- Ovarian cancer
- cancer stem cells
- tumor vasculature
- targeted therapies
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.
204 Craft Avenue
- breast cancer
- ovarian cancer
- estrogen receptor
- invasive lobular carcinoma
- bone metastases
- lobular carcinoma in situ
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.
The central theme of my research program is to investigate the metabolic and epigenetic control of senescence in the context of cancer. Cellular senescence is a stable cell cycle arrest that can be both tumor suppressive and tumor promoting in a highly context-dependent manner. Relatively little is known about metabolic changes that either induce or inhibit senescence. Using a combination of cell and molecular biology tools in addition to high-throughput approaches such as metabolomics and functional (epi)-genomics, my laboratory aims to mechanistically understand how to induce or overcome senescence. Our studies also include aspects of translational research utilizing both ovarian cancer and melanoma models to explore whether these newly-identified metabolic and epigenetic pathways can be targeted for novel cancer therapies. The lab is currently funded by: 1) an NCI R37 MERIT Award to understand pro-tumorigenic nucleotide metabolism in melanomagenesis; 2) an American Cancer Society Research Scholar Grant to investigate the role of isocitrate dehydrogenase 1 (IDH1)-mediated alpha-ketoglutarate production in histone methylation at homologous recombination genes in ovarian cancer; and 3) 2 NRSA F31s elucidating various metabolic and epigenetic mechanisms in ovarian cancer senescence. Pending grants include the role of nuclear acetyl-CoA production on histone acetylation and DNA damage response in ovarian cancer (NCI mPI R01) and how macropinocytosis of branched chain amino acids affects both tumor cell-intrinsic and immune cell responses to therapy (DoD Ovarian Cancer Research Program, a collaboration with Dr. Greg Delgoffe).
4401 Penn Avenue
Dr. Bailey studies pediatric sarcoma biology. Currently, her specific focus is studying the impact of the EWS-FLI1 fusion oncoprotein on the Ewing sarcoma tumor microenvironment.
- Translational bioinformatics
- oncology informatics
- tissue banking and pathology informatics
- prostate tumor cell biology
- research resource development
- content-based image retrieval and digital libraries
Biomedical Science Tower 3, Suite 3064 3501 Fifth Avenue
4249 Fifth Avenue
My research focuses on understanding how non-coding RNA directs gene regulation. My current research goals are to understand how RNA conformational change within ribonucleoprotein complexes regulates gene transcription and genome replication. To do this, we will utilize complementary biochemical, structural and computational techniques.
My research interest is focused on lncRNAs in breast cancer. I have strong collaborations with other members of the cancer center including Drs. Adrian Lee, Steffi Oesterreich, Partha Roy, and Uma Chandran. However, my primary role in the cancer center will be centered around training and diversity. I am the Director of the NCI (R25) and DDCF funded Hillman Academy that organizes ~70 internships to high school students annually with a special focus on training underrepresented minorities. I am also the vice chair of the education and training committee for the cancer center.
5117 Centre Avenue
- Mutant KRAS
- non-small cell lung carcinoma
- lung cancer
- Hsp90 inhibitors
- targeted cancer therapies
- acquired resistance
- brain metastases
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.
Because metastases account for the majority of mortality from cancer, my research interests center on elucidating the pathobiology of metastasis and using these discoveries to develop therapeutic targets. I am also interested in developing more sophisticated models of cancer metastasis that better incorporate the tumor microenvironment. In my research career thus far I have developed novel models and techniques for studying metastasis that have revealed mechanisms of how the liver, lymph node, and immune microenvironments may uniquely impact cancer cells. We are currently exploring the roles of a class of non-coding RNAs called small nucleolar RNAs (snoRNAs) in metastasis from lymph nodes in breast and lung cancer.
- Single-cell analysis, Machine learning, Microfluidics, Cancer cellular heterogeneity
Due to genomic and epigenetic instability of cancer cells, inter-patient and intra-patient heterogeneity in tumors creates formidable challenges in identifying optimal treatments. To address the challenges, I aim to establish comprehensive high-throughput multi-omics single-cell analysis including genome, epigenome, transcriptome, proteome, functional, and morphological methods. With large amounts of data collected from high-throughput single-cell multi-omics analysis, machine learning techniques can predict patient prognosis and suggest treatments for precision medicine. The integrated approach will change how we understand and treat cancer and ultimately improve outcomes for patients.
3501 Fifth Avenue, Suite 3081, Biomedical Science Tower 3 (BST3)
200 Lothrop Street
- cell proliferation
- redox signaling
- free radical
- nitric oxide
- lipid signaling
- drug discovery
- oxidative stress
- age-related disease
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.
