Glioblastomas are essentially universally lethal tumors despite aggressive therapy. Tumor invasion is a key contributor to the malignancy of glioblastomas as invasive tumor cannot be surgically resected and resists conventional therapies. Two key molecular events linked to glioma invasion are activation of the transforming growth factor-beta (TGF-beta) pathway and loss of PTEN tumor suppressor expression/function. TGF-beta is a multifunctional cytokine commonly expressed by malignant gliomas that regulates a diverse set of biological activities, including proliferation, apoptosis, differentiation, motility, extracellular matrix deposition, and angiogenesis. Although normal glia are growth-inhibited by TGF-beta, glioma cell lines are resistant to TGF-beta-mediated growth inhibition yet retain responsiveness to the tumor enhancing effects of TGF-beta - secretion of angiogenic factors, induction of invasion, and immune escape. The molecular mechanisms through which TGF-beta shifts from being a tumor suppressor to a tumor enhancer in advanced cancers are poorly understood. Like TGF-beta, PTEN expression and function are commonly altered in glioblastomas and contribute to the malignancy of these tumors. In preliminary studies, we show that (1) TGF-beta induces SMAD3 binding to PTEN, (2) loss of PTEN expression augments TGF-beta-mediated transcriptional regulation, and (3) loss of PTEN expression enhances TGF-beta-induced motility/invasion. In a recently published study, we demonstrated that a small molecule TGF-beta receptor inhibitor has activity against gliomas, illustrating the potential of TGF-beta targeted therapies. However, no single agent therapy is curative in malignant gliomas. Based on these studies, we hypothesize that loss of PTEN expression or function enhances TGF-beta signaling and invasiveness of glioblastomas, and that inhibitors of the PTEN pathway may increase the efficacy of TGF-beta inhibitors in treatment of glioblastoma. We now propose the following Specific Aims: (1) Identify the mechanism(s) by which PTEN regulates TGF-beta-mediated transcriptional activation and/or suppression. (2) Determine the impact of PTEN on TGF-beta-mediated glioma biology. (3) Determine whether inhibitors of downstream targets of PTEN -- AKT and mTOR - enhance the therapeutic efficacy of TGF-beta inhibitors in vitro and in mice bearing gliomas. Any promising new therapies can be directly translated into clinical trials at the Preston Robert Tisch Brain Tumor Center.
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