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An NCI-designated Comprehensive Cancer Center, affiliated with the University of Pittsburgh School of Medicine
Research
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Dr. Altschuler's laboratory studies mechanisms of signal transduction by the second messenger cAMP in cell proliferation. cAMP-dependent protein kinase (PKA) and Exchange protein activated by cAMP (Epac) represent the main effectors of cAMP action. Both pathways converge at the level of the small GTPase Rap1b, via its Epac-mediated activation and PKA-mediated phosphorylation. The role of Rap1 activation (Epac) and phosphorylation (PKA) coordinating the early rate-limiting events in cAMP-dependent cell proliferation are studied using a multidisciplinary approach including molecular and cellular biology techniques in vitro, as well as in vivo validation using transgenic/knock in technologies in endocrine tumor models.
The 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: 1. 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. 2. 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.
The research in the laboratory of Dr. Fernandez focuses on the pharmacogenomics of adverse drug reactions. The immunogenicity of protein-based therapeutics is a major problem that can lead to life-threatening complications and reduce or eliminate the therapeutic effects of biologics. The objectives of Dr. Fernandez’s research are to elucidate the mechanism of adverse drug reaction by identifying polymorphisms (variations) in genes that can explain why certain patients are predisposed to developing immune responses to biologics, to identify therapeutic strategies that can block and maintain therapeutic drug concentrations, and to develop clinical laboratory tests that can monitor drug bioavailability and immunogenicity to indicate when a drug substitution is appropriate. Dr. Fernandez has extensively studied the immune response to the chemotherapeutic agent, asparaginase, which is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy.
Glioblastomas are highly invasive primary tumors with poor prognosis despite current therapies. Individual targeted therapies have failed to offer long-term survival benefits, although combinations of rationally selected inhibitors may have significant therapeutic applicability for these tumors. Studies by our group and others have also shown aberrant, constitutive activation of NF-kB and Akt as common features of malignant gliomas, supporting their functional role in contributing to apoptosis resistance and refractory growth despite cytotoxic chemotherapy, irradiation, and molecularly targeted therapies. This activation may in part reflect deletions of NF-kB inhibitor-alpha, a common alteration in malignant gliomas, dysregulated stimulation by cell surface tyrosine kinases, such as EGFR and PDGFR-alpha, which are amplified in molecular subsets of malignant gliomas, and mutations in PTEN and other molecular targets that drive Akt and NF-kB activation. Thus, new therapeutic approaches are urgently needed. We have demonstrated that inhibition of NF-kB, Akt, and Bcl-2 may constitute a promising strategy to enhance the efficacy of conventional therapies, such as irradiation and cytotoxic chemotherapy, and potentiate the activity of agents targeted against growth signaling mediators.
My research interests center on applying a systems biology/pharmacology approach to develop more effective drug discovery strategies that utilize integrated phenotype/function-based analysis (where all targets involved are functioning in a more physiologic relevant environment) and to better understand the molecular mechanisms that cause drugs to succeed or fail in the clinic.
The Wipf group develops tools of synthetic organic chemistry in the search for innovative new therapies and therapeutics. We identify original synthetic methods, strategies and molecular mechanisms, and we apply them in medicinal chemistry and chemical biology, total synthesis, and natural products chemistry. We select target molecules on the basis of their unique architectures and biological activities, as well as for showcasing our synthetic methods. We employ insights from flow and photochemistry, material science and nanoparticle research to improve synthetic access and modify the properties of our target compounds. Most significantly, we are committed to collaborative drug discovery and development in diverse therapeutic areas, including oncology, neurodegeneration, fibrosis, neuromuscular diseases, inflammation, and immunology.
