Program Members

Co-Leaders

Ronald Buckanovich, MD, PhD
Contact:
204 Craft Avenue, B333
Pittsburgh PA
Phone: 412-641-4721
Research Interests and Keywords:
  • Ovarian cancer
  • cancer stem cells
  • tumor vasculature
  • targeted therapies
Summary
Cancer stem cells (CSC) are rare, inherently chemoresistant cells, which have the capacity to differentiate and generate the numerous cancer cell types observed in a tumor. CSC are hypothesized to be the primary source of cancer recurrence and ultimately a patient's demise. The primary objective of my laboratory is to understand cellular interactions in the tumor vascular/cancer stem cell niche with the goal of developing novel therapeutics targeting CSC proliferation and differentiation. In order to characterize these interactions, we have performed an extensive characterization of ovarian CSC and have begun to define a differentiation hierarchy of the ovarian CSC. In addition, we have characterized several components of the ovarian CSC niche; we have extensively characterized the ovarian tumor vasculature, tumor vascular associated leukocytes, and cancer associated mesenchymal stem cells. We have developed novel in vitro microfluidics devices as a means to study symmetric versus asymmetric divisions of CSC, and novel human in vivo tumor models for the study of ovarian CSC growth and differentiation. Finally, we have developed tumor vascular niche targeted nanoparticle platform with which to assess the efficacy of CSC targeted therapies delivered specifically to CSC. We are now perfectly placed to significantly develop the field of cancer stem cell based differentiation targeted therapies.
Steffi Oesterreich, PhD
Contact:
B411 Magee-Womens Research Institute
204 Craft Avenue
Pittsburgh PA
Research Interests and Keywords:
  • breast cancer
  • ovarian cancer
  • estrogen receptor
  • invasive lobular carcinoma
  • epigenetics
  • chromatin
  • coregulators
  • bone metastases
  • lobular carcinoma in situ
  • mutations
Summary
The main interest of Dr. Oesterreich's laboratory is to further our understanding of hormone action in women's cancers (including both breast and ovarian cancers), with the ultimate goal to use this knowledge for improved diagnosis and endocrine treatment. These studies include many aspects of translational breast cancer research utilizing basic biochemistry, molecular and cell biology, and cell lines, mouse models and clinical samples. Over the last few years, Dr. Oesterreich has developed a strong research interest in in situ and invasive lobular disease, the second most common yet understudied histological subtype of breast cancer. In her role as Director of Education at the Women's Cancer Research Center, Dr. Oesterreich is also very interested in providing outstanding training opportunities to the next generation of women's cancer researchers.

Members

Nduka Amankulor
Program(s): Cancer Biology
Research Interests and Keywords:
  • Microenvironment and immune escape in glioblastoma
  • oligodendroglioma
  • brain and spine metastases
Ivet Bahar
Program(s): Cancer Biology
Michael Becich, MD, PhD
Program(s): Cancer Biology
Contact:
5607 Baum Boulevard
Room 521
Pittsburgh PA
Research Interests and Keywords:
  • Translational bioinformatics
  • oncology informatics
  • tissue banking and pathology informatics
  • prostate tumor cell biology
  • research resource development
  • content-based image retrieval and digital libraries
Takis Benos, PhD
Program(s): Cancer Biology
Contact:
Department of Computational and Systems Biology
Biomedical Science Tower 3, Suite 3064 3501 Fifth Avenue
Pittsburgh PA
Phone: 412-648-3315
Andrea Berman
Program(s): Cancer Biology
Timothy Burns, MD, PHD
Program(s): Cancer Biology
Contact:
Hillman Cancer Center Suite 2.18
5117 Centre Avenue
Pittsburgh PA
Phone: 412-623-7877
Research Interests and Keywords:
  • Mutant KRAS
  • oncogenes
  • non-small cell lung carcinoma
  • lung cancer
  • TWIST1
  • chemoresistance
  • Hsp90 inhibitors
  • targeted cancer therapies
  • acquired resistance
  • brain metastases
Summary