4249 Fifth Ave
My research interests focus on the similarities and differences in chromatin structure among different cell types and how chromatin remodeling factors that modulate these differences regulate cell fate. The longterm goals of my laboratory are to comprehensively understand the functions, targets, regulation, and mechanisms of action of non-coding RNAs (ncRNAs) and chromatin regulatory factors with critical functions in the embryonic stem (ES) cell gene regulatory network, through development, and in disease states. Active research areas in my laboratory include: (1) identifying chromatin remodelers that regulate ncRNA expression; (2) determining the function of two uncharacterized classes of ncRNAs in ES cells; (3) characterizing molecular changes occurring in cancer cell lines with chromatin remodeler mutations; (4) optimizing and expanding the utilization of a novel technique for profiling chromatin binding proteins, CUT&RUN. Enabling these studies, my research spans the disciplines of genomics, cell and molecular biology, biochemistry, and genetics.
Activation of the PI3K pathway, through either oncogenic mutations or loss of tumor suppressors, is arguably the most prevalent transforming event in cancer. Much effort has focused on inhibitors of these pathways, but success to date has been tempered by on-target adverse effects driven by normal physiology that also relies on intact PI3K signaling. My research focuses on the regulatory and homeostatic mechanisms that control PI3K signaling at the level of its central lipid messengers. We aim to uncover how these lipid signals selectively couple to defined signaling outcomes; this basic knowledge will be transformative in predicting how oncogenic PI3K signaling can be selectively targeted while sparing normal physiology.
My lab employs innovative single-cell biochemistry approaches to study lipid signaling in living cells, employing a range of optical biosensors along with gene editing, optogenetic and chemigenetic tools. This approach uniquely empowers us to precisely edit and control cell signaling pathways to model physiology and disease alterations: we can dissect changes away from upstream and downstream pathway components, and notably mimic the effects of potential small-molecule modulators.
204 Craft Ave
My research group uses a variety of molecular, cellular, imaging and in vivo techniques to focus on two research areas in ovarian cancer biology: 1. The role of antioxidant enzymes and reactive oxygen species during tumor metastasis; and 2. The regulation of mitochondrial fission/fusion and mitochondrial metabolism in ovarian cancer progression. We concentrate our studies on patho-physiologically relevant models that include the use of patient-derived tumor cells, and have a number of well established institutional and national collaborations in the fields of mitochondrial biology, cell signaling and ovarian cancer. I am seeking membership of the cancer center to participate actively in the Cancer Biology program and broaden my future research by being exposed to collaborations and research efforts of the tumor immunology, genome stability and therapeutics programs. I hope to help build the research portfolio focused on gynecologic malignancies at the Hillman cancer center and plan to take an active role in ongoing team science initiatives focused on ovarian cancer (SPORE submission) and cancer metastasis (U54 submission). In addition, I hope to establishing new initiatives focused on redox biology and mitochondrial function in tumor progression.
204 Craft Avenue, A412
- Breast cancer
- steroid receptors
- growth factor signaling
- estrogen receptor
- progesterone receptor
- insulin-like growth factor
- tumor heterogeneity
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.
200 Lothrop Street
- Signal transduction
- growth factors
- liver development
- hepatic physiology
- liver disease
- liver cancer
- hepatocellular carcinoma
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."
Suite G27c, 5117 Centre Ave.
- Computational oncology
- Cancer epigenetics
- Omics approaches in immunology and immunotherapy
100 Technology Drive
My current cancer-related research is focused on i) RB1 tumor suppressor and ii) nutrient interventions that may suppress tumor growth.
RB1 is a tumor suppressor gene that is inactivated in a significant proportion of all cancer cases. A therapeutic approach that specifically targets defects in this tumor suppressor is currently not available. A synthetic lethal (SL) interaction occurs between two genes when the inactivation of either gene alone is viable but the inactivation of both genes simultaneously results in the loss of viability. My lab uses a cross-species approach to identify evolutionarily conserved SL targets for RB1-deficient cells. Our focus is to translate our findings from Drosophila screening and from bioinformatics analysis of human cancer cell lines and human cancer patients into appropriate mouse cancer models and ultimately in a clinical trial in human cancer patients.
4200 Centre Ave, Suite G34
Prostate cancer and benign prostatic hyperplasia are two diseases which present a significant burden for older men in the US. Although BPH is not usually life-threatening, the mechanisms contributing to BPH are largely unknown which makes it difficult to develop successful BPH prevention and treatment strategies. My research focus is developing and characterizing animal models of BPH and prostate cancer as powerful tools for measuring efficacy of small molecules designed to inhibit androgen receptor function in prostate cancer and of 5ARI and COX-2 inhibitors to reduce prostatic inflammation and improve bladder function in BPH.
Children’s Hospital of Pittsburgh, 4401 Penn Ave.
- molecular oncology
- tumor suppressors
- tumor metabolism
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.
