| Program Leader: C. Clevenger, MD, PhD |
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Program Co-Leader: S. Khan, MD |
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The Breast Cancer Program (BC) of the Robert H. Lurie Comprehensive Cancer Center embraces a multidisciplinary approach to integrate its basic, translational, and clinical components. The program seeks to identify the molecular markers for and the mechanisms that contribute to breast cancer progression, to develop new antagonists to these processes, and to translate these agents from pre-clinical models to the bedside. This vision is being accomplished under the leadership of Drs. Charles Clevenger and Seema Khan, noted breast cancer researchers with complementary skills and expertise. Specific areas of research focus that have been complemented by several recent faculty recruits include biomarkers, early detection, hormone-based signal transduction and transcription, and mouse models of breast cancer. Over the past five years the program has markedly increased its translational research activity and initiated several interactive clinical trials. These trials have spanned a diverse range of topics, including novel diagnostic and imaging techniques, innovative preventive and therapeutic interventions, and supportive care assessments. This research is conducted in the labs of 25 faculty from 11 departments within the Feinberg School of Medicine. Total current cancer-relevant peer-reviewed funding is $4,212,569 (direct) with 2,590,704 (direct) from NCI and $1,621,865 (direct) from other peer-reviewed sources. Between January 2001 and September 2006 there have been 301 publications from the current program members. Sixty-five (22%) of these publications represent intra-programmatic collaborations and 83 (28%) represent inter-programmatic collaborations. This research has been recently facilitated by the move of several program members onto the fourth floor of the recently completed Robert H. Lurie Biomedical Research building, which is dedicated to breast cancer and women's health research. Further growth of the program will occur within the upcoming year with the opening of an entire floor dedicated to breast cancer therapy in the new Prentice Women's Hospital of Northwestern Memorial Hospital.
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Hormones and growth factors mediate their actions in breast cancer through receptor-associated signal transduction networks resulting in specific patterns of gene expression. These signaling networks are not linear in nature, but are highly intertwined by intermediary cross-talk mechanisms. Signaling and its concomitant cross-talk in breast cancer have been directly linked to a number of salient phenomena in this disease, including tumor growth, metastasis, and hormone and chemotherapy resistance. Thus, these transduction pathways represent ideal targets for pharmacologic intervention. To that end, a variety of receptor-associated signaling pathways are under examination including those utilizing estrogens (Bulun, Chakravarti, Chatterton), prolactin (Clevenger), EGF/her2 family members (H. Band, V. Band), chaperones (Clevenger, Cryns, Lupu), kinases/small GTP-binding proteins (H. Band, V. Band, Clevenger, Cryns, Kiyokawa), and transcription factors (Bulun, Chakravarti, Clevenger). Several multi-disciplinary approaches including crystal and solution structural analysis, lentiviral siRNA delivery, nanoengineering, and small molecule drug screening are currently being utilized to dissect breast cancer signaling with the near-term goal of development of novel therapeutics.
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The translation of concepts from the laboratory to the clinic is facilitated by the examination of models of breast cancer in animals. Transgenic and knock-out mouse models have been developed by the group that will enable the in vivo assessment of the contribution of specific signaling proteins to the pathogenesis of breast cancer (H. Band, V. Band, Bulun, Chakravarti, Clevenger, Cryns, Lupu). In addition, xenografting of human breast cancer into athymic nude mice will further enable a direct assessment of the function of signaling proteins, but also enable the direct in vivo testing of newly developed pharmacologic agents (H.Band, V. Band, Bulun, Chatterton, Clevenger, Cryns, Lupu). The above models will enable the in vivo analysis of seminal events in the pathogenesis and progression of breast cancer including angiogenesis, metastasis, and drug resistance.
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The clinical program is coordinated through the leadership of Seema A. Khan, MD, and translational research projects are funded by the NCI, the Avon Breast Cancer Research Program gift, the Lynn Sage Breast Cancer Research Foundation at Northwestern Memorial Hospital, the Bluhm Family Program for Breast Cancer Early Detection and Prevention, and the previously active SPORE in Breast Cancer. The resulting clinical research covers the gamut of clinical problems in breast cancer. These begin with studies of inherited breast cancer susceptibility related to TGFb polymorphisms (Kaklamani, in collaboration with Pasche [CP, CGMT]), and in the biology and classification of BRCA gene mutations (Rubinstein). In addition, a family history tool for evaluation of high-risk families has been developed (Rubinstein). Nutritional studies extend from intervention studies of physical activity and diet (Van Horn, in collaboration with Gapstur [PC/CP]) to hormone measurements in a subset of participants of the Women's Health Initiative (Van Horn). Breast imaging research includes the development of systems for digital image display and annotation (Channin), studies of the actions of tamoxifen on premenopausal breast density (Morrow [former member], Chatterton, Hendrick [CP]). Other early diagnosis efforts include studies of minimal epithelial sampling (ductoscopy, ductal lavage, nipple aspiration fluid, and random fine needle aspiration) for breast cancer diagnosis and risk stratification, and Phase 2 studies of breast cancer prevention interventions that are evaluated using surrogate endpoints (Khan). Surgical therapy investigations include a study of disparities in surgical decision-making between Hispanic and non-Hispanic women with early breast cancer (Goel, Khan), and an analysis of the impact of primary tumor resection in women with de-novo metastatic disease (Khan). A variety of novel therapeutic strategies are under investigation, including innovative pharmaceutical agents such as nanoparticle bound taxane in combination with lapatinib (Kaklamani, Gradishar), new endocrine agents (Gradishar) and antiangiogenic therapy in breast cancer (Gradishar, Soff [former member of Breast Program]). Improvements in physician-patient communication are being sought through a study of patient perceptions of information gaps, in a collaboration between the Breast Cancer program and the Cancer Control program (Makoul, Khan, Gradishar). This extensive array of clinical research initiatives brings together investigators with a diverse array of skills, with the goal of achieving improvements in all facets of breast cancer care, which will lead to prolonged, high quality survival for women with breast cancer, and those at risk for it.
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