Lung cancer is the leading cause of cancer death in the United States and worldwide. Recent advances in the treatment of non-small cell lung carcinoma (NSCLC) have come from recognition that NSCLC is not a single disease entity, but rather a collection of distinct molecularly driven neoplasms. This paradigm is typified by the recent progress made in the treatment of patients with EGFR-mutant and EML4-ALK translocation-driven adenocarcinomas of the lung with tyrosine kinase inhibitors targeting these oncogenes. Unfortunately, little progress has been made in the treatment of patients with the most frequently observed driver oncogene, mutant KRAS. KRAS is mutated in approximately 25% of all NSCLC, and patients with this mutation have an increased risk of recurrence in early stage disease and have a worse prognosis with metastatic disease. My research and clinical interests revolve around the development of targeted therapies for KRAS-mutant NSCLC as well as novel strategies to overcome resistance to targeted therapies for EGFR-mutant and MET-altered NSCLC. The first line of research in my laboratory focuses on the role of the epithelial'mesenchymal transition transcription factor TWIST1 in oncogene-driven NSCLC. We have demonstrated the TWIST1 is essential for lung tumorigenesis for several key oncogenic drivers including KRAS mutant, EGFR mutant and MET mutant/amplified NSCLC. Furthermore, we have demonstrated that TWIST1 overexpression leads to resistance to EGFR and MET targeted therapies. We are currently examining the mechanism(s) through which this occurs and developing therapeutic combinations to overcome this resistance. Furthermore, we are exploring whether targeting the HGF-MET-TWIST1 pathway can be an effective strategy for preventing or treating lung brain metastases. Importantly, we have developed a novel TWIST1 inhibitor which serves a tool compound for our therapeutic studies and serves as the basis for our current drug screening efforts in order to develop a TWIST1 inhibitor that we can translate to the clinic. The second line of research in my lab focuses on studying the mechanisms of resistance to the Hsp90 inhibitor, ganetespib in KRAS-mutant NSCLC so that we can use to develop a rationally designed Hsp90 inhibitor combination for the clinic which can prevent or overcome resistance. Of note, we have recently demonstrated that the ERK-p90RSK-CDC25C pathway plays a key role in resistance to Hsp90 inhibitors through bypass of a G2/M checkpoint. These data suggest that the combination of an ERK inhibitor with an Hsp90 inhibitor maybe effective in KRAS mutant NSCLC and we hope to test this combination in early phase trials soon.
Carlos Camacho
Program(s): Cancer Biology
Contact:
University of Pittsburgh, Room 3077
3501 Fifth Avenue
Pittsburgh PA
Phone: 412-648-7776
Uma Chandran, PhD, MSIS
Program(s): Cancer Biology
Contact:
Room 513
5607 Baum Boulevard
Pittsburgh PA
Research Interests and Keywords:
  • Bioinformatics
Lan Coffman
Program(s): Cancer Biology
Contact:
Magee-Womens Research Institute, B401
204 Craft Avenue
Pittsburgh PA
Phone: 412-641-2016
Gregory Cooper
Program(s): Cancer Biology
Farzad Esni, PhD
Program(s): Cancer Biology
Contact:
John G. Rangos Research Center, Room 6123
One Children's Hospital Drive 4401 Penn Avenue
Pittsburgh PA
Research Interests and Keywords:
  • Pancreas
  • regeneration
  • pancreatic cancer
  • adult stem cells
  • macrophage
Summary
My lab studies pancreatic regeneration and cancer. Both tissue regeneration and cancer rely on complex interactions between cells that provide necessary signals for each process, and cells that are receptive to those signals. We have shown that the influx of macrophages during pancreatic regeneration not only serves to debride the site of injury, but it is also critical for creating microenvironments for cell-specific differentiation. In my lab, we also study a population of progenitor-like cells, which is highly abundant in the regenerating mouse pancreas. More importantly, we have identified a similar population in the adult human pancreas, which expands significantly in both chronic pancreatitis and Type 1 diabetic patients. These cells are normally found within the ductal network, but lack many ductal cell characteristics. Our lineage tracing studies show that while these cells under certain conditions can give rise to acinar and endocrine cells, upon oncogenic Kras activation, they transform to premalignant lesions and then to pancreatic invasive ductal adenocarcinoma. Pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Recent studies have suggested that it takes about 17 years from the time of tumor initiation to the time of patient's death. This timeline offers opportunities for early detection and intervention. Our goal is to better understand the transformation of noninvasive precursor lesions to invasive ductal adenocarcinomas.
