressed at low levels in normal tissues, but is induced in colon cancer (4), cervical cancer (5), estrogen receptor (ER)-positive breast cancer (6), and pancreatic cancer. Tumor cells upregulate SLC6A14 to meet their increased demand for essential amino acids and glutamine, indicating that SLC6A14 drives their “glutamine addiction.” Therefore, blocking the function of this transporter would starve these tumor cells to death. We have shown that this indeed is the case. Down-regulation of SLC6A14 in colon cancer cells, ER-positive breast cancer cells, and pancreatic cancer cells with shRNA suppresses the growth of these cells in mouse xenografts. We have also identified α-methyl-L-tryptophan (α-MLT) as a selective blocker of SLC6A14. α-MLT induces amino acid starvation and death in SLC6A14-positive cancer cells in vitro and inhibits their growth in mouse xenografts. The growth of SLC6A14-negative cancer cells is not affected under similar conditions, demonstrating lack of off-target effects. The blockade of SLC6A14 induces cell death in SLC6A14-positive tumor cells by three different mechanisms: it prevents the entry of essential amino acids, it targets the “glutamine addiction” behavior, and it inhibits mTOR (7). We have recently generated Slc6a14-null mouse. The mouse is viable and fertile, suggesting that SLC6A14 is not essential for normal tissues. Since cancer cells selectively induce SLC6A14 to meet their increasing demands for amino acids, we predicted that deletion of Slc6a14 would provide protection against cancer. This indeed is the case. α-MLT could be used as a drug in clinical trials for treatment of colon cancer, pancreatic cancer, cervical cancer, and ER-positive breast cancer. It can also serve as a lead compound for development of new and more potent anti-cancer drugs targeting SLC6A14. Another strategy is to develop monoclonal antibodies against SLC6A14 with ability to block the transporter function. Such biologicals would also be effective in the treatment of SLC6A14-positive tumors in a manner similar to the currently used cancer therapies with monoclonal antibodies targeting EGF receptor, VEGF receptor, and HER2. SLC6A14 is not a universal drug target for all cancers. Some cancers, e.g., ER-negative and triple-negative breast cancers, do not upregulate SLC6A14 and therefore will not respond to blockers of the transporter. But success of our studies demonstrating SLC6A14 as a viable drug target for colon cancer, cervical cancer, pancreatic cancer, and ER-positive breast cancer provides a rational basis for identification of new amino acid transporters as drug targets for other types of cancers because the SLC6A14-negative cancer subtypes must upregulate some other amino acid transporters to support their growth.