A tumor depends upon many cellular processes for growth and survival. Angiogenesis, for example, allows the tumor to create its own vascular supply and thus promotes growth, survival, and metastases. Cell proliferation, on the other hand, leads to sustained cell division and tumor growth. The molecular pathways leading to these processes are multiple, complex, and often redundant. Thus, therapies which have the potential to target different pathways would provide an effective strategy for treatment. RNA stability/translational efficiency is one level of gene regulation which interfaces with many of these pathways. Genes critical for malignant glioma (MG) progression, including growth, angiogenic and anti-apoptotic factors, are regulated at the RNA level by a common motif, the AU-rich element (ARE), present in the 3' untranslated region (UTR). Stressors such as hypoxia, inflammation and tumor therapy are often overcome by upregulation of these genes through RNA stabilization and enhanced translational efficiency. Vascular endothelial growth factor (VEGF), interleukin (IL)- 8, Bcl-2 and other inhibitors of apoptosis (cIAP1 and 2), all of which drive tumor progression in MG are extensively regulated at these levels. ARE-directed post-transcriptional regulation is tightly governed by RNA binding proteins (RBP) that bind to these cis elements. Certain RBPs such as tristetraprolin (TTP) and KH-type splicing regulatory protein (KSRP) bind to the ARE and negatively regulate the mRNA target by accelerating degradation and/or silencing translation. HuR, on the other hand, binds to the same elements but promotes mRNA stabilization and enhanced translation. Since our initial observation of HuR overexpression in MG, there have been multiple reports linking HuR to high grade malignancy and poor prognosis in all of the major solid tumors (e.g. breast, lung, prostate, and colon cancer). In the previous funding cycle, we have demonstrated that HuR is required for malignant glioma growth in vivo. This background provides the rationale for the current proposal which is to investigate the anti-cancer properties of a small molecule inhibitor of HuR (MS444) in malignant glioma. We have exciting in vivo preliminary data showing an anti-cancer effect and no significant toxicity. We also have data indicating that brain tumor initiating cells, normally resistant to standard therapy, are particularly sensitive to the inhibitor. We have found that HuR inhibition may target a critical survival pathway driven by NF-kB. Our hypothesis is that MS444 inhibits glioma growth by disrupting the posttranscriptional regulation of key tumor survival pathways provided by HuR.
The specific aims will use authentic primary glioma xenolines and mouse models to further characterize this nascent class (i.e. post- transcriptional regulation) of anti-cancer targets. The common occurrence of ARE-governed RNA regulation of growth and anti-apoptotic factors across many tumors broadens the relevance of this proposal MG.
Specific Aims : 1. To characterize the antitumor phenotype of the HuR inhibitor, MS-444, in malignant glioma. 2. To characterize the molecular impact of HuR inhibition on the NF-kB survival pathway in malignant glioma as a mechanism for the anticancer effects of MS444. 3. To assess the specificity of MS444 and other HuR inhibitors for binding to HuR and blocking mRNA binding.
Cancer remains a leading cause of death among veterans. Glioblastoma multiforme, a lethal tumor of the central nervous system, may be overrepresented in certain veteran populations with war-related exposures. There is no cure for this devastating cancer, and current therapy is at best palliative. This proposal will investigate a novel class of therapeutic targets that regulae production of growth and cytoprotective factors essential for brain tumor progression. The proposal raises hope for identifying novel treatments in this devastating cancer. Moreover, the regulatory pathways investigated here are present in many other cancers including prostate, lung and breast, which broaden the relevance of this proposal.
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