Background: The androgen receptor (AR) normally binds male hormones and is known to drive the growth and survival of prostate cancer, analogous to the role of estrogen receptor (ER) in breast cancer (BC). Overall ~75% of BCs have AR, but its expression varies by subtype (~88% of ER+, ~50% of Her2+, and ~20% of TNBC). Importantly, women do have circulating androgens and, in fact, these hormones are relatively more abundant than estrogen in postmenopausal women. We recently discovered that patients with ER+ tumors that had more AR than ER had a poorer response to tamoxifen or aromatase inhibitor treatments. In addition, there is a subset of triple-negative breast cancer (TNBC), which are ER-, PR-/Her2-, but retain expression of AR that seems to drive their growth and survival. In preclinical experiments, we tested various drugs that block AR activity and found that enzalutamide (enza), a pure AR blocker, not only inhibited growth of all subtypes of AR+ BC, but also uniquely inhibited estrogen-stimulated tumor growth in ER+AR+ preclinical models. Thus, our promising preclinical studies demonstrate that enza has significant anti-tumor activity in both ER+ and ER- BC that retain AR. In a recent Phase III trial, enza has demonstrated great benefit to men with advanced prostate cancer resistant to current hormone treatments. Our preclinical studies in BC recently led the company that makes this drug (Medivation and clinical trials partner, Astellas) to initiate a Phase I clinical trial in BC. Therefore, we are able to start our clinical evaluation of AR blockade immediately. Other potent AR blockers are also in development.
Objective: The objective of Stage I of this proposal is to rapidly generate preclinical data that will serve to guide the design of clinical trials described in Stage II of the grant. The objectives of Stage II are to (1) define the efficacy and safety of enza as a single agent and in combination with other clinically relevant agents in women with AR+ BC (for instance with Her2 targeting therapies in Her2+/AR+ BC) and (2) understand mechanisms of action of AR blockade with enza in the various subtypes of BC and identify mechanisms of preexisting or acquired resistance. Years 1-2 (Preclinical): We hypothesize that AR will serve as a viable target in all of the major subtypes of BC and that enza will effectively block AR function, resulting in effective BC treatment. In cell cultures and mouse models, we will determine if AR can serve as a viable therapeutic target in ER+ tumors that fail to respond or relapse on traditional endocrine therapies. We will also perform a non-biased molecular screen called a "synthetic lethal screen," designed to identify unanticipated cellular pathways that might be effectively targeted in combination with enza in TNBC.
Aims: (1) To test enza alone or in combination with currently approved therapies for different subtypes of BC. (2) To examine the mechanism of action of enza in ER+/AR+ BC. (3) To identify mechanisms of susceptibility and resistance to AR blockade in TNBC. Years 1-5 (Clinical): We will be participating in Phase I and II therapeutic trials of enza in women with metastatic BC to discover clinical benefit. In order to discover the mechanisms of action and potential resistance in AR+ BC in women, we will ask women are treated on enza-containing studies to undergo serial tumor biopsies of their metastatic tumors prior to treatment, during, and at time of progression.
Hypothesis: Our hypothesis is that molecular comparisons of tumor tissue obtained pre- vs. during treatment will identify biomarkers that indicate the action as well as efficacy of enza. Comparison of tumor tissue obtained pre- vs. at time of progression will also identify biomarkers associated with resistance mechanisms, and this information will guide subsequent trials. In Years 1-2, we will evaluate the efficacy of single agent enza in the different subtypes of AR+ BC. During Years 3-5, we will examine the effectiveness of enza in combination with specific other agents suited to the subtype of BC.
Aims: (1) Determine if enza is well-tolerated and has substantial anti-BC activity in women. (2) Discover biomarkers that predict who may benefit from enza treatment. (3) Understand if the most promising combinations of agents tested in Stage I are useful for the specific subtype of AR+ BC. Our group is advising our pharma partners in the clinical development of enza in BC; they will conduct studies designed to get the agent Food and Drug Administration (FDA) approved. Our grant focuses on further preclinical studies that will serve to guide the rational design of unique investigator-initiated clinical trials, designed together with our advocates, in order to understand which women will most benefit from this treatment.
Impact: Our results suggest that AR could serve as an important therapeutic target in almost 75% of breast cancers, including a subset of TNBC, and in patients with ER+ tumors that fail to respond or relapse while on traditional ER-directed endocrine therapies. This grant will validate AR as a target and determine if enzalutamide is effective for AR+ BC. Given that enzalutamide is likely to be FDA approved for prostate cancer in 2012, this work may have a rapid clinical impact on women with breast cancer.