The primary goals of this research area revolve around preclinical pharmacology of promising cancer chemopreventive agents derived from edible plants (e.g., cruciferous vegetables) and traditional (Ayurvedic) Indian medicine constituents (e.g., Withania somnifera). Cutting-edge molecular and cell biological techniques (e.g., metabolomics, proteomincs, gene expression) coupled with relevant animal models (chemically-induced as well as transgenic mouse models) and imaging techniques (MRI, bioluminescence, ultrasound) are used to study cancer chemoprevention with naturally-occurring small molecule compounds. Rapid translation of the preclinical findings is another critical objective of this research program, and the University of Pittsburgh Cancer Institute (UPCI) and Magee-Womens Research Institute (MWRI) provide stimulating environment to facilitate this goal. Innovation of this research is exemplified by seminal discoveries concerning the mechanism of anticancer effects of natural agents.
Epidemiological data suggest a link between various psychological factors and cancer initiation and progression. The goals of this research program are to: 1) understand the molecular pathways by which stress-induced hormones may influence development and progression of cancer in tissues that possess stress hormone receptors such as the breast and ovary; 2) decipher the direct interplay between stress hormones (cortisol, NE, and E) and chemotherapy; and 3) further characterize the effects of stress hormones on the adaptive immune system in women's cancers. Hormonal influences on cell cycle regulation, targeted molecular therapies, drug metabolism, drug resistance and cancer are being investigated using in vitro and in vivo models. Translation of these findings using quality of life questionnaires and stress/immune interventions are a main priority of this program.
Hormone receptor action and resistance to hormone therapy
The steroid estrogen mediates its potent mitogenic effects through the estrogen receptor (ER), which has been a successful target for endocrine therapy in breast cancer. Despite the success of such treatment, de novo or acquired resistance remains a major clinical problem. A better understanding of how ER works is critical for the development of more efficient therapies, and better prediction for who should receive which form of endocrine therapy. Towards this goal, we are studying genetic (e.g. polymorphism and mutations), and epigenetic changes in the ER pathway associated with resistance. We are using cell line, mouse models, and clinical samples for our studies. More recently, we have also begun to ask similar questions in ovarian cancer, with the goal of identifying patients which might benefit from endocrine treatment.
Cancer initiation, progression, and metastasis
Many laboratories in the WCRC are studying the fundamental processes of cancer initiation, progression, and metastasis. These include studies of oncogenes and tumor suppressor genes using cell lines and mouse models. Metastasis is an emerging theme, with investigators using mouse and in vitro organ models to identify critical pathways.
Molecular profiling of early disease and progression
Investigators in the WCRC are using a number of molecular profiling techniques (genomics, transcriptomics, epigenomics, proteomics) to interrogate molecular changes in early breast disease and progression to cancer. This program uses the unique Health Sciences Tissue Bank, which currently contains over 400 frozen breast tumors with associated normal tissue and blood. In addition, the cancer registry has information on 16,000 patients treated over the last 20 years, with 10,000 of these having active follow up. Molecular analysis is performed in the Cancer Genomics Facility or individual laboratories using multiple platforms including Illumina HiSeq, SOLiD 5500, Affymetrix and Agilent arrays, Nanostring Counter and more. In addition, the University of Pittsburgh has a rapid autopsy program allowing study of multiple sites of metastasis.
New targeted therapies
The last 20 years of research into the molecular biology of breast cancer has identified numerous potential therapeutic targets in breast cancer. The University of Pittsburgh and UPCI have a robust pipeline for drug development and validation. WCRC faculty collaborate with the Center for Translational Bioinformatics and the Chemical Biology Facility to identify new targets using high throughput molecular platforms and informatics. Candidate drugs are identified in high throughput screens and drug development performed in the Department of Chemistry. These drugs and other candidates are tested in the Phase 1 program of the UPCI Molecular Therapeutics and Drug Discovery Program, which examines pharmacodynamics and pharmacokinetics. Finally, drug efficacy is tested in the large Phase 1-3 clinical program at UPCI and Magee-Womens Hospital.
Faculty: Adrian Lee
Cancer stem cells and tumor heterogeneity
The cancer stem cell hypothesis posits that only a few cancer cells with stem-cell like behavior can propagate tumor formation. This hypothesis was originally proven in leukemia, and now substantial evidence exists in solid tumors such as breast cancer. Investigators in the WCRC are examining several properties of normal breast stem cells, and cancer stem cells. These studies include the use of genetically engineered mouse models, human immortalized and breast cancer cell lines, and fresh human breast cancers. Cancer stem cells are identified using cell sorting, lineage tracing, and microscopy and stem cell activity tested using a variety of assays.
