Recent analysis of cancer genomes suggests that complex phenotypes such as DNA damage resistance may result from perturbations of a biological network. Glioblastoma multiforme (GBM) is the most common and deadly primary adult brain cancer. Unfortunately, the majority of GBM show extreme resistance to radiation (RT) and chemotherapy (chemo). Accordingly, prognosis remains among the lowest of all tumors with a median survival of about one year. Despite this, 5-10% of GBM patients are relative long-term survivors with a median survival of 3-4 years. Through genome-wide analysis, we have discovered that these patients lack a biological network associated with RT/chemo resistance. This network is largely comprised of interferon- stimulated genes (ISGs) and is induced as part of the DNA damage response (DDR). We focus on characterizing the function of key genes in the network that strongly associate with patient survival, are predicted to regulate the network, and/or are genetically or epigenetically inactivated in GBM tumors from long- term survivors. In particular, we focus on signaling pathways that engage the network after DNA damage.
Specific Aim 1 explores how the network is activated by interferon-related signaling pathways. For this, we combine unbiased genome-wide approaches and in vitro functional assays.
Specific Aim 2 investigates how the network gene ISG15, an ubiquitin-like molecule, acts to negatively feedback on the network to limit the DDR. We characterize how ISG15 influences the chromatin environment to affect signaling events and investigate the importance of this on the DDR.
In Specific Aim 3, the biological relevance of the pathways is examined using a GBM mouse model. Here, we investigate the impact of the network on growth and RT response of GBM tumors in vivo. Through these aims, we will gain important insight into how the DDR intersects with the anti-viral response, and how the inactivation of a network of ISGs might contribute to prolonged survival of a subset of GBM patients.
Glioblastoma multiforme (GBM) is one of the most deadly cancers. We have identified a radiation and chemotherapy resistance network that is inactivated in rare long-term survivors of GBM. This proposal seeks to understand the role and function of key network genes in order to gain insight into how GBM can be rendered more responsive to therapy.
|Benci, Joseph L; Xu, Bihui; Qiu, Yu et al. (2016) Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. Cell 167:1540-1554.e12|
|Twyman-Saint Victor, Christina; Rech, Andrew J; Maity, Amit et al. (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373-7|
|Minn, Andy J (2015) Interferons and the Immunogenic Effects of Cancer Therapy. Trends Immunol 36:725-737|
|Mucaj, V; Lee, S S; Skuli, N et al. (2015) MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma. Oncogene 34:2204-14|
|Boelens, Mirjam C; Wu, Tony J; Nabet, Barzin Y et al. (2014) Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159:499-513|
|Mathew, Lijoy K; Skuli, Nicolas; Mucaj, Vera et al. (2014) miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma. Proc Natl Acad Sci U S A 111:291-6|
|Fox, Jamie L; Dews, Michael; Minn, Andy J et al. (2013) Targeting of TGF? signature and its essential component CTGF by miR-18 correlates with improved survival in glioblastoma. RNA 19:177-90|