STK17A is a relatively uncharacterized member of the death-associated protein family of serine/threonine kinases which have previously been associated with cell death and apoptosis. Our prior work established that STK17A is a novel p53 target gene that is induced by a variety of DNA damaging agents in a p53-dependent manner. In this study we have uncovered an additional, unanticipated role for STK17A as a candidate promoter of cell proliferation and survival in glioblastoma (GBM). Unexpectedly, it was found that STK17A is highly overexpressed in a grade-dependent manner in gliomas compared to normal brain and other cancer cell types with the highest level of expression in GBM. Knockdown of STK17A in GBM cells results in a dramatic alteration in cell shape that is associated with decreased proliferation, clonogenicity, migration, invasion and anchorage independent colony formation. STK17A knockdown also sensitizes GBM cells to genotoxic stress. STK17A overexpression is associated with a significant survival disadvantage among patients with glioma which is independent of age, molecular phenotype, IDH1 mutation, PTEN loss, and alterations in the p53 pathway and partially independent of grade. In summary, we demonstrate that STK17A provides a proliferative and survival advantage to GBM cells and is a potential target to be exploited therapeutically in patients with glioma.

Warmer temperatures are expected to increase the incidence of Lyme disease through enhanced tick maturation rates and a longer season of transmission. In addition, there could be an increased risk of disease export because of infected mobile hosts, usually birds. A temperature-driven seasonal model of Borrelia burgdorferi (Lyme disease) transmission among four host types is constructed as a system of nonlinear ordinary differential equations. The model is developed and parametrized based on a collection of lab and field studies. The model is shown to produce biologically reasonable results for both the tick vector (Ixodes scapularis) and the hosts when compared to a different set of studies. The model is used to predict the response of Lyme disease risk to a mean annual temperature increase, based on current temperature cycles in Hanover, NH. Many of the risk measures suggested by the literature are shown to change with increased mean annual temperature. The most straightforward measure of disease risk is the abundance of infected questing ticks, averaged over a year. Compared to this measure, which is difficult and resource-intensive to track in the field, all other risk measures considered underestimate the rise of risk with rise in mean annual temperature. The measure coming closest was “degree days above zero.” Disease prevalence in ticks and hosts showed less increase with rising temperature. Single field measurements at the height of transmission season did not show much change at all with rising temperature.

Neuroblastoma is the leading cause of cancer death in young children. Although treatment for neuroblastoma has improved, the 5-year survival rate of patients still remains less than half. Recent studies have indicated that bevacizumab, an anti-VEGF drug used in treatment of several other cancer types, may be effective for treating neuroblastoma as well. However, its effect on neuroblastoma has not been well characterized. While traditional experiments are costly and time-consuming, mathematical models are capable of simulating complex systems quickly and inexpensively. In this study, we present a model of vascular tumor growth of neuroblastoma IMR-32 that is complex enough to replicate experimental data across a range of tumor cell properties measured in a suite of in vitro and in vivo experiments. The model provides quantitative insight into tumor vasculature, predicting a linear relationship between vasculature and tumor volume. The tumor growth model was coupled with known pharmacokinetics and pharmacodynamics of the VEGF blocker bevacizumab to study its effect on neuroblastoma growth dynamics. The results of our model suggest that total administered bevacizumab concentration per week, as opposed to dosage regimen, is the major determining factor in tumor suppression. Our model also establishes an exponentially decreasing relationship between administered bevacizumab concentration and tumor growth rate.

Current targeted therapies for glioblastoma multiforme (GBM) fail to significantly improve clinical outcome. Identifying new molecular targets driving GBM tumorigenesis is imperative. Our previous study demonstrated that STK17A, a serine-threonine kinase in the death-associated protein family, is a bona fide p53 target gene. In silico analyses indicated that STK17A is highly overexpressed in GBM patients in a tumor grade-dependent manner. Furthermore, high STK17A expression correlated with poor clinical outcome and decreased survival of patients from multiple datasets. This correlation was independent of age, tumor subtype and known biomarkers such as EGFR, NF1, and IDH, suggesting STK17A may contribute to GBM development and progression. In vitro experiments confirmed increased mRNA and protein expression of STK17A in GBM cells compared to immortalized normal human astrocytes and other cancer types. ShRNA mediated STK17A knockdown in GBM cells decreased cell survival and sensitized cells to genotoxic stress. In addition, STK17A knockdown led to reduced tumor cell proliferation and clonogenicity, suggesting a tumor-promoting role for STK17A in GBM. Interestingly, STK17A depletion resulted in a cell morphological change from a spindle-like phenotype to a phenotype with a flattened, enlarged and more rounded shape that was associated with induction of actin stress fibers. This cytoskeleton remodeling was associated with impaired cell migration and invasion. In contrast STK17A overexpressing cells displayed a pronounced needle-like elongated phenotype. In addition genome-wide expression analysis of STK17A knockdown GBM cells revealed regulation of genes involved in glycolysis including PKM2, PGAM1 and HK2, suggesting that STK17A may also promote tumor growth and survival through regulating metabolism. Small molecule inhibitors that block the kinase activity of STK17A decreased cell survival of GBM cells cultured under both serum and serum-free conditions. Further investigation is required to understand the precise role of STK17A in GBM. Citation Format: Pingping Mao, Mary P. Jardine, Gilbert J. Rahme, Eric C. Yang, Janice Tam, Anita Kodali, Bijesh Biswal, Camilo E. Fadul, Arti B. Gaur, Mark A. Israel, Alexandre Pletnev, Michael Spinella. STK17A is a potential therapeutic target in glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4605. doi:10.1158/1538-7445.AM2014-4605

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