Trainee Spotlight: Jessica Wagner
I grew up surrounded by farms and orchards in rural Shrewsbury, Pennsylvania, a small town due south of Harrisburg, near the Delaware border. Growing up, I had a deep love of science and an equally desperate desire to escape my small town. When looking for colleges, I considered only those a minimum of an eight hour car ride away with strong science programs. In the end, I picked Clarkson University, an engineering school a full eleven hours away from home in the deep cold of upstate NY (in hindsight, Underarmour should have been purchased immediately!). In 2012, I received a B.S. in Chemistry and Biomolecular Science. During my undergraduate, I also became an EMT, and learned very quickly that, although I like helping people, pursuing a career in medicine as a clinician was not for me. I loved science, and research; therefore, I began graduate school at the Penn State Hershey College of Medicine. After joining Dr. Wafik El-Deiry’s laboratory in 2014, I moved to Fox Chase Cancer Center with him and transferred to Temple University. While in Philadelphia, I spend my time split between lab-work, writing (got to get those papers!), rock climbing, and volunteering with incredible children at the Make A Wish Foundation. Nothing is more fun than granting a wish, trust me! My current career goals are to defend (and get that Ph.D.!) and then pursue a post-doctoral position. Long term, I hope to work in government research.
Previously identified and characterized by the El-Deiry lab, ONC201, is a novel and potent anti-cancer small molecule effective in killing a variety of cancer subtypes through TRAIL-dependent cell death mechanisms. Although, ONC201 was revealed to display exceptional safety and therapeutic pharmacokinetic (PK) properties in a first-in-human phase I clinical trial, a subset of cancer cells lines/tissue types were resistant to ONC201 (mechanisms of resistance under investigation), likely through TRAIL-dependent mechanisms. To target ONC201-resistant cell types with TRAIL upregulating compounds, we synthesized a family of analogues (in collaboration with Provid Pharmaceuticals and Oncoceutics) in an effort to identify additional chemical family members with improved efficacy against a broader range of cancer types. We also hoped to identify and characterize efficacy, toxicity, pharmacokinetics, and mechanism of action of these analogues. Our end goal was to identify potential analogues that may produce anti-tumor efficacy in ONC201-resistant tumors or provide better therapeutic window against less ONC201-sensitive tumor types. Based on in vitro potency improvements in human cancer cell lines and therapeutic window approximations of cell death of cancer cells compared to normal human fibroblasts, select analogues were investigated in animals for toxicity, maximum tolerated dose (MTD), and anti-tumor efficacy. The most promising analogue, ONC212, was then further evaluated to establish the PK profile, whether it works when administered orally, and efficacy in tumor types. Compared to ONC201, we noted distinct and more rapid kinetics of activity as well as improved potency in multiple human cancer cell lines in vitro. This included liver and melanoma tumor types. Future studies on these analogues including differences in their mechanisms can help us develop potential therapies targeting different tumor types from just one class of drugs!
Jessica Wagner, Christina Leah Kline, Marie D. Ralff, Avital Lev, Amriti Lulla, Lanlan Zhou, Gary L. Olson, Bhaskara Rao Nallaganchu, Cyril H. Benes, Joshua E. Allen, Varun V. Prabhu, Martin Stogniew, Wolfgang Oster & Wafik S. El-Deiry (2017) Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anticancer effects of ONC212, Cell Cycle, 16:19, 1790-1799. PubMed