Bruce Freeman, PhD
Program(s): Cancer Biology
Contact:
E1340 Thomas E. Starzl Biomedical Science Tower
200 Lothrop Street
Pittsburgh PA
Research Interests and Keywords:
  • Inflammation
  • cell proliferation
  • redox signaling
  • free radical
  • nitric oxide
  • lipid signaling
  • pharmacology
  • drug discovery
Summary
Bruce Freeman, PhD is a biochemist and pharmacologist who investigates eukaryotic cell production and actions of reactive inflammatory and signal transduction mediators (e.g., superoxide, nitric oxide, peroxynitrite, electrophilic lipids). He is presently the Irwin Fridovich Professor and Chairman of the Department of Pharmacology and Chemical Biology at the University of Pittsburgh School of Medicine, is a founding member of the Vascular Medicine Institute and a member of the University of Pittsburgh Cancer Institute. His laboratory team has made seminal discoveries related to the tissue production and target molecule reactions of reactive inflammatory mediators, which in turn reveals the fundamental process of redox reaction-regulated cell signaling. These insights have led to Dr. Freeman's identification of new drug strategies for treating metabolic diseases, fibrosis and acute/chronic inflammatory disorders. His team pioneered the concept that nitric oxide has cell signaling and pathogenic actions modulated by a reaction with superoxide, yielding the oxidizing and nitrating species peroxynitrite. Their studies of heme peroxidases have also shown additional pathways leading to biomolecule oxidation and nitration. His laboratory also discovered that metabolic and inflammatory reactions of unsaturated fatty acids yield electrophilic nitro and keto derivatives of unsaturated fatty acids, products that manifest potent anti-inflammatory and tissue-protective signaling actions. His discovery of nitric oxide reactions with products various oxidases and peroxidases has also revealed clinically-significant mechanisms of catalytic nitric oxide consumption that occur during inflammation and metabolic syndrome. His mass spectrometry-based observations of peroxynitrite, peroxidase and electrophilic fatty acid-induced post-translational protein modifications further underscore the significance of redox reactions in regulating cell and organ function. This work has led to numerous issued patents and >250 peer-reviewed publications in high impact basic science and clinical journals. Previously, Dr Freeman was Professor of Anesthesiology, Biochemistry and Molecular Genetics and Environmental Health Sciences at the University of Alabama at Birmingham. He was also Vice Chair for Research in the Department of Anesthesiology and Director of the UAB Center for Free Radical Biology. Prior to service at UAB, he trained at the University of California and Duke University, where he also served on the faculty. He has been the recipient of a number of honors, including being named a Fulbright Research Scholar and serving as an invited lecturer at Nobel Forums. He and his lab team have won more than $40 million in extramural funding to support their research activities. Dr. Freeman's academic leadership has also propelled students, fellows and faculty colleagues into prominent basic science, clinical investigator and pharmaceutical industry positions.
Ferruccio Galbiati, PhD
Program(s): Cancer Biology
Contact:
W1057 Thomas E. Starzl Biomedical Science Tower
Pittsburgh PA
Research Interests and Keywords:
  • Caveolin
  • senescence
  • oxidative stress
  • cancer
  • aging
  • age-related disease
Summary
Most cells can not divide indefinitely due to a process termed cellular senescence. Because cancer cells need to escape cellular senescence in order to proliferate and eventually form tumors, it is well accepted that cellular senescence is a powerful tumor suppressive mechanism. In addition, since several molecular changes that are observed in senescent cells occur in somatic cells during the aging process, investigating the molecular mechanisms underlying cellular senescence will also allow us to better understand the more complicated aging process. Thus, molecules that regulate cellular senescence represent potential therapeutic targets for the prevention and treatment of cancer as well as the fight against aging. Our work is directed at unraveling the role of caveolin-1 as a novel mediator of cellular senescence. Caveolin-1 is the structural protein component of caveolae, invaginations of the plasma membrane involved in signal transduction. Caveolin-1 acts as a scaffolding protein to concentrate, organize, and functionally modulate signaling molecules within caveolar membranes. Our laboratory was the first to demonstrate that caveolin-1 plays a pivotal role in oxidative stress-induced premature senescence. We found that oxidative stress upregulates caveolin-1 protein expression through the p38 MAPK/Sp1-mediated activation of the caveolin-1 gene promoter. We also demonstrated that upregulation of caveolin-1 protein expression promotes premature senescence through activation of the p53/p21Waf1/Cip1 pathway by acting as a regulator of Mdm2, PP2A-C, TrxR1 and Nrf2. Moreover, we found that caveolin-1-mediated premature senescence regulates cell transformation and contributes to cigarette smoke-induced pulmonary emphysema, directly linking caveolin-1's function to age-related diseases. Taken together, our findings indicate that caveolin-1 plays a central role in the signaling events that lead to cellular senescence. Our current main research interest is the identification, at the molecular level, of novel signaling pathways that link caveolin-1 to oxidative stress-induced premature senescence and the characterization of their relevance to aging and age-related diseases using both cellular and animal models. These investigations will provide novel insights into the cellular and molecular mechanisms underlying aging and cancerous cell transformation and will identify novel molecular targets that can be exploited for the development of alternative therapeutic options in the context of age-related diseases, including cancer.
