A tremendous amount of progress has been made in identifying the pathways of pathological importance in cancer and in the validation of steps in these pathways as therapeutic targets. However, the genetic heterogeneity among cancers, and the utilization by different tumor types of different growth and survival pathways, has made it difficult to realize the therapeutic potential of even the most tractable targets. Addressing this impediment to progress is a central theme of the research being undertaken by members of the Women's Cancer Program, where the development of therapeutic strategies that are tailored to specific cancer subtypes is a primary focus.
These efforts have led to the identification of targets, the inhibition of which are likely to selectively impact triple negative breast cancer, endocrine resistant ER-positive breast cancers, inflammatory breast cancer, thyroid cancer, and gynecologic cancers. This successful strategy will be continued with efforts being directed towards (a) the definition of pathways of pathological importance in different women's cancers, the exploitation of which will yield new strategies for therapeutic intervention, (b) identification and validation of biomarkers which will help to define specific disease characteristics and/or report on the efficacy of treatment regimens, and (c) development of and accrual to innovative clinical trials that build upon the scientific expertise of the program members. These initiatives will be facilitated by the existing infrastructure of the program and by the new opportunities for interaction that are contemplated.
There are a large number of investigators within the DCI, the Duke School of Medicine, and Duke University who are actively engaged in research related to women's cancers. Of particular note is the participation of several faculty members within the Nicholas School of the Environment (NSOE) and the Pratt School of Engineering in research relevant to this program. Reflecting the breadth of our constituency, the activities of the Program are directed towards the establishment and maintenance of an infrastructure that fosters scientific interaction with the goal of generating novel strategies for the prevention, detection, and treatment of cancers that impact women's health.
Andrew Berchuck, MD, is one of the Co-Directors of the Woman's Cancer Program within the DCI. For the past 25 years Dr. Berchuck has been actively involved in caring for women with gynecologic cancers while also leading a nationally recognized program in translational ovarian cancer research. He is Director of the Duke Division of Gynecologic Oncology, which is involved in a wide range of clinical trials in ovarian cancer including cooperative trials of the Gynecologic Oncology Group. Dr. Berchuck also serves as Head of the Gynecologic Cancer Program in the DCI. He is one of the leaders of the North Carolina Ovarian Cancer Study that seeks to identify genetic polymorphisms that affect ovarian cancer susceptibility. He is also head of the Steering Committee of the Ovarian Cancer Association Consortium.
Kimberly Blackwell, MD, is the leader of the Breast Cancer Group and a Professor of Medicine, Division of Medical Oncology. Her expertise includes serving as the PI on over 50 Phase 1-3 therapeutic trials over the past decade, including two which have led to the approval of lapatinib and T-DM1 for the treatment of HER2+ metastatic breast cancer. Her translational work focuses on validating predictive markers for novel therapeutics including HER2 signaling, D-dimer, EPO receptor, and genetic profiling. She is a Susan G. Komen Research Scholar and has served a number of leadership roles with this program locally, nationally, and internationally. She has served as a mentor to many medical oncology fellows who have gone on to remain in academic breast cancer positions.
Donald McDonnell, PhD, Program Co-Director, is the Chairman of Pharmacology and Cancer Biology and the Glaxo-Wellcome Professor of Molecular Cancer Biology. He has published over 240 manuscripts on the role of nuclear receptors in the pathogenesis of cancers and in other endocrinopathies. He has either founded or been involved directly as a founder in three biopharmaceutical firms; an activity which highlights his interest and ability to perform actionable translational research. The primary focus of his work in the last ten years has been in the development of mechanism-based approaches to develop novel classes of androgen receptor and estrogen receptor modulators for use in the treatment and prevention of breast cancer.
The collective scientific goal of research efforts within the Women's Cancer Program is to translate discoveries in the basic biology of women's cancer into clinically actionable information, the exploitation of which will have a significant positive impact on the lives of cancer patients. Until recently the research efforts in this program were centered around breast and ovarian cancers. However, the breath of the research within the program has been expanded to include thyroid cancer and other endocrine neoplasias of particular importance in women.
To accomplish these objectives our program is configured into two thematic areas:
Area 1: Therapeutic/translational research that is not confined by clinical subgroups of women's cancers but which will provide insights that are broadly relevant to women's cancer as a class.
