Targeting De Novo NAD+ Synthesis Through the Kynurenine Pathway in Renal Cell Carcinoma
Abstract
Renal cell carcinoma (RCC) accounts for more than 85% of kidney cancer -- the sixth most common form of cancer in humans -- and is one of the few cancer subtypes for which incidence is on the rise. The majority of RCC cases are either diagnosed after metastasis has occurred or progress to metastatic disease following diagnosis. Once metastasis has occurred, RCC patients have a median survival of only 20 months. Available treatments show only limited effectiveness in treating RCC and novel approaches are critically needed. In this study we will evaluate the tryptophan-kynurenine metabolic pathway as a novel target for RCC treatment. Cancer cells alter their metabolism to meet the energy production demands of growing tumors and to avoid detection by the host immune system. This metabolic reprogramming is now recognized as a hallmark of cancer. Recent studies have specifically detected extensive metabolic reprogramming in RCC to the point where some researchers now consider RCC a metabolic disease. The reliance of cancer cells on high energy production and the degree of metabolic reprogramming in RCC make metabolic pathways particularly intriguing treatment targets for this type of cancer. One common metabolic alteration in RCC is activation of the kynurenine pathway. Kynurenine metabolism converts the amino acid tryptophan into the energy-carrying molecule nicotinamide adenine dinucleotide (NAD+). Activation of the kynurenine pathway thus provides two advantages to tumor cells: (1) reduced tryptophan suppresses immune activity in the tissues surrounding the tumor, allowing cancer cells to evade the host immune system; and (2) elevated NAD+ supports the high energy demands of the tumor. While tryptophan-mediated immune evasion is widely studied in a variety of cancers, the importance of NAD+ synthesis has been relatively neglected and represents a critical knowledge gap. In this study, we hypothesize that preventing NAD+ synthesis by blocking kynurenine metabolism will inhibit RCC cell growth and tumor pathology. To test this hypothesis, we will knock down three enzymes -- KYNU, ACMSD, and QPRT -- at critical metabolic branch points in the kynurenine pathway in both human and mouse RCC cells and determine the impact on both cellular behavior (growth, metastatic potential) and disease progression in mice. In the short term, this work will evaluate the potential for blocking NAD+ synthesis from tryptophan through the kynurenine pathway as a treatment strategy for RCC, laying the groundwork for a research program to fully characterize the role of this metabolic pathway in RCC pathology. In the long term, this work will lead to the development of new cancer drugs designed to block kynurenine metabolism. We anticipate that drugs designed to block NAD+ production can in turn be combined with drugs designed to prevent immune system evasion to achieve synergistic benefits.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110540
Entities
People
- George L Sutphin
Organizations
- United States Army
- University of Arizona