Madhavi Ganapathiraju
Program(s): Cancer Biology
Andrew Hinck
Program(s): Cancer Biology
Yang Hong
Program(s): Cancer Biology
Baoli Hu
Program(s): Cancer Biology
Yu Jiang
Program(s): Cancer Biology
Adrian Lee, PhD
Program(s): Cancer Biology
Contact:
Magee-Womens Research Institute
204 Craft Avenue, A412
Pittsburgh PA
Phone: 412-641-7739
Research Interests and Keywords:
  • Breast cancer
  • steroid receptors
  • growth factor signaling
  • estrogen receptor
  • progesterone receptor
  • insulin-like growth factor
  • tumor heterogeneity
Summary
The goal of the Lee laboratory is translational breast cancer research. The laboratory has two main areas of focus. The first involves targeting the insulin-like growth factor pathway in breast cancer. A major emphasis is upon the downstream signaling intermediates the insulin receptor substrates (IRSs) analyzing interactions with steroid hormone receptors (ER and PR), role in normal mouse mammary gland development, mechanisms of transformation of mammary epithelial cells in vitro and in mouse models, and roles in human breast cancer. The second area of research is studies on tumor heterogeneity and molecular changes during progression, with a particular focus on DNA and RNA structural rearrangements. The laboratory participated in the first comprehensive report of structural rearrangements in a breast cancer cell line (MCF7) and reported on a novel massively parallel fosmid-based mate-pair assay for determining structural rearrangements. This work focuses on different tumor areas, or tumors from different parts of the body (obtained via rapid autopsy) to identify novel changes that may offer therapeutic insight. In addition, the University of Pittsburgh is the largest contributor of tissue to The Cancer Genome Atlas (TCGA), and many results are validated in these index cases.
Yong Lee, PhD
Program(s): Cancer Biology
Contact:
Hillman Cancer Center
5117 Centre Avenue Lab 1.33
Pittsburgh PA
Phone: 412-623-1005
Research Interests and Keywords:
  • Colorectal cancer
  • TRAIL
  • chemotherapeutic agents
  • hyperthermia
  • NK cells
Summary
Colorectal cancer is one of the most common cancers in both men and women in the United States, and accounts for approximately 140,000 new cases annually. Hepatic metastases as the dominant site of life-limiting disease occur in approximately 20'50% of patients with colorectal cancer. Although regional treatment options including hyperthermic isolated hepatic perfusion (HIHP) and percutaneous IHP offer the benefits of both aggressive local treatment and limited systemic toxicity, the management of unresectable colorectal liver metastases remains a major unsolved issue and more effective novel regimens are needed. I am interested in developing a novel strategy for HIHP therapy. I hypothesize that a combinatorial treatment of chemotherapeutic agent oxaliplatin, biologic agent TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-armed natural killer (NK) cells and mild hyperthermia is effective to treat unresectable colorectal liver metastases. The specific aims of this project are to investigate: 1) the mechanism of synergistic anti-tumor efficacy caused by secretory TRAIL-armed NK cell-based multimodality treatment; and 2) the preclinical efficacy of this combinatorial treatment in a rat isolated hepatic perfusion model.