Area 2: Therapeutic/translational approaches for the specific subtypes of women's cancers.
For both of these sub areas the primary scientific goals and aims are:
Aim 1. Define pathways of pathological importance, the exploitation of which will yield new therapeutic intervention strategies.
Aim 2. Identify and validate biomarkers that will help to define specific disease characteristics and/or report on the efficacy of treatment regimens.
Aim 3. Develop and accrue innovative clinical trials that build upon the scientific expertise of the Program members.
The organizational structure of the Women's Cancer Program, the interactive nature of its constituent members, and the integration of the program into the efforts of the DCI as a whole have fostered a vibrant research community that has had a very positive outcome on patient care. Further, this strong research environment has helped us attract some of the most talented researchers in this field to Duke.
Choudhury, S, Almendro, V, Merino, VF, Wu, Z, Maruyama, R, Su, Y, Martins, FC, Fackler, MJ, Bessarabova, M, Kowalczyk, A, Conway, T, Beresford-Smith, B, Macintyre, G, Cheng, Y-K, Lopez-Bujanda, Z, Kaspi, A, Hu, R, Robens, J, Nikolskaya, T, Haakensen, VD, Schnitt, SJ, Argani, P, Ethington, G, Panos, L, Grant, M, Clark, J, Herlihy, W, Lin, SJ, Chew, G, Thompson, EW, Greene-Colozzi, A, Richardson, AL, Rosson, GD, Pike, M, Garber, JE, Nikolsky, Y, Blum, JL, Au, A, Hwang, ES, Tamimi, RM, and Michor, F et al. "Molecular profiling of human mammary gland links breast cancer risk to a p27+ cell population with progenitor characteristics." Cell Stem Cell 13, no. 1 (2013): 117-130. PMID: 23770079
Earp, MA, Kelemen, LE, Magliocco, AM, Swenerton, KD, Chenevix-Trench, G, Australian Cancer Study,, Australian Ovarian Cancer Study Group,, Lu, Y, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Despierre, E, Vergote, I, Lambrechts, S, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Friel, G, Moysich, KB, Odunsi, K, Sucheston-Campbell, L, Lurie, G, Goodman, MT, Carney, ME, Thompson, PJ, Runnebaum, IB, Dürst, M, Hillemanns, P, Dörk, T, Antonenkova, N, and Bogdanova, N et al. "Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA." Hum Genet 133, no. 5 (May 2014): 481-497. PMID: 24190013
Hamilton, E, Blackwell, K, Hobeika, AC, Clay, TM, Broadwater, G, Ren, XR, Chen, W, Castro, H, Lehmann, F, Spector, N, Wei, J, Osada, T, Lyerly, HK, and Morse, MA. "Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected]. (Published online)" J Transl Med 10 (February 10, 2012): 28-. PMID: 22325452
Kurokawa, M, Kim, J, Geradts, J, Matsuura, K, Liu, L, Ran, X, Xia, W, Ribar, TJ, Henao, R, Dewhirst, MW, Kim, WJ, Lucas, JE, Wang, S, Spector, NL, and Kornbluth, S. "A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53. (Published online)" Sci Signal 6, no. 274 (May 7, 2013): ra32-. PMID: 23652204
Nair, S, Aldrich, AJ, McDonnell, E, Cheng, Q, Aggarwal, A, Patel, P, Williams, MM, Boczkowski, D, Lyerly, HK, Morse, MA, and Devi, GR. "Immunologic targeting of FOXP3 in inflammatory breast cancer cells." PLoS One 8, no. 1 (2013): e53150-. PMID: 23341929
Nelson, ER, Wardell, SE, Jasper, JS, Park, S, Suchindran, S, Howe, MK, Carver, NJ, Pillai, RV, Sullivan, PM, Sondhi, V, Umetani, M, Geradts, J, and McDonnell, DP. "27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology." Science 342, no. 6162 (January 1, 2013): 1094-1098. NIHMS 545625. PMID: 24288332
Schildkraut, JM, Iversen, ES, Akushevich, L, Whitaker, R, Bentley, RC, Berchuck, A, and Marks, JR. "Molecular signatures of epithelial ovarian cancer: analysis of associations with tumor characteristics and epidemiologic risk factors." Cancer Epidemiol Biomarkers Prev 22, no. 10 (October 2013): 1709-1721. PMID: 23917454
