Identification of genes and pathways involved in Schwann cell tumor initiation, development and progression to develop novel drug targets
2013-06
Loading...
View/Download File
Persistent link to this item
Statistics
View StatisticsJournal Title
Journal ISSN
Volume Title
Title
Identification of genes and pathways involved in Schwann cell tumor initiation, development and progression to develop novel drug targets
Authors
Published Date
2013-06
Publisher
Type
Thesis or Dissertation
Abstract
In 2012 in the United States alone, over 1.6 million people were diagnosed with cancer and nearly 600,000 people died as a result of cancer. Cancer is a disease in which inherited or acquired genetic changes endow cells with abnormal properties such as the ability to rapidly grow and proliferate, resist normal mechanisms of cell death and senescence, induce angiogenesis, invade surrounding tissues and eventually metastasize throughout the body. Malignant peripheral nerve sheath tumors (MPNSTs) are tumors composed of Schwann cells that have acquired these oncogenic characteristics. MPNSTs occur spontaneously in the general population at a rate of 1 in 100,000 people per year, but more commonly occur in the context of Neurofibromatosis Type 1 (NF1), an inherited genetic disease that occurs in 1 in 2,500 live births. NF1 patients develop neurofibromas, benign tumors derived from Schwann cells throughout the peripheral nerves of the body, due to loss of the tumor suppressor gene Neurofibromin 1 (NF1). Ten percent of patients with NF1 will incur additional genetic mutations in NF1 null cells that lead to the transformation of a benign neurofibroma into an MPNST. With little known about the genetic changes that cause sporadic MPNSTs or transformation from neurofibromas to MPNST, the current treatments for patients with MPNSTs are surgical resection and non-specific chemotherapy and the 5-year survival rate remains very low at less than 25%. In an attempt to better understand the genetic drivers of Schwann cell tumors and identify potential pathways that could be targeted by small molecule inhibitors, we conducted a Sleeping Beauty (SB) unbiased, forward genetic screen in mice. This screen uncovered hundreds of genes that may play a role in Schwann cell tumor initiation, development, progression and maintenance. The following thesis will describe in detail, several of the important findings that came out of the SB screen including: the discovery and validation of canonical Wnt/<em>f</em>Ò-catenin signaling as a pathway that plays a role in Schwann cell transformation, progression and tumor maintenance, and the profound clinical implications of co-targeting the MAPK and PI3K pathways, shown to be co-activated in the SB screen using small molecule, targeted therapies.
Description
University of Minnesota Ph.D. dissertation. June 2013. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Dr. David A. Largaespada. 1 computer file (PDF); viii, 202 pages.
Related to
Replaces
License
Collections
Series/Report Number
Funding information
Isbn identifier
Doi identifier
Previously Published Citation
Suggested citation
Watson, Adrienne Leigh. (2013). Identification of genes and pathways involved in Schwann cell tumor initiation, development and progression to develop novel drug targets. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/156375.
Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.