Gang Li
Program(s): Cancer Biology
Xinghua Lu
Program(s): Cancer Biology
Peter Lucas
Program(s): Cancer Biology
Linda McAllister-Lucas
Program(s): Cancer Biology
George Michalopoulos, MD, PhD
Program(s): Cancer Biology
Contact:
450 Technology Drive
Suite 300
Pittsburgh PA
Research Interests and Keywords:
  • Growth factors and receptors in hepatocytes
  • growth regulation of human hepatocytes
  • hepatic carcinogenesis
Satdarshan Monga, MD
Program(s): Cancer Biology
Contact:
S400 BST South
200 Lothrop Street
Pittsburgh PA
Research Interests and Keywords:
  • Signal transduction
  • Wnt/beta-catenin
  • HGF/Met
  • EGF
  • PDGF
  • growth factors
  • liver development
  • hepatic physiology
  • liver disease
  • liver cancer
  • hepatocellular carcinoma
Summary
Dr. Monga's laboratory is focused on understanding the molecular mechanisms of liver growth and development in health and disease, especially in the context of regeneration and cancer. Several signaling pathways have been identified to direct such events, including the Wnt/beta-catenin, HGF/Met, and PDGFR pathways.

Liver development in mice is initiated at around E8-8.5 stages of gestational development. Once foregut endoderm gains competence hepatic signatures are initiated during the process of which undergo expansion and regulated differentiation into hepatocytes and biliary epithelial cells during the process of morphogenesis. One of the major focuses of the Monga laboratory is to identify the molecular basis of hepatic morphogenesis. More specificallyinduction. The primitive liver bud contains bipotential stem cells or progenitors how does the hepatic progenitor or the bipotential stem cell undergo self-renewal (symmetric division) lineage specification and differentiate further towards primitive bile duct cells or immature hepatocytes (asymmetric division) and then to fully differentiated cells? Using conditional null mice embryonic liver cultures and other modalities the lab is investigating the roles regulation and interactions of various pathways which will not only further our understanding of this fundamental biological process but might also provide insight into the molecular basis of disease that recapitulates development in adulthood hepatocellular cancer (HCC). HCC is the third leading cause of cancer death and remains a disease with poor treatment options. Targeting pathways that are normally upregulated during liver development at the time of peak proliferation and stem cell renewal represents a novel therapeutic measure for the treatment of HCC."

Hatice Osmanbeyoglu, PhD
Program(s): Cancer Biology
Contact:
UPMC Hillman Cancer Center Research Pavilion
Suite G27c, 5117 Centre Ave.
Pittsburgh PA
Phone: 412-623-7789
Research Interests and Keywords:
  • Computational oncology
  • Cancer epigenetics
  • Omics approaches in immunology and immunotherapy
Hongjiao Ouyang, DDS, PhD, DMD
Program(s): Cancer Biology
Contact:
630 Salk Hall
Pittsburgh PA
Phone: 412-648-8499
Research Interests and Keywords:
  • Bone development and homeostasis
  • tumor microenvironment
  • signal transduction
  • bone metastasis
  • multiple myeloma
Summary
Dr. Ouyang's laboratory investigates molecular and cellular mechanisms underlying the development, homeostasis, and diseases of mineralized tissues and to identify promising therapeutic targets to treat oral diseases and systemic diseases with prominent craniofacial manifestations, focusing on endoplasmic reticulum (ER) stress, Wnt and mammalian target of rapamycin (mTOR) signaling. In addition, Dr. Ouyang's research team is dedicated to understanding whether and how key regulators of bone development and homeostasis modulate bone microenvironment support of tumor bone metastasis, focusing on multiple myeloma bone disease, one of the most devastating tumor bone diseases that heavily affects craniofacial structures.
