bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-04-18: ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer
Authors: Flanagan JJ , Qian Y , Gough SM , Andreoli M , Bookbinder M , Cadelina G , Bradley J , Rousseau E , Willard R , Pizzano J , Crews CM , Crew AP , Taylor I , Houston J 
Published: May 2019

Abstract
ARV-471, an estrogen receptor (ER) alpha PROTAC, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ˜ 2 nM. PROTAC-mediated ER degradation decreases the expression of classically-regulated ER-target genes (PR, GREB1, TFF) and inhibits cell proliferation of ER-dependent cell lines (MCF7, T47D). Additionally, ARV-471 degrades clinically-relevant ESR1 variants (Y537S and D538G) and inhibits growth of cell lines expressing those variants. In an immature rat uterotrophic model, ARV-471 degrades rat uterine ER and demonstrates no agonist activity. Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant tumor volume regressions of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of &gt;90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (˜130% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC-degrader.
Citation Format: Flanagan JJ, Qian Y, Gough SM, Andreoli M, Bookbinder M, Cadelina G, Bradley J, Rousseau E, Willard R, Pizzano J, Crews CM, Crew AP, Taylor I, Houston J. ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-18.
Abstract P5-06-02: Organochlorine pesticide residues in human breast tissue and their relationships with clinical and pathological characteristics of breast cancer
Authors: Ellsworth RE , Kostyniak PJ , Chi L-H , Shriver CD , Costantino NS , Ellsworth DL 
Published: May 2019

Abstract
Agricultural pesticides are abundant environmental contaminants worldwide, prompting interest in studying their possible detrimental health effects. We examined organochlorine residues by quadrant (n = 245) in breast adipose tissues from 51 women with various stages of breast health to determine patterns of bioaccumulation within the breast and to assess relationships with patient clinical characteristics. Three organochlorine residues — 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (p,p′-DDE), hexachlorobenzene (HCB), and mirex — assayed by high resolution gas chromatography were abundant in breast tissue. p,p′-DDE (745 ± 1054 ng/g lipid) was the most prevalent residue, comprising 97.5% of the total chemical burden. Mean levels of p,p′-DDE and HCB were significantly correlated (P &lt; 0.001) with patient age at mastectomy, and levels of p,p′-DDE were correlated (P &lt; 0.05) with BMI. Pesticide concentrations did not differ significantly by breast quadrant and were not different in the quadrant(s) where the primary tumor was located compared to other cancer-free quadrants. In invasive cancer patients, organochlorine levels differed significantly based on clinical characteristics of the primary carcinoma, including stage, grade, ER status, and HER2 status, indicating that body burden of organochlorines may influence the development of specific subtypes of breast cancer. Potentially carcinogenic organochlorines were present at high levels within the human breast warranting further research to determine the impact of organochlorines in the etiology of breast cancer.
The opinions or assertions contained herein are the private ones of the author/speaker and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences or any other agency of the U.S. Government.
Citation Format: Ellsworth RE, Kostyniak PJ, Chi L-H, Shriver CD, Costantino NS, Ellsworth DL. Organochlorine pesticide residues in human breast tissue and their relationships with clinical and pathological characteristics of breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-06-02.
Abstract P5-07-03: Small molecule inhibition of smoothened in triple negative breast cancer-associated fibroblasts depletes cancer stem cells and sensitizes to cytotoxic chemotherapy in mice and humans
Authors: Swarbrick A , Cazet A , Hui M , O'Toole S , Lim E , Martin M 
Published: May 2019

