Holmen Lab

Deciphering Mechanisms That Drive Primary and Metastatic Brain Tumors

Primary and metastatic brain tumors represent unique clinical challenges and often confer poor prognosis. Our research program is focused on understanding the mechanisms that drive these tumors such that vulnerabilities can be identified and therapeutically exploited. To this end, we have generated novel mouse models that not only validate the role of specific genes in tumor formation but also assess whether they are required for tumor progression and/or maintenance. High-throughput sequencing efforts have yielded an abundance of information in many cancer types. In both low grade gliomas and high grade secondary glioblastomas, a common point mutation in the metabolic gene isocitrate dehydrogenase (IDH) was identified. While these findings represented a significant breakthrough in this disease, a role for IDH in the etiology of these tumors was unclear and whether mutant IDH or products of its activity could be productively targeted for therapeutic intervention had yet to be determined. Using our unique mouse model, we demonstrated that mutant IDH is a bona fide oncogene and its oncogenic effects are mediated through its production of the oncometabolite 2-hydroxyglutarate. Likewise, analysis of melanoma patient samples revealed high levels of AKT activation in brain metastases as compared with other sites of disease. We validated this in our melanoma mouse model and demonstrated that the mechanism by which activated AKT promotes melanoma brain metastasis is through activation of proteins involved in focal adhesions. Our work has made a significant impact in these fields and has the potential to improve outcomes for patients with these cancers.