Anette U. Duensing, MD
Assistant Professor of Pathology
Dr. Duensing is a member of the University of Pittsburgh Cancer Institute.
University of Pittsburgh Cancer Institute
Hillman Cancer Center Research Pavilion, Suite 1.8
5117 Centre Avenue
Pittsburgh, PA 15232
Office Telephone: 412-623-5870
Research InterestsThe majority of gastrointestinal stromal tumors (GISTs) are caused by oncogenic mutations in the KIT or PDGFRA protein kinases. GISTs are the prototypical example of a solid tumor entity that was fatal in the past but that can now be successfully treated with a novel class of drugs, small molecule kinase inhibitors. Imatinib mesylate (Gleevec®) is the first and most prominent inhibitor belonging to this group. Although imatinib has revolutionized the treatment of GIST, the occurrence of imatinib-resistant tumors is a problem for a large number of patients. It is therefore imperative to find novel treatment options for these patients. Although an FDA-approved second-line therapy (Sutent®) and an array of potential third-line therapeutic options are in clinical and preclinical trials, most of these compounds also target the activated KIT or PDGFRA kinase. This "kinase-centric" approach to novel therapies is difficult, however, because the most prominent imatinib-resistance mechanisms involve secondary mutations in KIT/PDGFRA genes themselves. Our laboratory therefore uses a different approach to identify novel treatments. We are focusing on two major strategies:
Over the past several years, we have successfully applied a candidate approach to find new therapeutic targets. Using this strategy, we are dissecting the molecular mechanisms of action of imatinib in the induction of apoptosis and tumor cell quiescence. Having identified the molecular players that are involved in these processes allows us to target these molecules for therapeutic purposes. The second major line of research employs medium- to large-scale screening strategies. We are currently using siRNA-based screens to identify survival genes that could be targeted for therapy in GIST. Furthermore, we are screening drug compound libraries to rapidly identify novel therapeutic agents.
We are also applying the above-mentioned strategies to other soft-tissue sarcomas, such as leiomyosarcomas.
Selected PublicationsView Dr. Duensing's publications on PubMed
Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CDM, Fletcher JA. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003; 299:708-710.
Duensing A, Medeiros F, McConarty B, Joseph NE, Panigrahy D, Singer S, Demetri GD, Fletcher CDM, Fletcher JA. Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 2004; 23:3999-4006.
Medeiros F, Corless CL, Duensing A, Hornick JL, Oliveira AM, Heinrich MC, Fletcher JA, Fletcher CDM. KIT-negative gastrointestinal stromal tumors: Proof of concept and therapeutic implications. Am. J. Surg. Pathol. 2004; 28:889-894.
Duensing A, Joseph NE, Medeiros F, Smith F, Hornick JL, Heinrich MC, Corless CL, Demetri GD, Fletcher CDM, Fletcher JA. Protein Kinase C theta (PKC ) expression and constitutive activation in gastrointestinal stromal tumors (GISTs). Cancer Res. 2004; 64:5127-5131.
Li FP, Fletcher JA, Heinrich MC, Garber JE, Sallan SE, Curiel-Lewandrowski C, Duensing A, van de Rijn M, Schnipper LE, Demetri GD. Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J. Clin. Oncol. 2005; 23:2735-2743.
Liu Y, Tseng M, Perdreau SA, Rossi F, Antonescu C, Besmer P, Fletcher JA, Duensing S, Duensing A. Histone H2AX is a mediator of gastrointestinal stromal tumor (GIST) cell apoptosis following treatment with imatinib mesylate. Cancer Res. 2007; 67:2685-2692.
Bauer S, Duensing A, Demetri GD, Fletcher JA. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-Kinase/AKT is a crucial survival pathway. Oncogene 2007; 26:7552-7559.
Liu Y, Parry JA, Chin A, Duensing S, Duensing A. Soluble histone H2AX is induced by DNA replication stress and sensitizes cells to undergo apoptosis. Mol. Cancer 2008; 7:61.
Liu Y, Perdreau SA, Chatterjee P, Wan L, Kuan, SF, Duensing A. Imatinib mesylate induces quiescence in gastrointestinal stromal tumor (GIST) cells through the CDH1-SKP2-p27Kip1 signaling axis. Cancer Res. 2008; 68:9015-9023.
Bauer S, Parry JA, Mühlenberg T, Brown MF, Seneviratne D, Chatterjee P, Chin A, Rubin BP, Kuan SF, Fletcher JA, Duensing S, Duensing A. Pro-apoptotic activity of Bortezomib in gastrointestinal stromal tumor (GIST) cells. Cancer Res. 2010; 70:150-159.
Duensing S, Duensing A. Targeted therapies of gastrointestinal stromal tumors (GIST) - the next frontiers Biochem. Pharmacol. 2010; 80:575-583.
Duensing S, Duensing A. Bortezomib: killing two birds with one stone in gastrointestinal stromal tumors. OncoTarget 2010; 1:6-8.
Reynoso D, Nolden LK, Yang D, Dumont SN, Dumont AGP, Conley AP, Zhou K, Duensing A, Trent J. Synergistic induction of apoptosis by the Bcl-2 inhibitor ABT-737 and imatinib mesylate in gastrointestinal stromal tumor cells. Mol. Oncol. 2011; 5:93-104.
Duensing A. Closing in on accurate risk prediction and disease management for patients with operable GIST. Lancet Oncol 2012; 13:220-221.