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Drug Resistance and Metastasis investigators

Ronald Buckanovich

Ronald Buckanovich

Program: Cancer Biology

412-641-4721 buckanovichrj@mwri.magee.edu 204 Craft Avenue, B333
Pittsburgh PA
Summary

Ovarian cancer is a disease that has high rates of resistance to both chemotherapy and immunotherapy. This therapeutic resistance drives a poor prognosis for patients with ovarian cancer. A primary focus of my group is to understand therapeutic resistance and develop therapeutic approaches to overcome this resistance. We are working to understand both cancer cell inherent mechanisms of therapeutic resistance and how interactions with host cells in the tumor microenvironment increase therapeutic resistance. 

We are currently focusing on understanding the biology of a population of slowly dividing/non-dividing or ‘quiescent’ cancer cells. These quiescent cells are inherently resistant to chemotherapy and radiation therapy – both of which kill fast growing cells. Upon exposure to chemotherapy, we find that these cells quiescent cells secrete novel factors to make neighboring cells resistant to both chemotherapy and immunotherapies. Following completion of chemotherapy treatment these quiescent cells can resume proliferation and drive disease recurrence. 

Furthermore, following chemotherapy exposure, these cells secrete additional factors which create an immunosuppressive microenvironment. Given the critical role of these cells in therapeutic resistance, we are developing novel therapeutic approaches to kill these otherwise resistant cells. Based on our findings we are currently running two different clinical trials to determine if we can prevent chemotherapy or immunotherapy resistance.  

Research Interests and Keywords
  • cancer stem cells,ovarian cancer,targeted therapies,tumor vasculature
Read More about Ronald Buckanovich
Timothy Burns

Timothy Burns

Program: Cancer Biology

412-623-7877 burnstf@upmc.edu Hillman Cancer Center Suite 2.18
5117 Centre Avenue
Pittsburgh PA
Summary

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. My four main research themes are 1) novel pre-clinical target validation and drug development (TWIST1 in oncogene driven NSCLC and TKI resistance; targeting metabolism in oncogene driven lung cancer); and 2) elucidating mechanisms of resistance for targeted inhibitors to develop rationale therapeutic combinations that can be tested in the clinic (Hsp90, ERK1/2 inhibitors and 4th generation EGFR TKIs) and 3) development of targeted therapy approaches for the treatment of brain metastases.  The first line of research in my laboratory focuses on the role of the EMT transcription factor TWIST1 in oncogene-driven NSCLC. We have demonstrated the TWIST1 is essential for lung tumorigenesis for KRAS mutant, EGFR mutant and MET mutant/amplified NSCLC and TWIST1 overexpression leads to resistance to EGFR and MET TKIs. We are examining the mechanism(s) through which this occurs and developing therapeutic combinations to overcome this resistance. 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 to develop a clinical TWIST1 inhibitor. The second line of research in my lab focuses on studying the mechanisms of resistance to targeted agents currently in phase 1 and 2 trials to develop rationale therapeutic combinations in the clinic. This is typified by our previous work with Hsp90 inhibitors and ongoing work on ERK inhibitors and a novel 4th generation EGFR TKI.  Finally, my lab is interested in lung cancer brain metastases, and we are exploring whether targeting the HGF-MET-TWIST1 pathway or downstream metabolic pathways can be an effective strategy for preventing or treating lung brain metastases. In additional to these preclinical studies, we are using both radiogenomic and cell free DNA approaches to predict molecular phenotypes of brain metastases to identify patients with brain metastases that can benefit from MET targeted therapy in the clinic.

Research Interests and Keywords
  • acquired resistance,brain metastases,chemoresistance,Hsp90 inhibitors,Lung Cancer,Mutant KRAS,non-small cell lung carcinoma,Oncogenes,targeted cancer therapies,TWIST1
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Ferruccio Galbiati

Ferruccio Galbiati

Program: Cancer Biology

feg5@pitt.edu W1057 Thomas E. Starzl Biomedical Science Tower
Pittsburgh PA
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.