Abstract
The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies.
In mouse models of triple negative breast cancer (TNBC), we use single cell genomics to show that Hh ligand produced by neoplastic cells reprograms cancer-associated fibroblast (CAF) gene expression, driving tumor growth and metastasis. Hh-activated CAFs upregulated expression of FGF5 and deposition of fibrillar collagen, leading to FGFR and FAK activation in adjacent neoplastic cells and the acquisition of a stem-like, drug-resistant phenotype.
Treatment with smoothened inhibitors (SMOi) reversed these phenotypes. Stromal treatment of TNBC patient-derived xenograft (PDX) models with SMOi downregulated the expression of cancer stem cell markers and sensitized tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden.
In the phase I clinical trial EDALINE, 3 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonedigib and docetaxel chemotherapy, with one patient experiencing a complete radiological response. Responders also exhibited high baseline FGFR activation and ECM deposition, suggesting a mechanism of action consistent with findings from the animal models.
These studies identify Hh signaling to CAFs as a novel mediator of cancer stem cell plasticity and drug resistance and an exciting new therapeutic target in TNBC.
Citation Format: Swarbrick A, Cazet A, Hui M, O'Toole S, Lim E, Martin M. Small molecule inhibition of smoothened in triple negative breast cancer-associated fibroblasts depletes cancer stem cells and sensitizes to cytotoxic chemotherapy in mice and humans [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-03.
Abstract P5-07-15: Adipose-derived peptides from breast cancer patients promote the malignancy of breast cancer MCF-7 cells
Authors: Fu Z , Li W , Wu H , Huang X , Li J , Sun C , Tang J , Yin Y 
Published: May 2019

Abstract
Adipose stromal/stem cells (ADSCs) could regulate malignancy behaviors of breast cancer, which was due to adipose-derived cytokines in part, such as leptin and resistin. Recently, peptides have been demonstrated to be potential targets for cancer therapy. It's valuable to analyze the characters of adipose-secreted peptides systematically. In this study, we isolated primary adipocytes from adipose tissue adjacent to breast tumor and breast benign lesions respectively, and then co-cultured breast cancer cells MCF-7 with tumor adjacent adipocytes (TAAs)/breast benign adipocytes (BBAs) separately. Compared to BBAs, TAAs could promote proliferation and migration ability of MCF-7. Then we extracted and purified peptides from supernatant of TAAs and BBAs using ultrafiltration, and the effects of TAAs-derived peptides compound on breast cancer cells appeared accordance with the adipose cells. 100 peptides, which were derived from 90 protein precursors, were found to be differentially secreted between TAAs and BBAs by LC-MS/MS (p &lt; 0.05). Gene Ontology (GO) and Pathway analyses appeared that these altered peptides were mainly contributed to cell adhesion, and regulation of Ras-protein signal transduction. These results showed that these differentially secreted peptides could regulate breast cancer cell malignancy, which indicated that they could be potential therapeutic targets and diagnostic bio-marker for breast cancer.
Citation Format: Fu Z, Li W, Wu H, Huang X, Li J, Sun C, Tang J, Yin Y. Adipose-derived peptides from breast cancer patients promote the malignancy of breast cancer MCF-7 cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-15.
Abstract P5-18-10: BHLHE40-AS1 is an enhancer associated long noncoding RNA critical to breast cancer progression
Authors: DeVaux RS , Schimjawicz H , Coarfa C , Behbod F , Herschkowitz JI 
Published: May 2019

Abstract
Increased emphasis on breast cancer screening has led to a dramatic increase in diagnosis of ductal carcinoma in situ (DCIS). DCIS lesions are nonobligate precursors of invasive ductal carcinoma (IDC) and thus, the current standard-of-care is aggressive therapy to prevent invasive and metastatic disease. However, only ˜40% of DCIS cases are predicted to progress leading to a current state of overtreatment and overdiagnosis. Thus, there is a critical need to identify functional determinants of progression of DCIS to IDC to allow discrimination between indolent and aggressive breast cancers and refine patient treatment strategies.We propose that long noncoding RNAs (lncRNAs) functionally drive breast cancer progression and their expression can discriminate between innocuous and potentially invasive DCIS.
Using biopsies from women with tandem DCIS and IDC lesions, we identified 35 lncRNAs whose expression can distinguish between pre-invasive and invasive disease. From this candidate list, the lncRNA BHLHE40-AS1 is found enriched in multiple breast cancer progression models, in HER2+ cell lines, and HER2+ patient tumors. Functionally, BHLHE40-AS1 is found to support tumor cell cycle and motility and may serve as a clinically relevant biomarker and therapeutic target in invasive breast cancer.
Further, BHLHE40-AS1 is expressed from a known super-enhancer that preliminary evidence suggests undergoes altered chromatin looping during breast cancer progression. Interestingly, over half of the candidate lncRNAs are associated with enhancer regions. Current studies are investigating super-enhancers, and associated lncRNAs that become acquired during breast cancer progression.
Citation Format: DeVaux RS, Schimjawicz H, Coarfa C, Behbod F, Herschkowitz JI. BHLHE40-AS1 is an enhancer associated long noncoding RNA critical to breast cancer progression [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-10.
Abstract P6-18-34: Treat ER+ight Canadian prospective observational study in HR+ advanced breast cancer: 3rd interim analysis
Authors: Doyle C , Califaretti N , Dent S , Iqbal N , Mates M , Kulkarni S , Bains P , Glenns V , Perri SR , Chia S 
Published: May 2019

