Abstract
Malignant gliomas are aggressive brain tumors that carry a grim prognosis to over 10,000 patients a year in the United States. The highest grade tumor, glioblastoma, has an average survival of one year with the current standard of care, which includes surgical resection, radiotherapy, and temozolomide chemotherapy. Heparin-binding EGF-like growth factor (HBEGF), first discovered in macrophages as a mitogen for vascular smooth muscle cells, is a ligand for epidermal growth factor receptor, the most commonly amplified receptor-tyrosine kinase in glioblastoma. About 30% of glioblastomas express HBEGF, and it is also commonly upregulated in tumors that express the common EGFR mutant, EGFRvIII. To date, HBEGF has not been evaluated for its ability to promote the development of malignant gliomas in vivo. Using a method for somatic cell gene transfer, we show that HBEGF cooperates with loss of tumor suppressors Cdkn2a and Pten to form malignant gliomas in vivo. These tumors share many characteristics found in human glioblastoma such as necrosis and nuclear atypia. We also demonstrate using high-throughput sequencing that these tumors share a common gene signature to the human glioblastoma samples from The Cancer Genome Atlas study. No tumors were seen with loss of Cdkn2a and Pten alone, which are the two most common tumor suppressors altered in glioblastoma. Our findings demonstrate that HBEGF can drive the development of high grade gliomas in the context of Cdkn2a and Pten loss and that these tumors closely resemble the human disease.
Citation Format: Clifford Shin, Sheri Holmen. HBEGF cooperates with Cdkn2a and Pten loss to form malignant gliomas. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 43.