Research Interests and Keywords
  • age-related disease,Aging,Cancer,Caveolin,Oxidative Stress,senescence
Read More about Ferruccio Galbiati
Adrian Lee

Adrian Lee

Program: Cancer Biology

412-641-7557 leeav@upmc.edu The Assembly
5051 Centre Ave
Pittsburgh PA
Summary

The laboratory studies the molecular basis of breast cancer development and resistance to therapy, with the goal to improve precision medicine and outcomes for breast cancer patients. The laboratory employs a systems biology approach, utilizing a combination of single cell and bulk sequencing, computational methods, and biological models to identify and validate new drivers and therapeutic targets. Hypotheses are tested in vitro and in vivo and then moved to clinical trials. The majority of studies incorporate analysis of human specimens, in collaboration with a large network of clinicians and nurses. This includes computational analysis and modeling of large biomedical and genomic datasets including electronic health record data. A major goal is new model development including patient-derived organoids and patient-derived xenografts. A major focus of the laboratory is identifying mechanisms of resistance to endocrine therapy, and new approaches to blocking breast cancer metastasis through precision medicine. This includes the study of estrogen receptor (ESR1) mutations and fusions and synergism with growth factor pathways. Methods include liquid biopsies and use of a rapid autopsy program,. A special focus is on the understanding of invasive lobular cancer (ILC), the second most common but understudied histological subtype of breast cancer. The laboratory has a very strong training environment, with attention to diversity and inclusion and each individuals’ successful career development. One of the top priorities is to maintain a healthy lab environment, ensuring high productivity and rigor.

Research Interests and Keywords
  • Breast Cancer,estrogen receptor,growth factor signaling,insulin-like growth factor,progesterone receptor,steroid receptors,tumor heterogeneity
Read More about Adrian Lee
Satdarshan Monga

Satdarshan Monga

Program: Cancer Biology

smonga@pitt.edu S400 BST South
200 Lothrop Street
Pittsburgh PA
Summary

Dr. Monga is the UPMC Endowed Chair for Experimental Pathology at the University of Pittsburgh, School of Medicine. He is a Professor of Pathology and Medicine and the Associate Dean of Research for the School. He is the Executive Vice Chair of Pathology and the Chief of the Division of Experimental and Translational Pathology. He is the inaugural Director of the Pittsburgh Liver Institute and also the founding Director of P30 funded Pittsburgh Liver Research Center (PLRC), which is 1 of the 17 NIDDK-funded Digestive Disease Research Core Centers and only 1 of the 3 with exclusive liver focus. He also runs a T32 funded training program in Regenerative Medicine. He is an academic physician and has focused on elucidating the cellular and molecular underpinnings of liver injury, repair, and liver cancer for more than 22 years and has been consistently funded by NIH and sponsored research agreements from industry throughout his career. He has published 208 articles, received numerous research and mentoring awards and served on boards of both industry and academia. He has made seminal contributions in this area especially in the understanding of the role of complex signaling pathways such as the Wnt, Hippo and others and several of his findings are now on the verge of being translated into patients. 

There are two major research themes within his laboratory. The first focus is in the broad area of liver physiology. This includes the areas of hepatic development, liver regeneration (following surgical resection, drug-induced injury or cholestasis) and metabolic zonation (division of labor within liver lobule). His work has elucidated the cell-molecule circuitry of liver regeneration following hepatectomy showing Wnt2 and Wnt9b release from endothelial cells to activate -catenin in hepatocytes to induce proliferation and regain of hepatic mass.  His work also showed an important role of -catenin in hepatoblast proliferation during development and then in hepatocyte maturation. In adult liver, his group has shown that Wnt2-Wnt9b from endothelial cells also control gene expression in hepatocytes located in pericentral region of the liver lobule and hence plays an important role in metabolic zonation. He showed an important redundancy between β-catenin and β-catenin at adherens junction where loss of any one of the two catenins was compensated by the other, whereas dual loss in hepatic epithelial or ‘hepithelial’ cells, led to disruption of blood bile barrier and excessive morbidity. The second major focus in the lab has been on understanding the role of β-catenin gene mutations in liver tumors especially hepatoblastoma and hepatocellular cancer. Since mutations in CTNNB1 are observed in 26-38% of all HCC patients, he has generated very relevant mouse models that represent subset of human HCC using sleeping beauty transposon/transposase and crispr/cas9. These models have lent themselves well to help understand the cooperation of mutant CTNNB1 with other oncogenes such as MET, NFE2L2, YAP and others. Their studies have revealed β-catenin to be a driver mutation whose therapeutic targeting may have a profound impact on the field. They have identified addiction of -catenin gene mutated HCCs to mTORC1 due to excess glutamine production by these tumors, as well as resistance to immune checkpoint inhibitors due to unique biology that leads to dearth of immune cell infiltration within the tumor microenvironment. Several discoveries from his lab are now ready to be translated into the clinic and may have both diagnostic and therapeutic implications.