Abstract
Treat ER+ight is the 1st prospective observational study in Canadian HR+ HER2– advanced breast cancer patients currently receiving endocrine therapy (ET) alone or in combination with targeted therapy (TT) in the first, second or third line setting (NCT02753686).
Methods: This pre-planned interim analysis describes baseline characteristics, treatment patterns and safety/toxicity of patients enrolled in ET and ET+TT cohorts. At data cut-off (November 2017), 200 patients were enrolled from 24 sites since March 2016. The median follow-up time at data cut-off was 8.1 months and 182 patients were evaluable for this analysis.
Results:
ET (n=73)ET + TT (n=109)Baseline Patient and Disease Characteristics Median age, years (range)71 (37-92)65 (39-87), p=0.017ECOG 0-1 (%)6274Median time since primary BC diagnosis, years (range)5 (0-37)6 (0-31)Median time with advanced BC diagnosis, years (range)1 (0-16)1 (0-8)Sites of Metastases (%) Bone only4027Visceral6073Location of Metastases (%) Lungs5747Liver2348, p=0.006Bone4846Lymph Nodes2735Enrollment Therapy (%) Everolimus+exemestane-29Fulvestrant17-Palbociclib+letrozole-16Palbociclib+fulvestrant-12Tamoxifen11-Exemestane6-Letrozole3-Anastrozole2-Palbociclib+exemestane-1Everolimus+tamoxifen-0.5Unknown11Start Dose of Targeted Therapy Everolimus (n=53); 10, 7.5, 5mg (%)-72, 4, 24Palbociclib (n=54); 125, 100mg, unknown (%)-89, 9, 2On-Study Adverse Events ≥15% (all-grade, %) Fatigue2332Nausea1224Diarrhea1120Cough815Alopecia316Neutropenia017
Conclusions: The majority of patients enrolled (64%) were receiving endocrine-based targeted therapy (CDK4/6 inhibitor or mTOR inhibitor) combinations. ET+TT patients were younger with more visceral disease and liver metastases compared to patients receiving endocrine therapy alone. Real-world starting dose of targeted therapies appears to be lower than the approved full dose for 11% of patients receiving palbociclib and 28% of patients receiving everolimus. Incidence of reported all-grade adverse events appears to be lower than previously reported in randomized trials and may be a consequence of real-world under-reporting of adverse events as well as the heterogeneous nature of the treatment cohorts. There does however appear to be a trend toward increased incidence of adverse events in the ET+TT cohort compared to the ET cohort.
Citation Format: Doyle C, Califaretti N, Dent S, Iqbal N, Mates M, Kulkarni S, Bains P, Glenns V, Perri SR, Chia S. Treat ER+ight Canadian prospective observational study in HR+ advanced breast cancer: 3rd interim analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-34.
Abstract A48: Ado-trastuzumab emtansine (T-DM1) controls tumor progression of established HER2-positive breast cancer brain metastases in mice
Authors: Ferraro Gino B. , Askoxylakis Vasileios , Kodack David P. , Badeaux Mark , Fukumura Dai , Engelman Jeffrey A. , Jain Rakesh K. 
Published: May 2019

