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Preclinical Discovery / Development of Novel Targets / Pathways and Novel Agents investigators

Daniel Altschuler
Contact:
Biomedical Science Tower, E-1348
200 Lothrop Street
Pittsburgh PA
Phone: 412-648-9751
Edward Chu, MD
Contact:
5150 Centre Avenue
Fifth Floor, Room 571
Pittsburgh PA
Research Interests and Keywords:
  • Colorectal cancer
  • cancer drug development
  • drug resistance
  • Chinese herbal medicine
  • early phase clinical trials
Summary

Dr. Edward Chu is involved in basic, clinical, and translational cancer research. His basic research interests are focused on the characterization of molecular mechanisms underlying the development of cellular drug resistance, especially as it relates to the fluoropyrimidine class of anticancer agents. His research group was the first to identify translational autoregulation as a novel regulatory mechanism in eukaryotes for controlling the expression of the folate-dependent enzymes, thymidylate synthase and dihydrofolate reductase. His clinical/translational research efforts focus on identifying novel drugs and treatment strategies for colorectal cancer and other GI cancers and in developing early phase clinical trials. He has a strong interest in integrating Chinese herbal medicine with standard cancer chemotherapy, with the goal of enhancing clinical activity and reducing toxicities.

Dennis Curran, PhD
Contact:
1101 Chevron Hall
Pittsburgh PA
Phone: 412-624-8240
Research Interests and Keywords:
  • Natural products total synthesis
  • new synthetic methods
  • stereochemistry
  • drug discovery
Summary
A major focus of our research is synthetic radical chemistry, and radical reactions are ideally suited for executing sophisticated cascade processes that build complex products from simple starting materials. For example, our recently developed combinatorial synthesis of the camptothecin class of anti-tumor agents features a cascade radical reaction of an isonitrile in the key final step. Using this route, we have made about 100 known and new camptothecin analogs, and some of the new ones are excellent pre-clinical candidates for the treatment of refractory solid tumors. In addition to developing new classes of cascade radical reactions directed towards other natural products, our work in the radical field focuses on new methods of stereoselection. Our recent introduction of methods for "stereoselection at the steady state" has open a new branch of kinetic stereocontrol. We have shown for the first time that it is possible to achieve stereoselection, solely by orchestrating reaction pathways and without any traditional stereoselective step such as a face or group selective reaction. In another project, we use traditional strategies for stereocontrol, but implement these with new classes of molecules like axially chiral amides. A second major focus of our group is the new field of "fluorous chemistry." Fluorous chemistry uses highly fluorinated reagents, catalysts, reactants, or substrates and capitalizes on the ready separation of fluorous reaction components like the tin hydride (C6F13CH2CH2)3SnH from standard organic (and inorganic) molecules. The new techniques are part of an emerging trend for using synthesis design to dictate separation, and we call these "strategy level separations." Fluorous reactions are highly suited for combinatorial chemistry and parallel synthesis. For example, in our Center for Combinatorial Chemistry, we use state-of-the-art technology to conduct parallel reactions, and then separate these by filtration over fluorous reverse phase silica gel. We are also developing several innovative new techniques including fluorous mixture synthesis and fluorous triphasic reactions.
Alexander Deiters, PhD
Contact:
Chevron Science Center
219 Parkman Avenue
Pittsburgh PA
Research Interests and Keywords:
  • Chemical biology
  • medicinal chemistry
  • synthetic chemistry
  • synthetic biology
  • microRNA
  • miRNA
  • optogenetics
  • photobiology
  • photochemistry
  • oligonucleotide
  • nucleic acid
  • amino acid
  • protein engineering
  • imaging
Summary
1) The discovery of new small organic molecules that inhibit or activate specific biological pathways is a major research topic in the lab. Our discovered microRNA inhibitors have therapeutic implications in cancer and viral infections. 2) We are genetically re-wiring the circuitry of bacterial and mammalian cells in order to give new functions to proteins and organisms. Our approach is based on the expansion of the genetic code with synthetic, unnatural amino acids. 3) Light is a unique control element that enables the regulation of biological processes with high spatial and temporal resolution. We are engineering light-responsive nucleic acids and proteins, and are applying them in cellular optobiological studies.
Neil Hukriede
Xia Jiang, PhD
Contact:
The Offices at Baum
Room 518, 5607 Baum
Pittsburgh PA
Phone: 412-648-9310
Research Interests and Keywords:
  • AI
  • machine learning
  • Bayesian Network
  • cancer informatics
  • biomarker discovery
  • epistasis learning
  • causal learning
  • prediction
  • decision support
Kazunori Koide, PhD
Contact:
Chevron Science Center
219 Parkman Avenue
Pittsburgh PA
Phone: 412-624-8767
Research Interests and Keywords:
  • Organic synthesis of natural products
  • anticancer agents
Summary
We are currently studying FR901464, a natural product that regulates cancer-related genes by novel mechanisms. This compound inhibits cancer proliferation at concentrations as low as 1 nM. To study FR901464, we completed a chemical total synthesis of this natural product. Combination of this powerful, stereocontrolled chemical synthesis and cell biology will provide insights into the molecular mechanisms of FR901464. More recently, we have developed an exceptionally active FR901464 analog (meayamycin) that inhibits tumor growth at 10 pM (analogouus to one pack of sugar (5 grams) in 400 Olympic swimming pools).
