Steven Angus, Ph.D.
1044 W. Walnut St.
Indianapolis, IN 46202
Phone: (317) 274-8911
Research Program Membership
Department of Pediatrics
Division of Hematology/Oncology
IU School of Medicine
Dr. Angus's research interests include:
My work has been focused on the adaptive responses and acquisition of resistance to targeted inhibitors in cancer. The use of targeted therapies, such as monoclonal antibodies or kinase inhibitors, has revolutionized treatment of many cancers (e.g. Gleevec for the treatment of BCR/ABL-positive chronic myeloid leukemia (CML)). However, patients almost invariably progress as their tumors adapt and therapeutic resistance develops during treatment. Adaptation and resistance mechanisms can be evaluated by expression changes, mutations and copy number changes, and epigenetic changes detected by deep sequencing approaches. However, therapeutic bypass of a targeted inhibitor incorporates a combination of genomic and non-genomic adaptive mechanisms and ultimately results in a resistant phenotype that depends on the expression and activity of distinct kinases. While at UNC-Chapel Hill, I developed expertise in an innovative and quantitative chemical proteomics approach to study all expressed kinases—termed multiplexed inhibitor bead/mass spectrometry (MIB/MS)—from cell lines, genetically engineered mouse models (GEMMs), patient derived xenograft models, and clinical specimens. This approach enables us to quantify the functional kinome by selectively enriching for kinases based on their activity and expression level, thereby identifying potential targets for combination therapy. We integrate our proteomic methodology with next-generation sequencing (RNAseq and ChIPseq) to elucidate the molecular basis of adaptive responses and resistance. I was responsible for the analysis of genomic and adaptive kinome responses from two clinical trials at UNC—HER2-targeting responses in a multi-center, 7-day, window-of-opportunity clinical trial (Angus et al., submitted) and kinome responses in metastatic melanoma patients that have progressed on combined BRAF and MEK inhibitor therapy (Angus et al., in preparation). More recently, I performed adaptive kinome analysis as part of the Children’s Tumor Foundation SYNODOS project studying benign meningioma and Schwannoma models in neurofibromatosis type 2 (NF2). The Johnson lab served as the Omics Core for the Developmental and HyperActive Ras Tumor (DHART) SPORE where I led efforts to evaluate kinome changes for participating research groups. Thus, my lab will continue to investigate adaptive response mechanisms to specific inhibitors in (1) breast cancer—FOXA1-dependent transcriptional response to lapatinib and (2) melanoma—the consequences of clinical BRAF inhibitor polypharmacology: PTK6 inhibition and therapeutic resistance. At IU, I will continue to perform kinome analysis for the DHART SPORE and will submit a pilot grant proposal studying the kinome during plexiform neurofibroma progression to malignant peripheral nerve sheath tumors in collaboration with the Clapp lab. This project will serve as a catalyst for funding opportunities. Furthermore, my lab will work with Drs. Renbarger and Pollock to study adaptive response determinants in pediatric sarcomas, taking advantage of recently developed patient-derived xenograft models. Our goal is to provide mechanistic insight into the kinome that leads to direct therapeutic application in these orphan diseases.
Post-doctoral Fellowship - Duke Univeristy, Durham, NC 2011-2012
Ph.D. - University of Cincinnati College of Medicine, Cincinnati, OH 07/2003