Researchers

Karen E. Pollok, PhD
Assistant Professor of Pediatrics
Adjunct Assistant Professor of Pharmacology & Toxicology
Director, In Vivo Therapeutics Core

Assistant Professor of Pediatrics, Pharmacology & Toxicology: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine

Director, In VIvo Therapeutics Core: Indiana University Simon Cancer Center

Postdoctoral Fellowship: The Walther Oncology Center and the Department of Microbiology and Immunology, Indiana University School of Medicine

PhD: Department of Microbiology and Immunology, University of Kentucky Medical Center, Lexington, KY.

E-mail: kpollok@iupui.edu

Pub Med Search

Current Research Interests:

Novel therapeutic approaches for treatment of brain cancers and cancers that metastasize to the brain.

Research:

Cancers such as glioblastoma multiforme (GBM) as well as metastatic cancers are extremely difficult to treat and many standard therapies result in severe toxicity to hematopoietic cells located in the bone marrow, spleen, and blood. Treatment strategies that incorporate small molecule inhibitors that effectively target key survival signaling networks in cancer cells but not in normal hematopoietic cells are being pursued. In order to develop therapies, our overall approach is to integrate both pharmacokinetic and pharmacodynamic characteristics of anti-cancer regimens in humanized xenograft animal models. Our ongoing projects include:

1. Orthotopic humanized adult and pediatric brain tumor models to evaluate therapeutic potential of blocking HDM2-mediated signaling to sensitize brain tumor cells to DNA-damaging agents. The overall goal is to improve upon the standard-of-care for GBM by modulation of the p53/p73-HDM2 signaling network. Our central hypothesis is that modulation of HDM2-protein interactions via small molecule antagonists will potentiate temozolomide and/or radiation-induced DNA damage responses in GBM cells and lead to increased cell death. We are investigating both the mechanisms of action of these combination treatments at both the molecular and cellular level. Novel in vivo imaging vectors and approaches are being used to assess tumor growth and target modulation. In a collaborative effort with synthetic and in silico chemists, we have identified families of lead compounds that have the potential to block HDM2-mediated signaling but also may have a higher propensity to cross the blood-brain-barrier (BBB) and the blood-tumor-barrier (BTB). There is an unmet clinical need to identify and characterize new therapeutics with increased ability to be delivered at biologically effective doses to the brain. While the BBB and the BTB can be highly permeable at the primary tumor site, the more invasive glioma cells tend to migrate along the intact blood vessels and establish cancerous lesions in areas with an intact BBB. Identification of small molecule inhibitors to critical signaling pathways such as the HDM2-signaling networks could improve treatment of these devastating tumors.
2. Therapeutic modulation of p53-independent HDM2-mediated signaling in human metastatic xenograft models. We are investigating the therapeutic potential of tumor-cell kill by modulating HDM2-dependent signaling via HDM2 antagonists independent of p53 activity in metastatic cancers such as neuroblastoma, melanoma, and breast.
3. Therapy-mediated hematotoxicity-Mechanisms and Models. We have recently developed a humanized bone-marrow mouse model to screen for regimen-induced toxicities to the hematopoietic compartment (S. Cai et al., 2011. Clinical Cancer Research. 17:2195-2206). We are continuing to validate and optimize this novel screening approach and also determine in injection of human mesenchymal cells into the bone marrow modulates the survival of human stem and progenitor cells exposed to chemotherapy. Additionally, we continue to investigate DNA-damage response mechanisms in hematopoietic cells following exposure to high-dose chemotherapy. Future studies will focus on exploring the utility of pharmacological inhibition of the cell cycle and whether alternative exposure to treatment could be used as a means to increase the time for DNA repair in hematopoietic stem and progenitor cells which could lead to maintenance of genome stability and improve cell survival.