Purpose There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ERα) antagonists, or that down regulate the expression of ERα, would have clinical utility in the treatment of advanced tamoxifen and aromatase resistant breast cancer. Whereas such compounds are currently in development, we reasoned, based on our understanding of ERα pharmacology, that there may already exist among the most recently developed Selective Estrogen Receptor Modulators (SERMs) compounds that would have utility as breast cancer therapeutics. Thus, our objective was to identify among available SERMs those with unique pharmacological activities and to evaluate their potential clinical utility using predictive models of advanced breast cancer. Experimental Design A validated molecular profiling technology was used to classify clinically relevant SERMs based on their impact on ERα conformation. The functional consequences of these observed mechanistic differences on (a) gene expression, (b) receptor stability, and (c) activity in cellular and animal models of advanced endocrine resistant breast cancer was assessed. Results The high affinity SERM bazedoxifene was shown to function as a pure ERα antagonist in cellular models of breast cancer, and effectively inhibited the growth of both tamoxifen sensitive and resistant breast tumor xenografts. Interestingly, bazedoxifene induced a unique conformational change in ERα that resulted in its proteasomal degradation, although the latter activity was dispensible for its antagonist efficacy. Conclusion Bazedoxifene was recently approved for use in the European Union for the treatment of osteoporosis and thus may represent a near-term therapeutic option for patients with advanced breast cancer.

Altered mitochondrial dynamics can broadly impact tumor cell physiology. Using genetic and pharmacological profiling of cancer cell lines and human tumors, we here establish that perturbations to the mitochondrial dynamics network also result in specific therapeutic vulnerabilities. In particular, through distinct mechanisms, tumors with increased mitochondrial fragmentation or connectivity are hypersensitive to SMAC mimetics, a class of compounds that induce apoptosis through inhibition of IAPs and for which robust sensitivity biomarkers remain to be identified. Further, because driver oncogenes exert dominant control over mitochondrial dynamics, oncogene-targeted therapies can be used to sensitize tumors to SMAC mimetics via their effects on fission/fusion dynamics. Collectively, these data demonstrate that perturbations to the mitochondrial dynamics network induce targetable vulnerabilities across diverse human tumors and, more broadly, suggest that the altered structures, activities, and trafficking of cellular organelles may facilitate additional cancer therapeutic opportunities.

Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line treatment for estrogen receptor (ESR1) positive breast cancer. However, tumor resistance limits the duration of response. The clinical efficacy of fulvestrant, a Selective Estrogen Receptor Degrader (SERD) that triggers receptor degradation, has confirmed that ESR1 often remains engaged in endocrine therapy resistant cancers. Recently developed Selective Estrogen Receptor Modulators (SERM)/SERD hybrids (SSHs) that facilitate ESR1 degradation in breast cancer cells and reproductive tissues have been advanced as an alternative treatment for advanced breast cancer, particularly in the metastatic setting. RAD1901 is one SSH currently being evaluated clinically that is unique among ESR1 modulators in that it readily enters the brain, a common site of breast cancer metastasis. In this study, RAD1901 inhibited estrogen activation of ESR1 in vitro and in vivo, inhibited estrogen-dependent breast cancer cell proliferation and xenograft tumor growth, and mediated dose-dependent downregulation of ESR1 protein. However, doses of RAD1901 insufficient to induce ESR1 degradation were shown to result in activation of ESR1 target genes and in stimulation of xenograft tumor growth. RAD1901 is an SSH that exhibits complex pharmacology in breast cancer models, having dose-dependent agonist/antagonist activity displayed in a tissue-selective manner. It remains unclear how this unique pharmacology will impact the utility of RAD1901 for breast cancer treatment. However, being the only SERD currently known to access the brain, RAD1901 merits evaluation as a targeted therapy for the treatment of breast cancer brain metastases.

Purpose Fulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first-or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment of metastatic breast cancer. Fulvestrant exhibits exceptionally effective antitumor activity in preclinical models of breast cancer, a success that has been attributed to its robust SERD activity despite modest receptor downregulation in patient tumors. By modeling human exposures in animal models we probe the absolute need for SERD activity. Methods Three xenograft models of endocrine therapy-resistant breast cancer were used to evaluate the efficacy of fulvestrant administered in doses historically used in preclinical studies in the field or by using a dose regimen intended to model clinical exposure levels. Pharmacokinetic and pharmacodynamic analyses were conducted to evaluate plasma exposure and intratumoral ER downregulation. Results A clinically relevant 25 mg/kg dose of fulvestrant exhibited antitumor efficacy comparable to the historically used 200 mg/kg dose, but at this lower dose it did not result in robust ER downregulation. Further, the antitumor efficacy of the lower dose of fulvestrant was comparable to that observed for other oral SERDs currently in development. Conclusion The use of clinically unachievable exposure levels of fulvestrant as a benchmark in preclinical development of SERDs may negatively impact the selection of those molecules that are advanced for clinical development. Further, these studies suggest that antagonist efficacy, as opposed to SERD activity, is likely to be the primary driver of clinical response.

Background: Breast Cancer is the most common cancer in women worldwide. Since 2008, Mwanza, Tanzania, has worked to provide comprehensive cancer services through its Zonal consultant hospital. New national guidelines focused on clinical breast exam requires that women be aware of and seek care for breast concerns. Therefore, this study aims to understand breast cancer awareness in Mwanza and describe women-level barriers, care-seeking behavior, and perspectives on breast cancer. Methods: A community-based survey was administered to conveniently sampled women aged 30 and older to assess women's perspectives on breast cancer and care-seeking behavior. Results: Among 1129 women with a median age of 37 (IQR: 31-44) years, 73% have heard of cancer and 10% have received breast health education. Women self-evaluated their knowledge of breast cancer (from 1-none to 10extremely knowledgeable) with a median response of 3 (IQR: 1-4). Only 14% felt they knew any signs or symptoms of breast cancer. Encouragingly, 56% of women were fairly-to-very confident they would notice changes in their breasts, with 24% of women practicing self-breast examination and 21% reporting they had received a past breast exam. Overall, 74% said they would be somewhat-to-very likely to seek care if they noticed breast changes, with 96% noting severity of symptoms as a motivator. However, fear of losing a breast (40%) and fear of a poor diagnosis (38%) were most frequent barriers to care seeking. In assessing knowledge of risk factors, about 50% of women did not know any risk factors for breast cancer whereas 42% of women believed long term contraceptive use a risk factor. However, 37% and 35% of women did not think that family history or being older were risk factors, respectively. Conclusions: The success of efforts to improve early diagnosis in a setting without population-based screening depends on women being aware of breast cancer signs and symptoms, risks, and ultimately seeking care for breast concerns. Fortunately, most women said they would seek care if they noticed a change in their breasts, but the low levels of cancer knowledge, symptoms, and common risk factors highlight the need for targeted community education and awareness campaigns.