Risk assessment and reduction
The Magee-Womens Hospital High Risk Breast/Ovarian Cancer Program was started in 2002 in recognition of the need for a more efficient model of providing care for women at increased risk for breast and ovarian cancer, including those with an inherited mutation in BRCA1 or BRCA2. The multidisciplinary format of the clinic allows patients to meet with a genetic counselor and an oncologist to review their family history and their risk for cancer, then undergo genetic testing and cancer screening as indicated. The Cancer Family Registry was also created, which enrolls women and their family members based on their personal and family cancer history and/or the presence of a known high-risk mutation. The goal of the CFR is to provide a resource for research regarding families at high risk for gynecologic cancer, whether from an epidemiologic, genetic counseling, clinical, or translational perspective.
Information regarding cancer history and lifestyle factors, such as childbearing and birth control pill use, are collected, along with blood and urine specimens. If women choose to undergo risk-reducing surgery at Magee, they are eligible for additional surgical specimen collection. To date, over 450 women have enrolled in the registry, of whom 146 carry a BRCA1 mutation and 91 a BRCA2 mutation. Seventy-five women have had surgical specimens collected at the time of risk-reducing removal of the fallopian tubes and ovaries. More than fifty women have had serial sample collection as they continue screening through the HRBOCP. The CFR has supported translational projects in breast and ovarian cancer research. In addition, data from the HRBOCP serves as a rich resource for clinical research.
Diagnostic, predictive, and prognostic biomarkers
A goal of the faculty in the WCRC is to identify novel diagnostic and prognostic markers for invasive and in situ breast cancer, study of predictive biomarkers in breast carcinoma and their correlation to clinical outcome. Other interests include identifying site of origin for "carcinoma of unknown primary" using immunohistochemistry and other ancillary techniques.
Imaging and screening
Despite much controversy surrounding the frequency of annual screening mammography, this modality remains the mainstay of early detection for breast cancer, and has been shown to reduce mortality by at least 25‰ in randomized population based studies. Still this test has significant limitations in that it is relatively nonspecific and has lower sensitivity in women with dense breast tissue. New, innovative modalities and software applications are proving useful to augment mammography and may help to overcome these limitations.
The Breast Imaging division of Magee Womens Hospital in concert with the Division of Imaging Research has a long history of research in new imaging modalities and continues through several grant funded projects to investigate new paradigms for the accurate and efficient diagnosis of breast cancer at its earliest stages. Currently, researchers are investigating advanced digital platforms including digital breast tomosynthesis in both the screening and diagnostic paradigms and cone beam computed tomography in diagnostic patients through several ongoing projects. Computer-aided detection methodologies have been created and studied and elastography is being validated as a method to assess mass stiffness and reduce unnecessary biopsies for benign lesions seen on ultrasound.
Molecular breast imaging, which is a type of functional imaging, may help in cancer detection and also in quantifying background tissue risk. Two separate systems are currently being placed and research will start in 2012. In our clinical practice, ultrasound and MRI are being used in the screening setting for different high risk populations with analysis of outcomes planned, and protocols are being developed to study the effects of breast density on screening detection. Finally, electrical impedance measurements are being validated as yet another alternative for cancer detection.
Understanding the normal development of the breast is an integral part of our program. Breast development occurs in three main timeframes during life: in utero, puberty, and during the childbearing years. WCRC investigators are currently studying pathways involved in normal breast development.
Translational breast cancer bioinformatics
This program focuses on computational methods for identifying signaling pathways underlying biological processes and diseases as well as statistical methods for acquiring knowledge from biomedical literature. The application of latent variable models to simulate biological signaling system and text mining is a main area of research.
Personalized medicine informatics
The goal of personalized medicine is to deliver the right therapy to the right patient at the right time. For cancer care, this will involve characterizing the patient and their cancer using progressively more sophisticated testing and then using these test results to predict the most effective and least toxic treatment for that individual. To support this effort it is essential to have a solid IT infrastructure to allow interoperability and integration of research, clinical and 'omics' data. The role of IT informatics is to facilitate and support the research efforts with applied technology and to provide an infrastructure to support the analysis, delivery and exchange of information from research to care.
To address the challenges of developing an IT infrastructure to support personalized medicine in cancer, we have assembled a multidisciplinary team to work in tandem and to collectively develop, implement and steer the ongoing evolution of the information management aspects of personalized medicine. This team comprises experts from the following: clinicians, faculty researchers, pathologist, IT experts, bioinformatician, biostatistician and partnerships with commercial vendors. The team's goal is to develop processes and databases for multi-dimensional integration and analysis of tumor and 'omic' data. We will achieve this goal in a staged manner by first addressing three small discrete research and clinical areas and developing scalable processes within breast cancer that will eventually expand to other cancers. The IT infrastructure will focus on integrating data from the following research areas:
- Integration of TCGA 'omic' data with patient and tumor variables
- Comparative effectiveness research on multi-gene tests
- Treatment and outcomes following neo-adjuvant therapy and diagnosis of metastatic disease