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Investigating Mechanisms of Action of New and Exisiting Anticancer Agents investigators

Nathan Bahary
Research Interests and Keywords:
  • Novel treatment strategies for GI cancers
  • developmental biology using the zebrafish model system
  • vasculogenesis
  • hematopoiesis
Edward Chu, MD
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

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.

Sanja Dacic, MD, PhD
Rm. PUH C608
UPMC-PUH 200 Lothrop St.
Pittsburgh PA
Research Interests and Keywords:
  • Lung neoplasms
  • biological tumor markers
Anette Duensing, MD
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
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.
Christian Fernandez
Donna Huryn
Kazunori Koide, PhD
Chevron Science Center
219 Parkman Avenue
Pittsburgh PA
Phone: 412-624-8767
Research Interests and Keywords:
  • Organic synthesis of natural products
  • anticancer agents
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).
John Schmitz, PhD
5117 Centre Avenue
Hillman Cancer Center G.27
Pittsburgh PA
Research Interests and Keywords:
  • Signal transduction
  • colorectal cancer
  • herbal medicine
Andreas Vogt, PhD
10047 BST3
3501 5th Ave
Pittsburgh PA
Research Interests and Keywords:
  • Drug discovery
  • high-content screening
  • zebrafish
  • phenotypic assays
  • dual specificity phosphatase
  • breast cancer
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.
Wen Xie, MD, PhD
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
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.
Jan-Hendrik Beumer, PharmD, PhD
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
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
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.
Alexander Deiters, PhD
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
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.
Umamaheswar Duvvuri, MD, PhD
Eye and Ear Institute, Suite 300
203 Lothrop Street
Pittsburgh PA
Research Interests and Keywords:
  • Otolaryngology
  • translational science of head and neck cancer
Neil Hukriede
Paul Johnston, PhD
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
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.
Ajay Niranjan
UPMC Presbyterian, B400
200 Lothrop Street
Pittsburgh PA
Phone: 412-647-9699
Dandan Sun
Peter Wipf, PhD
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
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.