Guillermina Lozano, PhD MD Anderson Cancer Center
- Status: Completed
- Year(s): 2016
- Grant Type: Investigator
- Research Type: Clinical
- Primary Tumor Site: Pancreas
- Area of Inquiry: Models
The objective of this project is to generate and characterize mouse models to better understand pancreatic neuroendocrine tumors and the cooperating events that contribute to tumor development. A faithful animal model will be invaluable for identifying novel vulnerabilities and therapeutic targets for pancreatic neuroendocrine tumors. Dr. Lozano’s laboratory has extensive experience in generating mouse models to study the effects of specific mutations on tumor development. Previous NETRF-funded researchers discovered mutations in the DAXX and ATRX genes in tumors from patients with non-functioning pancreatic neuroendocrine tumors. Despite these promising findings, the precise role of ATRX and DAXX in neuroendocrine tumor development is yet to be understood and treatments exploiting these findings have yet to be developed. Furthermore, researchers do not have the research tools they need to develop potential new therapies for patients exploiting these mutations.
Wasylishen AR, Estrella JS, Pant V, Chau GP, Lozano G. Daxx Functions Are p53-Independent In Vivo. Mol Cancer Res. 2018 Oct;16(10):1523-1529. doi: 10.1158/1541-7786.MCR-18-0281. Epub 2018 Jun 14.
Cancers arise from DNA mutations that alter the properties of the cell, allowing for uncontrolled cell growth and tumor development. DNA mutations have been profiled in many different cancers, including pancreatic neuroendocrine tumors (PanNETs). Remarkably, the mutations in PanNETs are different than other cancers and we currently do not understand how these mutations lead to disease. This knowledge is essential to develop new therapies. Our work focuses specifically on DAXX and ATRX, genes with DNA mutations in approximately 43% of PanNETs. Because mouse models have been essential for research understanding the relevant functions of genes, we have created a new mouse model that allows us to remove DAXX from all cells in the pancreas. With this model we have thoroughly explored the normal functions of DAXX and evaluated what happens when DAXX is lost. We demonstrate that DAXX plays an important role when the pancreas is stressed or injured. The loss of DAXX impairs the ability of the pancreas to recover and return to normal. This is because DAXX maintains the general structure and regulation of DNA in the cell, which ultimately controls what proteins are present and how the cells and tissue behave. Our current work investigates this role in greater detail. We are combining state of the art DNA analysis with our existing and three additional new mouse lines to deepen our understanding of DAXX biology and the consequences of DAXX mutations. We are currently completing similar studies to understand ATRX function(s) using mouse models. Our early data suggest that DAXX and ATRX can both work together and independently in the pancreas. Combined, these studies continue to advance our understanding of how mutations in DAXX and ATRX lead to PanNETs and will provide the foundation for future work to identify new treatments for these cancers.
- State: Texas
- Grant Duration: 2 years
- Awards: Petersen Investigator Award
NETRF funds laboratory research to understand the development of neuroendocrine tumors and translational research to explore new concepts in treatment. Research grant descriptions and research updates from NETRF are not intended to serve as medical advice. It can take years for research discoveries to be fully validated and approved for patient care. Always consult your health care providers about your treatment options.