Department of Defense

Breast Cancer Center of Excellence

BC050277 – A New Therapeutic Paradigm for Breast Cancer Exploiting Low-Dose Estrogen-Induced Apoptosis
V. Craig Jordan, OBE, Ph.D., D.Sc.; Lori J. Goldstein, MD, Co-PI

Background. Considerable advances in the treatment of breast cancer have been made during the past 30 years in a proportion of those patients that are estrogen receptor alpha (ER) positive. However, the majority of patients eventually became unresponsive to treatments targeted to the ER (e.g. tamoxifen or aromatase inhibitors) because of the development of antihormonal resistance. ER positive but antihormone unresponsive tumors remain a challenge and must be a priority for treatment. Currently the only treatment option is to use combinations of cytotoxic chemotherapies.

Objective/Hypothesis. The discovery that ER-positive breast cancer treated exhaustively with antihormonal (“antiestrogenic”) therapy will undergo rapid apoptosis when exposed to low estrogen concentrations provide an opportunity to exploit a novel vulnerability of the cancer cell. The synergy provided by an integrated team of patient advocates and medical scientists creates an opportunity for our Center of Excellence (CoE) to establish a new therapeutic paradigm for breast cancer by using estrogen to kill antihormone-resistant cells. The laboratory team will discover the proteins and pathways involved in ER mediated apoptosis. We hypothesize that the ER can be used precisely to reactivate antihormonal sensitivity so that patients can be maintained longer on successful antihormonal treatments.

Specific Aims. The goal of the CoE is to use ER-mediated estrogen-induced apoptosis to aid patients with antihormone refractory breast cancer. To achieve this goal, the interdependent and synergistic group will perform four major interconnected Tasks at separate sites to address the overall CoE specific aims: 1) conduct clinical trials to determine dose-response apoptotic effects of estrogen (diethylstilbestrol (DES)) in patients following the failure of two successive antihormonal therapies (Task 1). 2) prepare samples from unique models in vivo and in vitro, of estrogen induced apoptosis in breast cancer cells resistant to either selective ER modulators (SERMs) or long-term estrogen deprivation (Task 2). 3) identify protein signatures of estrogen-induced survival or apoptosis in tumor cells or serum (Task 3). 4) analyze gene expression arrays of estrogen induced apoptosis or survival in breast cancer and interrogate cells with siRNAs (Task 4). 5) validate the subcellular map of survival after melding data (Tasks 2,3,4) with clinical samples (Task 1).

Study Design. Two clinical trials of patients with ER-positive tumors that have responded to and failed two consecutive antihormonal therapies will be completed. The clinical trialists in partnership with the Y-ME National Breast Cancer Organization, will create a Clinical Trials Consortium, to determine: a) the response and quality of life of patients receiving standard 15 mg DES therapy and b) evaluate the response to lower-dose DES therapy. Samples will be collected to determine early response signatures in the blood and in accessible tumor tissue. Multidisciplinary laboratory scientists at Georgetown University (GU), TGen and Fox Chase Cancer Center (FCCC) will employ well described models in vivo and in vitro to establish mechanisms of estrogen-induced apoptosis. Coded biological samples from experiments with models (Task 2) will be sent from FCCC to GU (Task 3) for proteomics and TGen (Task 4) for genomic analysis. We will create a database of survival and apoptotic pathways using gene array melded with proteomics from existing ER positive cell lines and tumors grown in athymic mice. All sites will mine data from our tripartite secure web. We will subsequently interrogate pathways at Task sites (2-4) to determine which pathways must be reactivated or suppressed to induce ER mediated apoptosis. The clinical material from Task 1 will be used to validate survival and apoptotic pathways.

Relevance. Antihormone-refractory breast cancer following sequential successful treatments is an increasing problem in clinical practice. We address patient needs in our synergistic CoE proposal. Laboratory studies indicate that antihormone-resistant cells will be destroyed and antihormonal therapy will again be effective. We will deliver an inexpensive, safe, new clinical treatment paradigm, using an optimal dose of short-duration estrogen treatment to reduce tumor burden through apoptosis. Breast cancer growth will subsequently be controlled with aromatase inhibitors. Our complementary laboratory studies will create molecular maps of survival and apoptosis from our unique models of antihormone resistance that will be validated with clinical samples. Overall, the synergistic scientific effort will create a platform for evaluation of specific agents in the future to restrict tumor cell survival and enhance apoptosis further.