Edward Prochownik
Program(s): Cancer Biology
Partha Roy
Program(s): Cancer Biology
J. Peter Rubin
Program(s): Cancer Biology
Shilpa Sant, PhD
Program(s): Cancer Biology
Contact:
527 Salk Hall
3501 Terrace Street
Pittsburgh PA
Phone: 412-648-9804
Research Interests and Keywords:
  • Biomimetic microenvironments
  • tissue engineering
  • 3D tumor models
  • drug delivery
Summary
The goal of our laboratory is to develop an independent and multidisciplinary research program at the interface of biomaterials, controlled drug delivery, and tissue engineering. We use an interdisciplinary approach to build biomimetic microenvironments in vitro based on our expertise in the pharmaceutical sciences, materials sciences, cell biology and micro/nanotechnologies. Specifically, we aim to develop tissue-engineered tumor models that recreate the three-dimensional structure, cell-cell/cell-matrix interaction, stromal environments, and signalling cues present in vivo. These three-dimensional models will be used for understanding the pathophysiology of the disease as well as for preclinical evaluation of drug safety and efficacy.
Frank Sciurba, MD, FCCP
Program(s): Cancer Biology
Contact:
UPMC Montefiore Hospital - NW628
3459 Fifth Avenue
Pittsburgh PA
Research Interests and Keywords:
  • Molecular epidemiology
  • pharmacogenomics
  • cancer susceptibility
Malabika Sen
Program(s): Cancer Biology
Jonathan Silverstein, MD, MS, FACS, FACMI
Program(s): Cancer Biology
Contact:
Department of Biomedical Informatics
Room 433, 5607 Baum Boulevard, Suite 500
Pittsburgh PA
Phone: 412-624-8950
Research Interests and Keywords:
  • Clinical Informatics
  • Imaging/Visualization/Virtual Reality
  • Vocabularies
  • Virtual Organizations
  • Learning Health Systems
  • Oncology Informatics
Alexander Sorkin, PhD
Program(s): Cancer Biology
Contact:
3500 Terrace Street
S368 Biomedical Science Tower (South)
Pittsburgh PA
Laura Stabile, PhD
Program(s): Cancer Biology
Contact:
Hillman Cancer Center
5117 Centre Avene Lab 2.7
Pittsburgh PA
Phone: 412-623-7821
Research Interests and Keywords:
  • Hormones
  • estrogen
  • estrogen receptor
  • epidermal growth factor receptor
  • fibroblast growth factor receptor
  • hepatocyte growth factor
  • vascular endothelial growth factor
  • signal transduction
  • lung cancer
  • targeted cancer therapies
Summary
Dr. Stabile's laboratory is focused on the role of growth factors and hormones in the development of non-small cell lung cancer. Estrogen receptor signaling has been shown to be important in inducing proliferation in lung tumor preclinical models as well as promoting aggressive disease in lung cancer patients. We have demonstrated both genomic and non-genomic effects of estrogen in the lung and have elucidated cross-talk between the estrogen signaling pathway and multiple growth factor pathways including epidermal growth factor receptor, fibroblast growth factor receptor, hepatocyte growth factor and vascular endothelial growth factor. These preclinical studies have led to clinical trials examining the effectiveness of the anti-estrogen fulvestrant combined with targeted therapies for advanced stage lung cancer. Current interests include: 1) examining the mechanistic link between inflammation and estrogen signaling in lung carcinogenesis; 2) identification of dietary factors that modify lung cancer risk; and 3) development of novel therapeutic and prevention strategies involving hormonal manipulation and/or anti-inflammatory therapies in select high-risk populations.
Gary Thomas
Program(s): Cancer Biology
George Tseng
Program(s): Cancer Biology
Yulia Tyurina
Program(s): Cancer Biology
Man-Tzu Wang
Program(s): Cancer Biology
Xiaosong Wang, MD, PhD
Program(s): Cancer Biology
Contact:
