Investigating the Interactions of Glutamine Amidotransferases and MEK-ERK Signaling to Develop Novel Therapeutic Strategies for NF1-Associated Tumors
Abstract
People with the genetic condition neurofibromatosis type I (NF1) have a considerably increased risk for cancer compared to the general population. Many such tumors cannot be removed with surgery and do not respond well to traditional chemotherapy. The goal of the proposed research is to investigate whether a new type of medicine called a glutamine amidotransferase inhibitor can effectively treat tumors in NF1 patients. Glutamine amidotransferases are metabolic proteins that use the amino acid glutamine to build nutrients that cancer cells need to grow and survive. At least eight glutamine amidotransferases exist in human cells, including tumor cells. Our research group has shown that glutamine amidotransferase inhibitors are effective treatments in many tumor models; one inhibitor called DRP-104 (or sirpiglenastat) is already in human clinical trials. Several pieces of evidence support investigating the role of glutamine amidotransferases in NF1-associated tumors and the therapeutic value of DRP-104. First, other researchers have shown that the MEK-ERK signaling pathway, which is active in NF1-associated tumors, increases the activity of glutamine amidotransferases. Second, our previous studies of an early version of DRP-104 in NF1 malignant peripheral nerve sheath tumor (MPNST) cells and an animal model found that this glutamine amidotransferase inhibitor blocked MPNST growth. When we examined the nutritional differences between treated and untreated MPNST cells, we found differences in several classes of nutrients that suggest additional processes to target in combination with glutamine amidotransferase inhibitors. Third, DRP-104 has a unique design that improves delivery of the medicine to tumor cells and prevents it from causing side effects in non-tumor cells. Our proposed research will consist of three major classes of experiments. First, we will refine our understanding of the role of glutamine amidotransferases in NF1-associated tumor cells. We will study the effects of DRP-104 on tumor cell use of glutamine and will examine NF1-associated tumor cells for markers of MEK-ERK pathway interaction with glutamine amidotransferases. Second, we will examine how effectively DRP-104 blocks the growth of a range of NF1-associated human tumor cells (glioma, MPNST, melanoma, breast cancer), both alone and in combination with other medicines that have been effective in NF1-associated tumors. We are particularly interested in examining MEK inhibitors (MEKi) in combination with DRP-104, as MEKi are already used clinically in NF1 patients. Third, we will test DRP-104 in several NF1-associated tumor models in mice to determine how well it blocks tumor growth and if side effects are observed in mice. We will also test the best combination medicine with DRP-104 from the cell-based studies in mouse models. Our research will help three groups of people: (1) people with NF1 who have tumors related to their genetic syndrome; (2) people with NF1 who have other non-tumor symptoms from the disease (i.e., muscle weakness) as the studies proposed under Aim 1 will also help us to better understand the biology of glutamine metabolism downstream of MEK-ERK signaling in NF1 patient cells; and (3) people without NF1 whose tumors have a neurofibromin mutation. This mutation is observed in subsets of several common adult cancers, including melanoma and lung cancer, which are both among the top five cancers diagnosed annually in military Veterans, making this proposal directly relevant to members of the Armed Forces and their families. This project is highly clinically applicable, as we propose to test two classes of medicines, DRP-104 glutamine amidotransferase inhibitor and MEKi, which are separately already in the clinic for oncology applications. The benefits of this research include novel treatments for NF1-associated tumors and new insights into NF1 disease biology. We anticipate that based on our findings, DRP-104 could
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210948
Entities
People
- Kathryn Lemberg
Organizations
- Johns Hopkins University
- United States Army