Posted October 17, 2013
Jennifer Richer, Ph.D., and Anthony Elias, M.D., University of Colorado Cancer Center
Dr. Jennifer Richer and Dr. Anthony Elias at the University of Colorado (CU) Cancer Center are discovering more about how androgens drive breast cancers. This pair is leading the charge toward proving the androgen receptor (AR) as an important breast cancer target. The collaboration started in 2001 when Anthony Elias, M.D. breast cancer program director at CU Cancer Center and professor of medical oncology at the CU School of Medicine, took the clinical observation that certain estrogen-receptor positive breast cancers responded less well to anti-estrogen therapy to colleague Jennifer Richer, associate professor of pathology and co-director of the CU Cancer Center Tissue Processing and Procurement Core. Dr. Richer and Dr. Elias were convinced that, in these cases, something else was driving the cancer. With the support of a DoD BCRP Clinical Bridge Award in 2002, Dr. Richer discovered that AR mRNA and protein expression are markedly decreased in estrogen receptor alpha positive (ER+) tumors that respond to neoadjuvant endocrine therapy, but remain steady or increased in tumors that fail to respond. These data led her to postulate that tumors that demonstrate resistance to anti-estrogen therapies may have switched from estrogen-driven growth to growth driven by androgens. In 2008 the BCRP awarded her an Idea Award to further investigate the role of AR in breast cancer. Under the Idea Award, Dr. Richer compared the anti-androgen bicalutamide, traditionally used to treat prostate cancer, to a novel anti-androgen, enzalutamide, in the early stages of development. Dr. Richer found that the new anti-androgen blocked not only androgen-mediated proliferation of breast cancer cells but also estrogen-stimulation of proliferation. The fact that this drug binds to AR, but not to ER, suggested that AR influences ER action through a novel, unidentified mechanism and that this activity is abrogated by enzalutamide (a pure antagonist), but not by bicalutimide (a partial agonist).
Dr. Richer and Dr. Elias presented these preclinical findings in breast cancer to collaborators at Medivation, the company that developed enzalutamide. In April 2012 Medivation with Astellas Pharma, initiated a first-of-its-kind phase I clinical trial at CU Cancer Center, Memorial Sloan Kettering, Karmanos Institute, and George Mason University using enzalutamide to treat advanced breast cancer patients who have not responded to standard of care therapies. Two months later, Medivation and Astellas announced enrollment of the first patient in a global phase II clinical trial evaluating enzalutamide as a single agent for the treatment of advanced, AR-positive, triple-negative breast cancer (TNBC). The U.S. Food and Drug Administration approved enzalutamide in August 2012 for the treatment of castration-resistant prostate cancer. Around the same time, Dr. Richer and Dr. Elias submitted a collaborative application to the DoD BCRP Clinical Translational Research Award funding opportunity, together with colleagues at Memorial Sloan Kettering, Karmanos Institute, and George Mason University, proposing to validate the benefit of enzalutamide alone or in combination with breast cancer standard of care and to incorporate findings into their own investigator-initiated trials with patients. This application was recommended for funding and the new project, "Targeting Androgen Receptor in Breast Cancer: Enzalutamide as a Novel Breast Cancer Therapeutic," was awarded in August 2013.
The partnership between Dr. Richer and Dr. Elias is a model example of translational cancer research in action. Dr. Elias made an observation in the clinic, Dr. Richer explored the mechanisms in the laboratory, and now these investigators are taking the research back to the clinic, where it is hoped to have a direct impact on breast cancer patients.
Abstracts and Invited Symposia Presentations:
Elias AD, Cochrane DR, Jacobsen BM, Cittelly DM, Howe EN, Jean A, Spoelstra NS, Bernales S, Protter AA, Richer JK. MDV3100, an androgen receptor signaling inhibitor, inhibits tumor growth in AR-positive breast cancer cell lines in vivo: evidence to justify clinical trials. ASCO 2012, A-564.
Elias A, Richer JK, LoRusso P, Peterson AC, Steinberg J, Mordenti J, Lopez C, Hudis C, Traina T. MDV3100-08: A phase 1 open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of MDV3100 in women with incurable breast cancer. ASCO 2012, TPS668.
D'Amato NC, Bernales S, Jacobsen BM, Cochrane DR, Guerrero J, Gómez F, Protter AA, Elias AD, Richer JK. Preclinical Evaluation of Enzalutamide in Breast Cancer Models. SABCS 2012 P2-14-02.
D'Amato NC, Cochrane DR, Barton VN, Thor AD, Elias AD, Richer JK. Targeting the androgen receptor in multiple breast cancer subtypes, Invited symposium presentation. AACR Advances in Breast Cancer. October 2013, IA18.
Traina TA, Yardley, DA, Patel M, Schwartzberg L, Elias A, Gucalp A, Peterson AC, Hannah A, Gibbons J, Khondker Z, Hudis CA, LoRusso P. A phase 1 open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of enzalutamide (previously MDV3100) alone or in combination with an aromatase inhibitor in women with advanced breast cancer. SABCS 2013 PD3-6 (A938), accepted, poster discussion.
Harvell DM, Spoelstra NS, Singh M, Finlayson C, Borges V, Phang T, Trapp S, Hunter L, Dye WW, Elias A, Horwitz KB, Richer JK. Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance. Breast Cancer Res Treat. 2008 Dec;112(3):475-88. PMID: 18327671
Harvell DM, Richer JK, Singh M, Spoelstra NS, Finlayson C, Borges V, Elias A, Horwitz KB. Estrogen regulated gene expression in response to neoadjuvant endocrine therapy of breast cancers: tamoxifen agonist effects dominate in the presence of an aromatase inhibitor. Breast Cancer Res Treat. 2008 Dec;112(3):489-501. PMID: 1833824