Hillman Cancer Center, Room G.5a
5117 Centre Ave.
Pittsburgh PA
Phone: 412-623-1587
Research Interests and Keywords:
  • Cancer genomics
  • integrative bioinformatics
  • cancer genetics
  • cancer cell biology
Summary
The Cancer Genome Project Initiatives have generated a daunting amount of genomic and deep sequencing data for tens of thousands of human tumors. An overarching challenge of this post-genomic era is to identify and recognize the cancer drivers and targets from these big genomic data, especially those that can be therapeutically targeted to improve the clinical outcome. The mission of our lab is to apply a multiple disciplinary approach inclusive of integrative bioinformatics, cancer genetics, molecular cancer biology, and translational studies to identify driving genetic aberrations and appropriate cancer targets on the basis of deep sequencing and genomic profiling datasets. Our research projects are composed of both computational and laboratory components. Our dry lab researches focus on developing innovative and integrative computational technologies to discover causal genetic and epigenetic alternations, viable therapeutic targets, and predictive biomarkers in cancer. In particular, we have innovated a concept signature (ConSig) analysis that employs molecular fingerprints for high-throughput interpretation of the biological function of candidate targets in cancer (Nature biotech 2009). In addition, we have formulated a 'fusion breakpoint principle' that describes the intragenic copy number aberrations characteristic of recurrent gene fusions, thus enabling genome-wide detection of copy number breakpoints generating gene fusions. Based on these principles we further developed a powerful bioinformatics tool called 'Fusion Zoom' that identifies recurrent pathological gene fusions via integrative analyses of RNA sequencing, copy number, and gene concept datasets (Nature Commun 2014). Further, we have discovered the crucial application of ConSig analysis in revealing the primary oncogenes targeted by genomic amplifications, and developed a new integrative genomic analysis called 'ConSig-Amp' to detect viable cancer targets. Moreover we also developed an integrated computational-experimental approach called HEPA-PARSE for the genome-wide detection of clinically important tumor specific antigen (TSA) targets (Cancer Research 2012). Our wet lab researches focus on experimentally characterizing individual genetic and epigenetic aberrations in breast cancer such as recurrent gene fusions, genomic amplifications, and epimutations, as well as qualifying viable cancer targets and predictive biomarkers for the development of precision therapeutics in breast cancer. Our current disease focus is clinically intractable breast cancers, such as luminal B or basal-like tumors. In particular, by applying the FusionZoom analysis to the RNAseq and copy number data from The Cancer Genome Atlas, we have discovered a novel recurrent gene fusion involving the estrogen receptor gene in a subset of breast cancers. This fusion called ESR1-CCDC170 is preferentially present in 6-8% of luminal B tumors -- a more aggressive subtype of estrogen receptor positive breast cancer. To date, this is the first and most frequent gene fusion yet reported in this tumor entity (Nature Commun. 2014). We are now assessing the druggability of this fusion with the goal of developing effective targeted therapy against this genomic target. We expect that our new discoveries will yield novel insights into the recurring genetic abnormalities leading to breast cancer initiation, progression, and therapeutic resistance, and establish viable targets for effective intervention.
Zhou Wang, PhD
Program(s): Cancer Biology
Contact:
Shadyside Medical Center, Suite G40
5200 Centre Avenue
Pittsburgh PA
Research Interests and Keywords:
  • Androgen receptor
  • prostate cancer
  • tumor suppressors
  • intermittent androgen deprivation therapy
  • U19/EAF2
Summary
One major focus of my research is to identify and characterize androgen-response genes in the prostate. One of the androgen response genes, U19/EAF2, plays an essential role in androgen action and prostate cancer progression. U19/EAF2 is directly regulated by androgens in prostate epithelial cells. U19/EAF2 downregulation and loss of heterozygosity were observed in more than 80% of advanced human prostate cancer specimens, indicating its essential role in prostate cancer progression. Overexpression of U19/EAF2 in all of the assayed prostate cancer cell lines induced apoptosis both in vitro and in vivo. Furthermore, we showed that U19/EAF2 gene knockout in mice resulted in lung adenocarcinoma, hepatocellular carcinoma, and B cell lymphoma, demonstrating that U19 is a tumor suppressor. Although no prostate cancer was detected in U19 knockout mice, prostate hyperplasia and high grade PIN (prostatic epithelial neoplasia) was observed in the prostate, demonstrating that U19/EAF2 plays a critical role in prostate cancer. Our current research focuses on the roles of U19-binding partners and U19-downstream genes.

Another area of research interest is androgen receptor (AR) intracellular trafficking in prostate cancer cells, especially in androgen-refractory prostate cancer cells. In androgen-sensitive prostate cancer cells, AR is localized to the cytoplasm in the absence of ligand. The presence of ligand induces nuclear translocation of AR and the nuclear localized, liganded-AR transactivates downstream genes. However, in androgen-refractory prostate cancer cells, AR is localized to the nucleus in the absence or presence of ligand. Ligand-independent AR activation is thought to play a critical role in the development of androgen-refractory prostate cancer. Ligand-independent AR nuclear localization is a prerequisite for AR to undergo ligand-independent activation. Elucidating the mechanism of AR ligand-independent nuclear localization may provide insights into the mechanism of androgen-refractory prostate cancer development, which may lead to new targets for the treatment of androgen-refractory prostate cancer.

