Conference Proceeding

Alpha-Methyl-L-tryptophan as a novel, dual-target, anticancer drug for multiple cancer types

Dr. Vadivel Ganapathy,
Professor,Texas Tech University Health Sciences Center,USA

-Methyl-L-tryptophan (-MLT) is currently used in tracer quantities in humans as a PET (positron emission tomography) probe in 11C-labeled form to study the status of serotonergic neurons in the brain. As it is a tryptophan derivative, it crosses the blood-brain barrier via the amino acid transporter LAT1 (SLC7A5) and is taken up into serotonergic neurons for subsequent conversion into -methyl serotonin.

Dr. Vadivel Ganapathy carried out his Post - doctoral research in Madras University, India and Post-doctoral Training in Hyderabad University, India. Later he started working as an assistant research scientist at Georgia Regents University. He as many honors and awards. Presently he is working as professor of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, United States.

-Methyl-L-tryptophan (-MLT) is currently used in tracer quantities in humans as a PET (positron emission tomography) probe in 11C-labeled form to study the status of serotonergic neurons in the brain. As it is a tryptophan derivative, it crosses the blood-brain barrier via the amino acid transporter LAT1 (SLC7A5) and is taken up into serotonergic neurons for subsequent conversion into -methyl serotonin. This is the basis of its use as a PET probe for serotonergic neurons. Because of its use in humans, though in tracer quantities, all the toxicologic and pharmacokinetic studies have already been completed for this compound in various laboratory animals. We have recently discovered that this compound is a potent blocker of the amino acid transporter SLC6A14 and also the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase-1 (IDO1). SLC6A14 is a unique amino acid transporter as it accepts 18 of the 20 proteinogenic amino acids as its substrates; in addition, its transport process is highly active and concentrative as it is energized by three different driving forces, namely a Na+ gradient, a Cl- gradient, and the membrane potential. The substrates of this transporter include glutamine, leucine, and arginine. Interestingly, this transporter is highly up-regulated in several cancers: pancreatic cancer, colon cancer, cervical cancer, thyroid cancer, and estrogen receptor-positive breast cancer. Most cancer cells are addicted to glutamine, and SLC6A14 drives this glutamine addiction in those cancer types in which the transporter is up-regulated. As such, pharmacological blockade of the transporter is expected to interfere with this glutamine addiction and also cause amino acid starvation in these cancer cells, thus blocking their growth and proliferation. As glutamine and leucine are potent activators of mTORC1, blockade of this transporter also leads to suppression of mTOR signaling, which in turn leads to inhibition of growth and proliferation of these cancer cells. Our studies have demonstrated unequivocally that -MLT as a blocker of SLC6A14 interferes with mTOR pathway and proliferation of SLC6A14-positive cancer cells in vitroin cell culture and also in vivo in mouse xenografts (pancreatic cancer, colon cancer, and ER-positive breast cancer) and in spontaneous mouse models of cancer (breast cancer). IDO1 is an immunosuppressive enzyme; when its expression is induced in antigen-presenting dendritic cells, it promotes tryptophan degradation and depletes this essential amino acid in the surroundings such that T cells that interact with these antigen-presenting cells cannot proliferate and undergo anergy. This enzyme is induced in dendritic cells present in the tumors and in tumor-draining lymph nodes. This provides a mechanism for the tumors to evade the immune system; otherwise, the T cells would be activated by the neoantigens expressed on the tumor cells and kill them. Thus, pharmacological blockade of IDO1 has potential in cancer therapy because it can boost the ability of the immune system to fight cancer. Several IDO1 inhibitors are in various stages of clinical trials as anticancer drugs. Our discovery that -MLT is an inhibitor of IDO1 implies that this compound has potential as an anticancer drug not only by blocking the amino acid transporter SLC6A14 but also by inhibiting the immunosuppressive enzyme IDO1. Our studies thus have discovered a novel dual-target chemo-immunotherapy agent for the treatment of cancer. As -MLT is already in use in humans as a PET probe and also as all the necessary pharmacokinetic and toxicologic studies have already been completed for the compound, it is ready to be taken to clinical trials for the assessment of its therapeutic efficacy in cancer patients.

Published: 11 May 2017