3501 Terrace Street
- Biomimetic microenvironments
- tissue engineering
- 3D tumor models
- drug delivery
Room 433, 5607 Baum Boulevard, Suite 500
- Clinical Informatics
- Imaging/Visualization/Virtual Reality
- Virtual Organizations
- Learning Health Systems
- Oncology Informatics
Dr. Singhi's current research focus is primarily translational in the area of gastrointestinal, pancreatic, hepatobiliary and peritoneal pathology, and can be summarized in the following areas:
(1) Clinical diagnostic test development. In conjunction with other members of pathology, gastroenterology, surgical oncology and radiology, Dr. Singhi has been involved in the development of multiple clinical diagnostic tests for the evaluation of pancreatic cysts, biliary strictures, neuroendocrine tumors, and early detection of neoplasms involving the hepatopancreatobiliary tract. His research is supported by grants from the Pancreatic Cancer Action Network (PanCAN), National Pancreas Foundation (NPF), the University of Pittsburgh and the Institute for Precision Medicine (IPM) at the University of Pittsburgh. For more information regarding such tests as PancreaSeq (pancreatic cysts), BiliSeq (biliary strictures) and PanNeuroSeq (pancreatic neuroendocrine neoplasms), please refer to the Molecular & Genomic Pathology Laboratory website: http://mgp.upmc.com.
(2) Pathologic evaluation of non-neoplastic pancreatic pathology. In collaboration with several investigators, Dr. Singhi is involved in a multi-institutional effort to characterize various non-neoplastic pancreatic diseases, such as genetically and environmentally associated chronic pancreatitis.
(3) Co-director of the Biospecimen Repository and Processing Core (BRPC) of the Pittsburgh Liver Research Center (PLRC): http://livercenter.pitt.edu. Histopathologic and genetic characterization of peritoneal mesothelioma. In conjunction with members of the Division of Thoracic Pathology, Molecular & Genomic Pathology, and Surgical Oncology, Dr. Singhi's team has identified the genetic landscape of peritoneal mesothelioma with the goal of identifying biomarkers for prognostication and treatment stratification of patients.
(4) The epigenetic pathogenesis of pancreatic neuroendocrine tumors. In collaboration with investigators at the UPMC Division of Gastroenterology, Hepatology and Nutrition, and UPMC Hillman Cancer Center. This represents an international observational trial to evaluate prognostic biomarkers for pancreatic neuroendocrine tumors and determine the underlying epigenetic pathogenesis of these increasingly prevalent neoplasms.
5117 Centre Avene Lab 2.7
- estrogen receptor
- epidermal growth factor receptor
- fibroblast growth factor receptor
- hepatocyte growth factor
- vascular endothelial growth factor
- signal transduction
- lung cancer
- targeted cancer therapies
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.
200 Lothrop Street
I am an ion channel physiologist with long term interests in basic ion channel regulation and activation and the contributions of altered channel function to disease. I have been funded all my career by NHLBI, NIA and NIEHS and have developed strong interests in the contribution of ion channel dysfunction to cellular, molecular and metabolic remodeling in vascular proliferative diseases and lung obstructive diseases. Nevertheless, I have consistently maintained an interest in the nascent and exciting field of "ion channels and cancer". I have consistently had one postdoc (sometimes two) working on ion channel dysregulation in breast and colon cancer and glioblastomas and we have published several influential papers on the subject.
5117 Centre Ave, Rm 2.6f
Our research focuses on understanding the cancer systems biology of the tumor microenvironment. We are interested in studying how different cell types with varying lineages, and with different signaling and signal processing capabilities come together within the spatial context of the microenvironment to give rise to malignant phenotypes in individual patients, whether they be neoplastic transformation, cancer progression, recurrence, or response to therapy. Our specific interest is in gastrointestinal cancers (GI), particularly colorectal cancer, but we aim to expand our study to other solid tumors. We also work on cancer prognosis in GI patients at risk of developing cancer, for example, patients with inflammatory bowel disease or Barret's esophagus. Our research work utilizes high dimensional microscopy and optical imaging combined with imaging science, mathematical and systems modeling, and data science in general. In this latter context we aim to intelligently incorporate omics data into our research, to better integrate biological understanding with improved patient outcomes.
5117 Centre Ave.
- Cancer genomics
- integrative bioinformatics
- cancer genetics
- cancer cell biology
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.
5200 Centre Avenue
- Androgen receptor
- prostate cancer
- tumor suppressors
- intermittent androgen deprivation therapy
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.
5200 Centre Avenue, Suite 415
- Orthopaedic oncology
- sarcoma basic biology
- translational research
- Drug resistance
- cancer therapeutics
- personalized cancer medicine
200 Lothrop Street
- Hepatocyte Growth Factor (HGF)
- Physiological and pathological role of the HGF/Met axis in normal tissue homeostasis and disease processes including cancer
- Tumor microenvironment
- Drug resistance
- Cancer metastasis
- Systems modeling of cell-cell interactions
Understanding cell behavior in native tumor microenvironments and developing new strategies to deliver therapeutics directly to tumor cells are critical in improving and extending patients’ lives. Our lab employs a quantitative approach that integrates microfluidics, systems biology modeling, and in vivo experiments to investigate the role of the tumor microenvironment on breast and ovarian cancer growth, metastasis and drug resistance. Our goal is to develop bioengineered tumor microenvironment platforms and apply them to improve understanding of tumor-stromal signaling mechanisms in order to: (1) discover biomarkers that guide new drug development and improve prognosis, (2) develop new strategies to improve existing treatment protocols and (3) engineer microfabricated tools that enable screening and personalization of cancer therapies.