Pieper Laboratory

The Pieper lab is interested in developing better therapies for the treatment of glioma. Gliomas are among the most incurable of human malignancies, and even with aggressive therapy, the average survival of patients with GBM, the most refractory form of glioma, averages less than 2 years. GBMs display a wide variety of genetic and epigenetic alterations that are thought to contribute to gliomagenesis. The altered signaling pathways in GBM, however also serve as targets for inhibition of tumor growth. Projects in the Pieper lab are directed at better understanding which pathways are critical for glioma formation, and in rationally developing therapies that target these pathways. Studies also focus on the means by which alterations in signal transduction pathway lead to drug resistance. The studies combine pharmacology and molecular biology with cellular and animal models to help move findings in the lab to the clinical setting.

Current Research Projects

Epigenetic Mechanisms Package DNA

PTEN-mediated Regulation of Apoptotic Sensitivity
Loss of PTEN tumor suppressor protein function is among the earliest and most common alterations in glioma, and results in enhanced tumor cell survival. We are interested in discovering which PTEN-dependent pathways are important in enhancing tumor survival, and in particular in how PTEN loss alters the sensitivity of glioma cells to pro-apoptotic agents including TRAIL.

Epigenetic Mechanisms Package DNA

PTEN-mediated Regulation of Immunoresistance
Glioma patients are typically immunosuppressed, which in turn is thought to contribute to tumor formation and growth. Attempts to stimulate the immune system have been only marginally successful, presumably because sufficient levels of immune effector cells cannot be achieved. Recently however, in collaboration with the Parsa lab, we showed that an additional limitation to immune-based therapy is the ability of glioma cells to express the cell surface protein B7-H1 and eliminate attacking T cells. Surprisingly, expression of B7-H1 is regulated by the same PTEN-dependent pathways that regulate apoptotic sensitivity, suggesting that PTEN loss co-ordinately confers resistance to both apoptotic and immune-based cell death. Our current studies are investigating how this occurs and how these findings can be used to stratify patients for immune-based protocols and/or reverse the inherent resistance of glioma cells.

PTEN-mediated Regulation of Protein Stability
PTEN loss leads to increased Akt signaling and an mTOR-dependent increase in the translation of mRNAs, including those encoding pro-survival proteins. We recently found, however, that PTEN loss is also associated with global alterations in protein stability, which in turn is accomplished by a PTEN-mediated regulation of ubiquitination. We believe that PTEN uses co-ordinate regulation of linked deubiquitinase/ubiquitin ligase “switches” to accomplish global regulation of protein stability, and that this regulation is critical for PTEN’s tumor suppressor functions. As such we are interested in uncovering the full range of proteins regulated in this manner, and the PTEN-regulated ubiquitin ligases that contribute to these events.

Temozolomide Action
The majority of glioma patients will be treated with the DNA methylating agent temozolomide (TMZ). Although this agent effectively prolongs survival, nearly all patients eventually develop TMZ resistance and succumb to their disease. We are interested in identifying pathways (including those involving DNA damage sensors and cell cycle checkpoint proteins) that lead to TMZ resistance and that might serve as targets for sensitization of tumors to this important chemotherapeutic agent. We are also interested in uncovering the signaling pathways that determine cell fate following TMZ-induced G2 arrest.