Research Interests and Keywords
  • EGF,growth factors,hepatic physiology,Hepatocellular carcinoma,HGF/Met,Liver cancer,liver development,liver disease,PDGF,Signal Transduction,Wnt/beta-catenin
Read More about Satdarshan Monga
Steffi Oesterreich

Steffi Oesterreich

Program: Cancer Biology

oesterreichs@upmc.edu The Assembly
5051 Centre Ave
Pittsburgh PA
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.

Research Interests and Keywords
  • bone metastases,Breast Cancer,Chromatin,coregulators,Epigenetics,estrogen receptor,invasive lobular carcinoma,lobular carcinoma in situ,mutations,ovarian cancer
Read More about Steffi Oesterreich
Edward Prochownik

Edward Prochownik

Program: Cancer Biology

(412) 692-6795 procev@chp.edu Rangos Research Center, Room 5124
Children’s Hospital of Pittsburgh, 4401 Penn Ave.
Pittsburgh PA
Summary

 Dr. Prochownik is interested in cancers resulting from the de-regulated expression of the c-Myc oncoprotein. He is using animal models of pediatric and adult liver cancer (hepatoblastoma and hepatocellular carcinoma) to ascertain the molecular, biochemical and metabolic changes that accompany tumor progression, regression and recurrence. He is utilizing over-expression and knockout models to determine how genes that cooperate with or are affected by Myc such as ChREBP and pyruvate dehydrogenase specifically contribute to the metabolic and molecular landscapes of these tumors.

Research Interests and Keywords
  • c-Myc,Molecular oncology,tumor metabolism,tumor suppressors
Read More about Edward Prochownik
Partha Roy

Partha Roy

Program: Cancer Biology

Summary

The overall research focus of the Roy laboratory is studying the role of actin-binding proteins and actin-regulated transcription factors in physiological and pathological events. Specific focus areas are actin-binding proteins (profilin, Ena/VASP) and their regulation, MRTF-SRF transcriptional axis, fundamental mechanisms of cell migration, cancer biology (breast and renal cancer), cell signaling, vascular-immune cell crosstalk, and angiogenesis (in both developmental and pathological settings). We seek to a.) understand molecular mechanisms of various aspects of cancer metastasis, regulation of tumor microenvironment and therapy response of cancer cells, and b.) Discover novel therapeutic agents. Our laboratory uses a variety of experimental approaches including CRISPR/RNAi, protein-protein interactions, 2D gel electrophoresis, genetically engineered mouse models of cancer and angiogenesis, mouse models of atherosclerosis, tumor xenografts, metastasis assays, in vitro, ex vivo and in vivo angiogenesis assays, functional genomics and proteomics, live-cell imaging at single cell level, computationally-guided small molecule screening and bioinformatics.