We are also interested in translating our research findings into prostate cancer patient treatment. We plan to determine whether intermittent androgen ablation therapy (IAAT) of prostate cancer can be enhanced by 5 alpha-reductase inhibitor, which blocks testosterone conversion to dihydrotestosterone (DHT). We have generated preliminary data indicating that inhibition of the conversion of testosterone to DHT by 5 alpha-reductase inhibitor can enhance the expression of tumor suppressive androgen-response genes during the regrowth of a regressed normal or cancerous prostate. The enhanced expression of tumor-suppressive androgen-response genes should retard the tumor regrowth. Using an androgen-sensitive human prostate xenograft tumor as a model, we showed that 5 alpha-reductase inhibitor finasteride enhanced the efficacy of IAAT. We are establishing collaborations with medical oncologists, urologists, and pathologists to evaluate whether IAAT can be enhanced by 5 alpha-reductase inhibitors in a clinical trial.

In collaborations with Drs. Joel Nelson, Paul Johnston, and Peter Wipf, our lab is trying to identify and develop small molecular inhibitors of AR nuclear localization and function in prostate cancer cells, particularly in castration-resistant prostate cancer cells. Recent studies showed that these small molecules can inhibit prostate cancer cells resistant to the second generation anti-androgen MDV3100. Ongoing research will identify analogs of our lead compounds for pre-clinical and clinical studies.

Rebecca Watters
Program(s): Cancer Biology
Kurt Weiss, MD
Program(s): Cancer Biology
Contact:
UPMC Shadyside Medical Center
5200 Centre Avenue, Suite 415
Pittsburgh PA
Phone: 412-802-4137
Research Interests and Keywords:
  • Orthopaedic oncology
  • sarcoma basic biology
  • osteosarcoma
  • translational research
Summary
In addition to specializing in pediatric and adult orthopaedic oncology, Dr. Weiss directs a basic science laboratory dedicated to the study of sarcomas ' cancerous tumors that arise in musculoskeletal tissues. As a bone cancer survivor himself, Dr. Weiss brings passion and enthusiasm to the laboratory, clinic, and operating room.
Alan Wells
Program(s): Cancer Biology
Contact:
Scaife Hall, S713
3550 Terrace Street
Pittsburgh PA
Phone: 412-647-7813
Jianhua Xing
Program(s): Cancer Biology
Da Yang, MD, PhD
Program(s): Cancer Biology
Contact:
308 Pavilion
Pittsburgh PA
Phone: 412-383-5145
Research Interests and Keywords:
  • Drug resistance
  • genomics
  • epigenetics
  • cancer therapeutics
  • biomarkers
  • personalized cancer medicine
Summary
The research of Dr. Yang's laboratory focuses on using integrated genomic and functional studies to identify mechanisms of resistance to cancer therapeutics, and to develop novel approaches and biomarkers to enable personalized cancer medicine. Currently, ongoing work involves: 1) mechanistic studies of resistance to cancer therapeutics, especially targeted therapy for pathways with the most prevalent genomic alterations in human solid tumors; and 2) characterization of genetic and epigenetic alterations of non protein-coding components (ncRNAs) of the genome, such as miRNA and lncRNA genes in solid tumors. His approaches have proved successful in several instances, including the identification of miR-506 as a tumor suppressor that inhibits epithelial-to-mesenchymal transition (EMT) and cell cycle pathways, and the discovery of BRCA2 gene mutations that lead to genome instability and cisplatin response in ovarian cancer.
Reza Zarnegar, PhD
Program(s): Cancer Biology
Contact:
S-411A S-BST
200 Lothrop Street
Pittsburgh PA
Research Interests and Keywords:
  • Hepatocyte Growth Factor (HGF)
  • physiological and pathological role of the HGF/Met axis in normal tissue homeostasis and disease processes including cancer
Ioannis Zervantonakis
Program(s): Cancer Biology
Mei Zhang
Program(s): Cancer Biology