Yan Lin, PhD
Contact:
130 De Soto Street
Pittsburgh PA
Research Interests and Keywords:
  • Cancer bioinformatics
Lee McDermott
John Schmitz, PhD
Contact:
5117 Centre Avenue
Hillman Cancer Center G.27
Pittsburgh PA
Research Interests and Keywords:
  • Signal transduction
  • colorectal cancer
  • herbal medicine
Flordeliza Villanueva
Qiming Wang, PhD
Contact:
E1354 BSTWR
200 Lothrop Street
Pittsburgh PA
Research Interests and Keywords:
  • Signal transduction
  • protein kinases & phosphatases
  • structural pharmacology
  • cancer pharmacology
  • drug discovery
Shandong Wu
Xiang-Qun Xie, PhD, MBA
Contact:
3501 Terrace Street
529 Salk Hall
Pittsburgh PA
Research Interests and Keywords:
  • GPCR CB2 membrane protein
  • multiple myeloma
  • in silico drug design
Jan-Hendrik Beumer, PharmD, PhD
Contact:
G27E Hillman Cancer Center
Pittsburgh PA
Research Interests and Keywords:
  • Pharmacokinetics and metabolism of anti-cancer drugs
  • nucleoside analogues and epigenetic drugs
David Clump, MD, PhD
Contact:
UPMC Shadyside Hospital
Department of Radiation Oncology 5230 Centre Avenue, Posner Tower
Pittsburgh PA
Research Interests and Keywords:
  • Head and neck cancer
  • squamous cell carcinoma
  • stereotactic radiosurgery
  • IMRT
  • DNA damage repair
  • normal tissue protection
  • ATM
Summary
Dr. Clump specializes in integrating his clinical practice, which focuses on the treatment of head and neck malignancies as well as stereotactic radiosurgery, with his translational laboratory interests. As part of UPCI and UPMC CancerCenter, Dr. Clump is uniquely positioned to investigate the effects of radiation on both tumor as well as normal tissues. In this regard, he studies the DNA damage response following radiation therapy and is examining the effects of these cellular changes on tumor control as well as systemic effects.
Diwakar Davar, MD
Contact:
Hillman Cancer Center Research Pavilion, Suite 1.32d
5117 Centre Avenue
Pittsburgh PA
Phone: 412-623-7368
Research Interests and Keywords:
  • Tumor immunobiology
  • tumor microenvironment
  • checkpoint inhibition
  • early phase clinical trials
  • immunotherapy
  • melanoma
Summary
My research interests are in translational science. Specifically, I am interested in designing early-phase clinical trials based on an improved understanding of tumor immunobiology and host-tumor-microenvironment interactions. Additionally, I am interested in the mechanisms underlying non-response to checkpoint inhibition and novel approaches to overcome this non-response. My clinical interests are in the management of advanced melanoma and the development of early phase studies to test novel immunotherapeutic approaches singly and in combination in patients with advanced cancer.
Anette Duensing, MD
Contact:
Hillman Cancer Center Research
Pavilion, Suite G.17 5117 Centre Avenue
Pittsburgh PA
Phone: 412-623-7731
Research Interests and Keywords:
  • Gastrointestinal stromal tumor
  • GIST
  • targeted therapies
  • Gleevec
  • sarcoma
Summary
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.
Donna Huryn
Paul Johnston, PhD
Contact:
Salk Hall Room 1014
3501 Terrace Street
Pittsburgh PA
Phone: 412-383-6605
Research Interests and Keywords:
  • Prostate cancer
  • melanoma
  • head and neck cancer
  • squamous cell carcinoma
  • assay development
  • high throughput screening
  • high content screening
  • HTS
  • HCS
  • drug discovery
Summary
Dr. Johnston has over two decades of drug discovery experience in the pharmaceutical, biotechnology and academic sectors. Since joining the University of Pittsburgh Department of Pharmacology & Chemical Biology in 2005 to help design and build the infrastructure for a high-throughput drug discovery screening center at the Drug Discovery Institute, Dr. Johnston has led 21 screening campaigns, and reconfigured the NCI 60 cell line assays for cancer drug combination screening. In 2011, Dr. Johnston joined the Department of Pharmaceutical Sciences in the School of Pharmacy to establish chemical biology laboratories, where he has continued to conduct his research in high-throughput and high-content screening (HTS/HCS) assay development and implementation, and to establish drug discovery collaborations throughout the scientific community. His research has focused on pursuing chemical biology approaches to identify small molecules with the potential to be developed into new therapies for prostate cancer, melanoma and head and neck cancer.
