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Notes From Our Labs – February 2019

From the Lab of Corrine Linardic at Duke University: Our lab is still working on the role of dysregulated developmental pathways in fusion-positive and fusion-negative rhabdomyosarcoma. As an example, we’ve delved very deeply into the role of Hippo signaling in rhabdomyosarcoma. This is a really interesting pathway because it’s the same one that controls organ size (for example, liver) during normal development of organisms, ranging from fruit-flies all the way up the evolutionary ladder to humans. We are trying to understand how dysregulated Hippo signaling impacts both types of rhabdomyosarcoma, and from there working on identifying new therapeutic targets. From the Lab of Charles Keller at cc-TDI Big Data Analytics of a massive drug screen by Cell of Origin We have partnered with a major pharmaceutical company to conduct an unprecedented screen of more than 640,000 compounds that, when combined, could offer new treatments for pediatric cancers that haven’t seen progress in decades such as: Rhabodmyosarcoma, Neuroblastoma, DIPG, ETMR, Wilms’ tumor and Osteosarcoma. The screen has produced a short list of high-priority drugs that will allow cc-TDI to follow the best leads for treating these types of cancer and drive them to clinical trials. To do this, we will combine machine learning powered by an Intel spin-out and an engineering-forward “Cancer Math” approach to reveal cell signaling inter-dependencies for each cell-of-origin and mutational profile combination. From these aims, we will create a knowledge base not only of tumor cell pathway inter dependencies, but also therapeutic approaches to inducing tumor cell death or myodifferentiation that translate quickly to national & international cooperative group clinical trials. From the Lab of Eleanor Chen at University of Washington am a physician scientist with clinical and research interests in sarcoma pathogenesis and therapeutic target discovery. My current research focus is on understanding the pathogenesis of rhabdomyosarcoma (RMS), a devastating pediatric cancer with less than 30% survival rate for patients with advanced disease. Identifying and characterizing novel and essential genes regulating RMS tumor growth and progression will improve our understanding of RMS pathogenesis and translate into potential novel therapeutic strategies to improve survival outcome of RMS patients. RMS, like several other sarcoma subtypes, is driven by dysregulated activity of epigenetic regulators. My laboratory has previously utilized tools in chemical genetics, functional genomics, gene editing and pre-clinical animal models to characterize the essential role of the Histone Deacetylases in regulating RMS tumor growth and differentiation (Vleeshouwer-Neumann et al., 2015; Phelps et al., 2016). We will use similar set of tools to identify and characterize other essential epigenetic regulators in RMS. Our other ongoing projects include characterizing novel kinases essential for regulating cancer stem cell function in RMS as well as essential downstream mediators of RAS, a major driver of cancer growth and progression for the embryonal subtype of RMS. From the Lab of Chris Vakoc at Cold Springs Harbor Laboratories Rhabdomyosarcoma is a highly metastatic soft tissue malignancy of childhood for which new therapies are desperately needed. The clinical management of RMS patients has been largely unchanged over the past three decades, and is currently limited to surgical resection, radiotherapy, and combination chemotherapy. In this context, a mechanism-based targeted therapy would have potential for a transformative impact on RMS patient outcomes. The Vakoc group at Cold Spring Harbor Laboratory is using the latest innovations in genome editing technology to reveal new therapeutic targets in rhabdomyosarcoma. The unique focus of their approach is a technique called domain-focused CRISPR screening, which allows for high-resolution mapping a functionally important surfaces of proteins for their critical role in cancer maintenance. This tool is ideally suited for revealing ‘druggable pockets’ on proteins, which might serve as targets for targeted therapies in rhabdomyosarcoma patients.