Scientific Accomplishments

Scientific Accomplishments

Members of the Center’s Neurologic Oncology Program have made scientific progress in understanding the basic biology of brain tumors, in developing ways which might ultimately be useful in predicting patient response and survival, and in understanding how to better treat brain tumors. The majority of members of the Program served as first or senior authors on publications in high impact journals in the previous funding period. These accomplishments, as well as other examples of the collaborative nature of the members of the Neurologic Oncology Program are featured below. In each case, these accomplishments were shared efforts between multiple members of the Neurologic Oncology Program and other Center Programs, all of which were greatly facilitated by the direct or indirect support of the Center. The top six highlights from Neurologic Oncology Program members are:

  • In a 2007 article in Science (Merkle et al., Science, 2007), Dr. Alvarez-Buylla lab examined the factors that influence neural stem cell differentiation by examining the role of primary cilia in neural development.  Neural stem cells were known to display a single hair-like cilia in which components of the sonic hedgehog (Shh) signaling pathway were concentrated, although the role of this cilia in brain development and cancer were unknown. In a pair of follow-up studies published in Nature Neuroscience and Nature Medicine, (Alcantara Llaguno et al., Cancer Cell, 2009; Han et al., Nat Med, 2009; Han YG, Nature Neuroscience, 2008; Lim et al., Nature, 2009; Merkle et al., Science, 2007) the Alvarez-Buylla lab created animals defective in genes required for cilia formation, and studied the consequences of this defect in neural stem cells. Their studies clearly showed that cilia were found in human medulloblastomas driven by Shh signaling, but were not present in the majority of medulloblastomas driven by genetic alterations downstream of Shh signaling.

  • Dr. Rowitch lab has shown that the transcription factor olig2 was required for proliferation of neural progenitors and for glioma formation, and that this was accomplished by olig2-mediated repression of the tumor suppressor protein p21. In a study published in Neuron (Ligon et al., Neuron, 2007), the Rowitch lab showed that the ability of olig2 to drive proliferation in progenitor populations was dependent on olig2 phosphorylation at a unique triple serine motif in the protein, and that this event was developmentally regulated, helping to explain the ability of olig2 to regulate both proliferation and differentiation in the progenitor cell compartment. In a follow-up study published in Cancer Cell (Schuller et al., Cancer Cell, 2008), the Rowitch lab further expanded the role of olig2 in brain cancer by showing that in addition to regulating p21, olig2 also regulates post-translational modification of p53 in both normal and malignant neural progenitors, and in doing so, antagonizes the interaction of p53 with promoter elements of multiple target genes. Because low levels of p53 are adequate for biological responses to genotoxic damage in cells lacking olig2, these results show that olig2, which is expressed in high levels in virtually all high-grade gliomas, not only helps drive the gliomagenesis, but also contributes to the known drug resistance of these tumors.

  • In work published in Nature Biotechnology (Harris et al., Nat Biotechnol, 2010), the lab of Dr. Costello evaluated the usefulness of several different sequencing-based methods used for measuring genome-wide DNA methylation, and showed that two chromatin immunoprecipitation approaches were the most cost effective and comprehensive. These innovative approaches will ultimately be used to map DNA methylation patterns in stem cells, brain tumors, and brain tumor stem cells as part of the NIH Human Epigenome Mapping Project led by Dr. Costello.

  • The laboratory of Dr. Weiss studies how various tumors are known to vary in their sensitivity to chemotherapy, oligodendrogliomas being far more sensitive than gliomas for reasons that have not been determined. Research published in Cancer Cell by the Weiss lab helped address this issue, as well as clarify the role of stem cells in brain tumor development (Persson et al., Cancer Cell, 2010). In this publication, Weiss and colleagues showed that oligodendroglial tumors derive from progenitor cells and not aberrant stem cells, as has been shown for gliomas. Furthermore the group showed that these progenitor cells were more chemosensitive than glial stem cells, providing not only a possible explanation for the enhanced chemosensitivity of oligodendrogliomas, but also a target cell for oligodendroglioma-directed therapies.

  • Dr. Wrensch working with John Wiencke, Ph.D. (Cancer Genetics and Pediatrics Malignancies Programs), and Joe Wiemels, Ph.D. (Hematopoietic Malignancies Program), published the first identification of variations in the human genome associated with brain tumor susceptibility. This first of its kind work, which was published in Nature Genetics (Wrensch et al., Nat Genet, 2009), was based on single-nucleotide polymorphism analysis and genome-wide association, and identified polymorphic regions on chromosomes 9p21 (near CDKN2B) and 20q13.3 as regions associated with an increased risk of high-grade glioma. These findings were confirmed in two other data sets in collaborative efforts with investigators in the NIH-funded cancer centers at the Mayo Clinic and University of Texas MD Anderson, and represent the first success in defining genetic factors that contribute to brain tumor formation.

  • Dr. Pieper discovered that PTEN, a commonly deleted tumor suppressor gene in glioblastoma, plays a key role in activating mTOR, and also plays a role in the ability of mTOR to translationally regulate expression of the anti-apoptotic protein FLIPs (Kanamori et al., J Neurosurg, 2007; Nakamura et al., Cancer Res, 2008; Panner et al., Cancer Res, 2010; Panner et al., Cancer Res, 2009; Panner et al., Cancer Res, 2007). Because the pattern of FLIPs expression was strikingly similar to that of B7-H1—a tumor-associated immunosuppressive cell surface protein that induces B cell apoptosis and immunosuppression—studies were initiated in the lab of Dr. Parsa to investigate the connection between PTEN expression and B7-H1 mediated immunosuppression. The results of these studies (Anderson et al., Neurosurgery, 2007; Chi et al., J Neurosurg, 2008; Crane et al., J Immunother, 2009; Han et al., Neuroreport, 2009; Parsa et al., Nat Med, 2007), some of which were published in Nature Medicine (Anderson et al., Neurosurgery, 2007; Chi et al., J Neurosurg, 2008; Crane et al., J Immunother, 2009; Han et al., Neuroreport, 2009; Parsa et al., Nat Med, 2007), show that loss of PTEN activates expression of B7-H1 in glioblastoma cells and in primary glioblastoma, and that B7-H1 activation in tumors is associated with loss of immunosurveillance. For the first time, these studies linked loss of a tumor suppressor pathway with the generation of immunoresistance, and helped explain why tumors are frequently not recognized by the immune system.