Scientific Accomplishments

> Understanding the Underlying Biology of Brain Cancer
> Predicting Patient Disease, Response, and Survival
> Improving the Therapy of Brain Tumors


Theme 1: Understanding the Underlying Biology of Brain Cancer

Proliferating neural stem cells (NSCs) exist in the subventricular zone of the adult human brain and continually give rise to new neurons, glia, and, when genetically or epigenetically altered, tumor cells. The presence of NSCs in the human brain was discovered in 2004 by Dr. Arturo Alvarez-Buylla, and in a 2014 publication the Alvarez-Buylla lab provided insight into the role that cilia protruding from these cells play in NSC differentiation and cancer (Tong et al., Proc Natl Acad Sci U S A, 2014). Despite the known importance of cilia, however, work in the Alvarez-Buylla lab showed that deletion of cilia in mice resulted in defects only when targeted to a very narrow hedgehog-regulated subdomain of the subventricular zone. These studies have motivated a re-examination of the role cilia play in signal transduction in NSCs and suggest that cilia-regulated regions of the subventricular zone may play an especially important role in brain development and possibly tumor development. Like NSCs, oligodendrocyte precursor cells (OPCs) also play a role in the generation of normal brain cells (in this case oligodendrocytes) and, when disrupted, brain tumors. The lab of Dr. David Rowitch uncovered a novel mechanism regulating the differentiation of OPCs that may in turn have significant implications for our understating of OPC-driven brain tumors (Yuen et al., Cell, 2014). In this study, the Rowitch lab showed that the oxygen-sensing molecule HIF1α controls the expression and secretion of Wnt7a/7b in OPCs. Secreted Wnt7a/7b in turn arrests OPC differentiation and stimulates the proliferation of nearby endothelial cells and angiogenesis. Because most brain tumors contain olig2+ OPCs, these studies raise the possibility that brain tumors use a Wnt7a/7b-driven pathway to both suppress differentiation and drive angiogenesis. More importantly, the studies also suggest that Wnt7a inhibitors in clinical development may also be useful agents in the treatment of OPC-driven brain tumors.

Theme 2: Predicting Patient Disease, Response, and Survival

Epidemiologists in the Neurologic Oncology Program previously identified seven polymorphic DNA variants that were associated with increased risk of developing glioblastoma (GBM). In 2014, eight different program members including neurosurgeons (Dr. Mitchel Berger), neuro-oncologists (Drs. Susan Chang and Michael Prados), biostatisticians (Dr. Annette Molinaro), and epidemiologists (Drs. Judith Walsh, Wiencke, Wiemels, and Wrensch) identified two new risk loci for GBM that were associated with genes encoding TERT, the enzyme involved in telomere elongation, and TERC, the RNA component of the telomerase complex (Walsh et al., Nat Genet, 2014). Importantly, these investigators showed the TERC and TERT polymorphic variants associated with increased risk of GBM were also associated with increased constitutive telomere length. These studies not only provided the first direct link between telomere length and cancer risk but also provided two new markers that may be useful in the stratification of GBM patient risk. One of the most important recent discoveries in brain tumor biology was the observation that nearly all lower-grade gliomas contain mutations in the gene encoding isocitrate dehydrogenase (IDH). This mutation is responsible for the accumulation of cellular 2-hydroxyglutarate, an oncometabolite that alters the function of enzymes involved in chromatin remodeling and is believed to directly contribute to the generation of brain tumors. Members of the Neurologic Oncology Program led by Drs. Sarah Nelson and Ronen published three manuscripts in 2014 that may have an impact on our ability to monitor and treat IDH-mutant brain tumors (Chaumeil et al., Cancer Res, 2014, Koelsch et al., Magn Reson Med, 2014, Park et al., Cancer Res, 2014). The imaging group led by Drs. Nelson and Ronen showed that the extent of conversion of hyperpolarized [13C]αKG to [13C]glutamate, and the conversion of hyperpolarized [13C]lactate to [13C]pyruvate could be measured and used as surrogate measures of IDH status and response to the commonly used chemotherapeutic agent temozolomide, respectively. The groups also showed that hyperpolarized metabolic imaging could be accomplished not only in rodent models but also in the nonhuman primate setting. These studies pave the way for using hyperpolarized metabolic imaging for the diagnosis of IDH mutant brain tumors as well as for the non-invasive imaging of therapeutic response.

Theme 3: Improving the Therapy of Brain Tumors

A 2015 publication in Cancer Cell from the lab of Dr. William Weiss describes an advance that may lead to improved treatment of MYC-driven brain tumors (Hill et al., Cancer Cell, 2015). A variety of tumors, including brain tumors, are driven by aberrant expression of MYC family members. MYC proteins, however, have been considered undruggable based on their lack of small molecule binding surfaces. The Weiss lab, however, showed that the stability of MYCN is regulated by a kinase-independent function of Aurora A, and that the conformation of Aurora A could be inhibited by a novel class of pharmacologic agents that lead to MYCN degradation and suppression of tumor growth. These studies pave the way for new therapeutic approaches to MYC-driven brain tumors, as well as the many other types of MYC-driven cancers.