The Lankenau Institute for Medical Research
Dr. George Prendergast, President and CEO of the Lankenau Institute for Medical Research (LIMR), was quoted extensively in a Journal of the National Cancer Institute article by Ken Garber entitled ‘Evading Immunity: New Enzyme Implicated in Cancer.’ As an expert on immune response inhibitors and tumor immune escape, Dr. Prendergast comments throughout the article about current research on enzyme inhibitors that may block cancer progression.
The JNCI article focuses on the newest research findings in immunotherapy. One of the latest strategies in the fight against cancer, immunotherapy is the use of molecules to enhance the immune system so that it can better attack the tumor. But researchers have found that this approach is not completely effective in eradicating tumors, because cancer can suppress the immune system. This process is called immune escape and involves cancer cells hijacking enzymes which circumvent the body’s response to disease.
One such enzyme, IDO, or indoleamine 2,3-dioxygenase, has been shown to block T cell activation and therefore bypass the immune system by way of a process called tryptophan metabolism. “The way to think about IDO is as a modifier on the signals that control immune response,” says Dr. Prendergast, “a rheostat on a switch.” (Prendergast GC, Metz R, Muller AJ. Towards a genetic definition of cancer-associated inflammation: role of the IDO pathway. Amer. J. Pathol. 176: 2082-2087 ). Tryptophan, an essential amino acid, is the rarest of the amino acids that make up cellular proteins. But when an inhibitor such as IDO breaks down tryptophan, proteins cannot be made, effectively starving the cells. This situation creates a stress response which suppresses T cell proliferation. Additionally, as demonstrated recently by a research group in Germany, the tryptophan catabolite byproduct kynurenine, generated by not only IDO but a second enzyme called TDO, contributes directly to immune suppression by cancers as well.
As for effective cancer therapies, clinical trials of IDO inhibitors are ongoing. Dr. Prendergast believes immunotherapy-chemotherapy combinations, or what he calls immunochemotherapy, will be most useful, because immune suppression by tumors is now known to render chemotherapy less effective than it otherwise would be in eradicating cancer cells. Introduction of molecules to enhance the immune response while receiving chemotherapy may increase chemotherapy’s efficacy. Dr. Prendergast makes the analogy, “By getting off the brake, you can stand on the gas and now move.” Along with Dr. Alexander Muller, his long-standing scientific collaborator at LIMR, Dr. Prendergast first demonstrated the validity of such an approach in a large preclinical study several years ago, challenging existing ideas that chemotherapy and immunotherapy could never cooperate with each other (Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, and Prendergast GC. Inhibition of indoleamine 2,3-dioxygenase, a target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nature Med. 11, 312-319 ).
Most cancer researchers now believe that immune escape is necessary for tumor survival. Some immunologists suggest even more. “The most radical idea in cancer immunology is, who cares if you have cancer cells. What you have is a problem in managing them. That’s the disease,” Dr. Prendergast states. “Not that you have cancer cells – all older people have cancer cells, [but] most of them don’t have cancer because they manage them.”
For the complete JNCI article, please visit the Journal of the National Cancer Institute.
Founded in 1927, the Lankenau Institute for Medical Research (LIMR) is an independent, non-profit biomedical research center located in suburban Philadelphia on the campus of the Lankenau Medical Center. Part of Main Line Health, LIMR is one of the few freestanding, hospital-associated medical research centers in the nation. The faculty and staff at the Institute are dedicated to advancing an understanding of the causes of cancer, heart disease and diabetes. They use this information to help improve diagnosis and treatment of these diseases as well as find ways to prevent them. LIMR is also committed to extending the boundaries of human health and well-being through technology development and the training of the next generation of scientists and physicians. For more information, please visit www.limr.org.