Sfakianos, GP, Iversen, ES, Whitaker, R, Akushevich, L, Schildkraut, JM, Murphy, SK, Marks, JR, and Berchuck, A. "Validation of ovarian cancer gene expression signatures for survival and subtype in formalin fixed paraffin embedded tissues." Gynecologic Oncology 129, no. 1 (2013): 159-164. PMID: 23274563
Verma, S, Miles, D, Gianni, L, Krop, IE, Welslau, M, Baselga, J, Pegram, M, Oh, DY, Diéras, V, Guardino, E, Fang, L, Lu, MW, Olsen, S, and Blackwell, K. "Trastuzumab emtansine for HER2-positive advanced breast cancer." New England Journal of Medicine 367, no. 19 (2012): 1783-1791. PMID: 23020162
Wardell, SE, Nelson, ER, Chao, CA, and McDonnell, DP. "Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease." Clin Cancer Res 19, no. 9 (May 1, 2013): 2420-2431. PMID: 23536434
Zhang, L, Huang, NJ, Chen, C, Tang, W, and Kornbluth, S. "Ubiquitylation of p53 by the APC/C inhibitor Trim39." Proc Natl Acad Sci U S A 109, no. 51 (December 18, 2012): 20931-20936. Open Access copy. PMID: 23213260
Wardell, SE, Ellis, MJ, Alley, HM, Eisele, K, VanArsdale, T, Dann, SG, Arndt, KT, Primeau, T, Griffin, E, Shao, J, Crowder, R, Lai, JP, Norris, JD, McDonnell, DP, and Li, S. "Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer." Clinical Cancer Research : an official journal of the American Association for Cancer Research 21, no. 22 (November 2015): 5121-5130. PMID: 25991817
Allensworth, JL, Evans, MK, Bertucci, F, Aldrich, AJ, Festa, RA, Finetti, P, Ueno, NT, Safi, R, McDonnell, DP, Thiele, DJ, Van Laere, S, and Devi, GR. "Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer." Molecular Oncology 9, no. 6 (June 2015): 1155-1168. PMID: 25769405
Adam, MA, Pura, J, Gu, L, Dinan, MA, Tyler, DS, Reed, SD, Scheri, R, Roman, SA, and Sosa, JA. "Extent of surgery for papillary thyroid cancer is not associated with survival: an analysis of 61,775 patients." Annals of surgery 260, no. 4 (October 2014): 601-605. PMID: 25203876
Kelemen, LE, Lawrenson, K, Tyrer, J, Li, Q, Lee, JM, Seo, JH, Phelan, CM, Beesley, J, Chen, X, Spindler, TJ, Aben, KK, Anton-Culver, H, and Antonenkova, N. "Genome-wide significant risk associations for mucinous ovarian carcinoma." Nature genetics 47, no. 8 (August 2015): 888-897. PMID: 26075790
Worni, M, Akushevich, I, Greenup, R, Sarma, D, Ryser, MD, Myers, ER, and Hwang, ES. "Trends in Treatment Patterns and Outcomes for Ductal Carcinoma In Situ." Journal of the National Cancer Institute 107, no. 12 (December 2015): djv263-. PMID: 26424776
Myers, ER, Moorman, P, Gierisch, JM, Havrilesky, LJ, Grimm, LJ, Ghate, S, Davidson, B, Mongtomery, RC, Crowley, MJ, McCrory, DC, Kendrick, A, and Sanders, GD. "Benefits and Harms of Breast Cancer Screening: A Systematic Review." JAMA Pub314, no. 15 (October 2015): 1615-1634. PMID: 26501537
Adam, MA, Pura, J, Goffredo, P, Dinan, MA, Reed, SD, Scheri, RP, Hyslop, T, Roman, SA, and Sosa, JA. "Presence and Number of Lymph Node Metastases Are Associated With Compromised Survival for Patients Younger Than Age 45 Years With Papillary Thyroid Cancer." Journal of Clinical Oncology: official journal of the American Society of Clinical Oncology 33, no. 21 (July 2015): 2370-2375. PMID: 26077238
Duke Cancer Institute constellates the world-class resources of Duke University, Duke Health and the Duke Comprehensive Cancer Center into a collaborative powerhouse. We are poised to drive a paradigm shift in the way long-established cancer centers and institutes have been waging this war.Learn More