Song Li, MD, PhD
Contact:
639 Salk Hall
Pittsburgh PA
Research Interests and Keywords:
  • Targeted delivery of therapeutics
  • gene regulation
Xinyu Liu, PhD
Contact:
Chevron Science Center
219 Parkman Avenue 507 CHVRN
Pittsburgh PA
Research Interests and Keywords:
  • Natural product biosynthesis
  • synthetic chemistry
  • drug discovery
Daniel Premkumar, PhD
Contact:
John G. Rangos Research Center
Children's Hospital Drive 45th and Penn Avenue
Pittsburgh PA
Phone: 412-692-9233
Research Interests and Keywords:
  • Cancer pharmacology
  • anti-glioma therapeutics
  • glioblastoma
  • signal transduction
Summary
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.
Mark Schurdak, PhD
Contact:
10045 BST 3
Pittsburgh PA
Research Interests and Keywords:
  • Systems biology
  • pharmacology
  • drug discovery
  • high-content screening
Andreas Vogt, PhD
Contact:
10047 BST3
3501 5th Ave
Pittsburgh PA
Research Interests and Keywords:
  • Drug discovery
  • high-content screening
  • zebrafish
  • phenotypic assays
  • dual specificity phosphatase
  • breast cancer
Summary
My major research interests center around the discovery of small molecules with phenotypic assays in clinically relevant cellular and whole organism models. It is becoming increasingly clear that better models of the in vivo milieu are needed to improve the discovery of new drug candidates. Zebrafish, C. elegans, and Drosophila in particular provide unique opportunities to discover novel potential therapeutics using functional assays in a living animal as a complement to cellular and tissue model approaches. Together with members in the Departments of Neurology and Developmental Biology, I have established methodology for zebrafish chemical screening, generated automated image analysis tools for quantification of reporter gene expression, and automated neurobehavioral assays in multiwell plate formats. Currently, active zebrafish discovery projects include kidney and heart regeneration, angiogenesis and vascular malformations, early safety assessment, and neurodegenerative diseases. Cancer-related research efforts include the discovery of small molecule modulators of mitogen-activated protein kinase phosphatases (MKPs), PUMA, profilin-1, and estrogen receptor alpha as treatments for metastatic breast and colon cancer.
Peter Wipf, PhD
Contact:
Chevron Science Center, Suite 758
219 Parkman Avenue
Pittsburgh PA
Phone: 412-624-8606
Research Interests and Keywords:
  • Anti-cancer therapeutics
  • drug discovery
  • anti-inflammatory agents
  • heterocyclic chemistry
  • kinase inhibitors
  • medicinal chemistry
  • mitochondrial targeting
  • natural products
  • organic synthesis
  • radiation dermatitis
  • radiation mitigation
  • radiation protection
  • reactive oxygen species scavengers
  • toll-like receptors
Summary
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.
Wen Xie, MD, PhD
Contact:
633 Salk Hall
Pittsburgh PA
Research Interests and Keywords:
  • Drug metabolism
  • gene regulation
  • nuclear hormone receptors
  • breast cancer
  • prostate cancer
  • colon cancer
  • liver disease
  • metabolic syndrome
Summary
Dr. Xie's laboratory studies orphan nuclear receptor-mediated regulation of genes encoding drug metabolizing enzymes and transporters. The same enzymes and transporters are also responsible for the homeostasis of endogenous chemicals (endobiotics) that include steroid hormones, cholesterol, lipids, bile acids and bilirubin. Research in the Xie lab has helped to establish members of the orphan nuclear receptor family, such as PXR (pregnane X receptor), CAR (constitutive androstane receptor), LXR (liver X receptor) and ROR (retinoid-related orphan receptor), as xeno- and endo-sensors that sense xeno- and endobiotics which, in turn, lead to enzyme and transporter gene regulation. This regulation has broad implications in drug metabolism and drug development. Moreover, these orphan receptors can be explored as therapeutic targets for the treatment and prevention of human diseases, such as cholestasis, jaundice, gallstone disease, breast cancer, prostate cancer, colon cancer, and metabolic syndrome. To better understand the transcriptional regulation of enzymes and transporters and the significance of this regulation in vivo, the Xie lab has created a wide array of genetic engineered mice with compromised (gene knockout), heightened (transgenic), or humanized receptor activities. The humanized mice, created by replacing the mouse receptor with its human counterpart, have provided unique tools to dissect orphan nuclear receptor-mediated gene regulation through molecular, genomic, and pharmacological approaches. Research in the Xie lab has been funded by the National Cancer Institute (NCI), National Institute of Environmental Health Sciences (NIEHS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Child Health and Development (NICHD), National Center for Complementary and Alternative Medicine (NCCAM), Department of Defense (DOD), Susan G. Komen Breast Cancer Research Foundation, and the American Heart Association (AHA). Dr. Xie is the recipient of the University of Pittsburgh Chancellor's Distinguished Research Award, the James R. Gillette International Society for the Study of Xenobiotics (ISSX) North American New Investigator Award, the American Society for Pharmacology and Experimental Therapeutics (ASPET) Division for Drug Metabolism Early Career Achievement Award, and the Joseph Koslow Endowed Chair in Pharmaceutical Sciences.
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