Research Interests and Keywords
  • Actin Cytoskeleton,angiogenesis,Breast Cancer,cell migration,Metastasis,Renal cancer
Read More about Partha Roy
J. Peter Rubin

J. Peter Rubin

Program: Cancer Biology

Summary

Dr. Rubin is a noted expert on adult stem cells derived from fat tissue and advanced reconstructive surgery. Dr. Rubin leads a program that is devising innovative strategies for the use of adipose (fat)-derived stem cells to not only address problems of tissue regeneration but also other diseases that benefit from stem cell-based therapies. He is co-director of the Adipose Stem Cell Center and co-director of the UPMC Aesthetic Plastic Surgery Center. His laboratory research focuses on applications of adult adipose-derived stem cells for restoring damaged tissues after trauma and cancer therapy. He currently is the lead investigator for clinical trials using technologies designed to improve the lives of wounded military personnel. He recently founded and directs the Center for Innovation in Restorative Medicine at the University of Pittsburgh Medical Center, an advanced clinical accelerator unit with expertise in regulatory affair, preclinical testing, and clinical trials design and management.

Read More about J. Peter Rubin
Alexander Sorkin

Alexander Sorkin

Program: Cancer Biology

sorkin@pitt.edu 3500 Terrace Street
S368 Biomedical Science Tower (South)
Pittsburgh PA
Summary

The focus of the research in the laboratory is currently split into two major directions which are apparently distinct from each other with respect to the biological systems involved, their relation to the human disease, and experimental models used. However, the main idea underlying both directions is conceptually the same - to understand how endocytosis and post-endocytic trafficking regulates function(s) of the transmembrane proteins, such as receptors and transporters.

The first direction is the elucidation of the molecular mechanisms of endocytosis of growth factor receptors using a prototypic member of the family, epidermal growth factor (EGF) receptor, and analysis of the role of endocytosis in spatial and temporal regulation of signal transduction by the EGF receptor. The second direction is elucidating the role of trafficking processes in the regulation of dopaminergic neurotransmission by the plasma membrane dopamine transporter (DAT).

Research Interests and Keywords
  • EGF Receptor,Endocytosis,head and neck cancer
Read More about Alexander Sorkin
Flordeliza Villanueva

Flordeliza Villanueva

Program: Cancer Biology

Summary

Dr. Villanueva's research focuses on the development of medical diagnostic and therapeutic strategies based on ultrasound and ultrasound contrast agents (gas-filled microspheres, or microbubbles). Her work has consistently bridged fundamental imaging sciences with translational biomedical research. As an Established Investigator of the American Heart Association, she has been a leader in the development of microbubbles for the assessment of myocardial perfusion, and ultrasound molecular imaging with targeted microbubbles for the detection of inflammatory and angiogenic endothelial markers in pre-clinical models of heart disease. Dr. Villanueva's lab has pioneered the development and application of microbubbles as molecular probes, and acoustic detection strategies for optimizing imaging sensitivity. Her lab group has applied fundamental principles of ultrasound and the physics of microbubble acoustic behaviors to develop novel targeted molecular therapeutics, whereby nucleic acid loaded microbubbles (siRNA, miRNA, plasmid), in the presence of precisely tuned ultrasound, selectively enhance membrane permeability and deliver payloads to the target site. These studies are conducted at the Center for Ultrasound Molecular Imaging and Therapeutics, a translational multidisciplinary research facility which epitomizes the reciprocal relationship between imaging sciences and biomedical translational research.

Research Interests and Keywords
  • Drug and Gene Delivery,Molecular Imaging,Ultrasound,Ultrasound Contrast Agents
Read More about Flordeliza Villanueva
Zhou Wang

Zhou Wang

Program: Cancer Biology

wangz2@upmc.edu Shadyside Medical Center, Suite G40
5200 Centre Avenue
Pittsburgh PA
Summary

One focus of my lab is to investigate the mechanisms regulating androgen receptor (AR) nuclear localization, particularly androgen-independent AR nuclear localization in castration-resistant prostate cancer (CRPC) which is the second leading cause of cancer death in American men.  AR remains to be the key driver in majority of CRPC tumors resistant to the current AR targeting agents. AR nuclear localization is necessary for its function as a transcription factor. According to the classical model of AR nucleocytoplasmic trafficking, AR is present in the cytoplasm in the absence of androgens, which can be imported into the nucleus in the presence of androgens, and the imported AR will be exported upon androgen withdrawal. However, this model is not supported by our recent discovery that imported nuclear AR is degraded, but not exported, upon androgen withdrawal and that unliganded AR can be also imported and rapidly degraded in the nucleus. These findings promoted us to investigate the mechanism of nuclear-specific AR degradation. Identification and characterization of factors responsible for nuclear-specific AR degradation will allow us to investigate if and how these factors are dysregulated in CRPC cells. In addition, we will continue developing novel AR antagonists, with collaborations with experts in medicinal chemistry and structural biology, to identify and characterize small molecules that can inhibit androgen-independent AR nuclear localization in CRPC.

