FeiginLab

our science

Our lab seeks to understand the molecular causes of cancer in order to develop better therapies and improve patient outcome. Through a combination of computational and experimental methods, we study how genes are regulated in cancer, and how changes in gene regulation and cell signaling networks drive tumor progression.

G-protein coupled receptors as cancer drug targets

GPCRs transduce extracellular signals from a variety of ligands through the plasma membrane, resulting in the modulation of intracellular signaling pathways.  This is accomplished in large measure by the activation of heterotrimeric G-proteins and downstream second messengers.  Composed of over 900 members in humans, GPCRs are seven-transmembrane proteins that regulate many physiological processes including vision, olfaction, taste, behavior and autonomic nervous system transmission.  This wide array of functions has resulted in the extensive utilization of GPCR targeted therapeutics, accounting for 30-50% of all currently used drugs.  The wide use of GPCR drugs can also be attributed to GPCR localization on the cell surface, abrogating the requirement for a drug to be cell permeable, as well as the ability of GPCRs to bind a variety of ligands, including antibodies, peptides and small molecules.  Furthermore, GPCR signaling can be tightly regulated through the utilization of agonists, antagonists and inverse agonists. However, drugs targeting GPCRs are rarely utilized in cancer treatment, despite evidence that GPCRs mediate many aspects of tumorigenesis, including cell proliferation, invasion, immune cell recruitment and secondary niche generation. Genomic analyses have uncovered GPCR mutations, copy number alterations and gene expression and methylation changes in a wide variety of cancers. We hypothesize that determining the biological implication of these genomic alterations will allow utilization of GPCR targeted therapeutics in those patients with GPCR-driven tumors. Our lab uses computational methods to select high priority GPCR targets, followed by experimental validation and therapeutic evaluation in three-dimensional cell culture and mouse models. 

Gene regulatory alterations as cancer drivers

Non-mutational alterations in cancer represent a major, underappreciated and targetable contributor to cancer pathogenesis. While the role of protein coding mutations has been extensively studied, our knowledge of mechanisms driving differential gene regulation in cancer remains largely unexplored. We have previously demonstrated that somatic mutations within gene regulatory regions can significantly alter the expression of cancer drivers, regulate oncogenic pathways, and provide prognostic information (Feigin, Garvin et al. 2017). Our current focus is a mutation-independent gene regulatory process, alternative polyadenylation (APA). APA generates mRNAs with distinct 3’ ends, frequently resulting in altered 3’-untranslated region (UTR) length. Changes in 3’-UTR length can modulate mRNA stability, function or subcellular localization through disruption of miRNA or RNA-binding protein regulation. APA factors are frequently dysregulated in cancer and thought to promote tumorigenesis by altering the expression of oncogenes and tumor suppressors. We performed the first large-scale single tumor type analysis of APA in cancer, revealing APA signatures associated with poor patient outcome, and uncovered the casein kinase CK1alpha as a novel therapeutic target in PDA (Venkat et al. 2020). We are now extending this work to understand the mechanisms by which APA factors are dysregulated in cancer, as well as determining the feasibility of targeting APA therapeutically.