Research Interests and Keywords
  • Androgen Receptor (AR),Androgen-Independent Activation of AR,AR Protein Degradation,Castration-Resistant Prostate Cancer (CRPC),Novel AR Antagonists,Nucleocytoplasmic Trafficking of AR,Prostate cancer
Read More about Zhou Wang
Kurt Weiss

Kurt Weiss

Program: Cancer Biology

412-802-4137 weiskr@UPMC.EDU UPMC Shadyside Medical Center
5200 Centre Avenue, Suite 415
Pittsburgh PA
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.

Research Interests and Keywords
  • Orthopaedic oncology,Osteosarcoma,sarcoma basic biology,translational research
Read More about Kurt Weiss
Alan Wells

Alan Wells

Program: Cancer Biology

412-647-7813 wellsa@upmc.edu Scaife Hall, S713
3550 Terrace Street
Pittsburgh PA
Summary

The Wells Laboratory research program, in close collaboration with its research partners, aims to understand cell migration in terms of how motility processes are regulated, and understand how this regulation of migration plays a role in physiologic and pathologic situations. We are integrating the knowledge gained from our biochemical and biophysical mechanistic studies into our investigations concerning conditions of dysregulated (tumor invasion) and orchestrated (wound healing and organogenesis) cell motility. As part of understanding the motility response, we are investigating both how this particular integrated cell response is selected from among others and the metabolic consequences of motility. This integrative approach provides reinforcing insights and novel avenues for exploration into the basic signaling pathways as well as functioning of whole organism. As a model system, we explore motility signaling from the epidermal growth factor receptor (EGFR) in adherent cells. EGFR plays a central role in the functioning in a wide variety of both stromal and epithelial tissues, and is the prototype for other receptors with intrinsic tyrosine kinase activity. Thus, these studies should have widespread implications.

The two central foci are tumor progression and wound repair. In tumor progression, we examine breast and prostate carcinoma invasion and metastases in terms of molecular signals and the special micro-environments. For this, the laboratory uses human tissues, animal models, and a unique 4-dimensional liver microtissue. In would repair, the current model system is skin wound healing, in which the communications between the epidermis, dermis, and blood vessels is parsed at the molecular levels. The role of stem cells in the natural repair process and as a rationale therapeutic is also being investigated. These two areas are re-inforcing as many of the key molecules and cellular processes are part of the generalizable onco-fetal-wound program. 

Research Interests and Keywords
  • Breast Cancer,Dormancy,Melanoma,Metastasis,Microphysiologic Systems (MPS),Prostate cancer
Read More about Alan Wells
Reza Zarnegar

Reza Zarnegar

Program: Cancer Biology

rezazar@pitt.edu S-411A S-BST
200 Lothrop Street
Pittsburgh PA
Summary

The focus of Dr. Zarnegar’s laboratory is to decipher the molecular mechanisms by which Hepatocyte Growth Factor (HGF) and its receptor MET regulate hepatocyte growth and metabolism. In particular, their focus is on the regulation of hepatic glucose and fat metabolism and its implication in Fatty Liver Disease. Studies are also aimed at exploiting  HGF/MET in chronic liver diseases inflicted by liver inflammation, hepatocyte degeneration and hepatitis such as NASH. Dr. Zarnegar’s laboratory also studies HGF gene mutation in human cancer such as breast, colon, and liver cancer and how to target HGF/MET axis in cancer.

Research Interests and Keywords
  • Hepatocyte Growth Factor (HGF),Liver cancer,MET,NASH
Read More about Reza Zarnegar

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