Abstract
Brain metastases represent a major problem in the treatment of HER2-positive breast cancer due to the poor efficacy of HER2-targeted therapies in the brain microenvironment. The antibody drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. We tested the hypothesis that T-DM1 could overcome trastuzumab resistance in murine models of brain metastases.
Methods: We optimized established animal models of HER2-positive breast cancer brain metastases. We treated mice bearing BT474 (intracranial and intracarotid injections) or MDA-MB-361 (intracranial injection) tumors in the CNS with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling.
Results: Treatment with T-DM1 delayed tumor growth in comparison to trastuzumab and control IgG and improved survival. These findings were consistent between HER2-driven and PI3K-driven breast tumors. In BT474 tumors, median survival was 112 days for T-DM1 and 28 days for trastuzumab (p&lt;0.05). Mechanistic studies revealed no difference in HER2 downstream signaling, drug distribution or immune cell enrichment between T-DM1 and trastuzumab treated mice. A significantly increased apoptotic rate was measured for brain metastases treated with the antibody-drug conjugate.
Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven or PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. The results of our studies indicate that T-DM1 is effective in the brain microenvironment and will directly inform clinical trials in patients with HER2+ breast cancer brain metastases.
Citation Format: Gino B. Ferraro, Vasileios Askoxylakis, David P. Kodack, Mark Badeaux, Dai Fukumura, Jeffrey A. Engelman, Rakesh K. Jain. Ado-trastuzumab emtansine (T-DM1) controls tumor progression of established HER2-positive breast cancer brain metastases in mice. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A48.
Abstract A49: WAVE3 modulates sensitivity of TNBCs to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis
Authors: Davuluri Gangarao , Schiemann William P. , Plow Edward F. , Sossey-Alaoui Khalid 
Published: May 2019

Abstract
Chemoresistance allows for disease to recur and ultimately causes the death of most breast cancer patients. This scenario is particularly relevant in patients harboring triple-negative breast cancer (TNBC) tumors for which there are no effective FDA-approved drugs. However, a recent study determined that TNBCs can be segregated into 6 genetically distinct subtypes that do in fact exhibit differential rates of pathological complete response (pCR) to standard-of-care chemotherapies. Of these, the mesenchymal and mesenchymal stem-like subtypes of TNBCs exhibit the lowest rates of pCR when treated with standard-of-care chemotherapies. WAVE3 is an actin-cytoskeleton remodeling protein, and recent studies have highlighted a potential role for WAVE3 in promoting tumor progression and metastasis in TNBC. However, whether WAVE3 activity is involved in the development of chemoresistance in TNBCs remains unclear. Here we show that loss of WAVE3 expression resensitizes human TNBC cells to doxorubicin and docetaxel, as measured by increased apoptosis and cell death. We also show that WAVE3 knockdown in the chemotherapy-treated TNBC cells results in inhibition of STAT1 phosphorylation, as well as a significant decrease in expression levels of its downstream effector HIF-1α. Since HIF-1α is a major activator of VEGF-A production, and therefore a stimulator of tumor angiogenesis, loss of HIF-1α in the WAVE3-knockdown cells resulted in the inhibition the chemotherapy-mediated VEGF-A secretion and the downstream activation of angiogenesis, a phenomenon that often accompanies chemoresistance. Our data identify a critical role of WAVE3 in sensitizing TNBC to chemotherapy by inhibiting the STAT1/HIF-1α/VEGF-A signaling axis, and support the possibility that WAVE3 inhibition may be a promising target for TNBC cancer therapy.
Citation Format: Gangarao Davuluri, William P. Schiemann, Edward F. Plow, Khalid Sossey-Alaoui. WAVE3 modulates sensitivity of TNBCs to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A49.
Abstract A59: Macrophages orchestrate early dissemination of HER2+ cancer cells
Authors: Linde Nina , Mortha Arthur , Saenger Nicole , Sosa Maria , Tardio Ethan , Fehm Tanja , Karn Thomas , Merad Miriam , Aguirre-Ghiso Julio 
Published: May 2019

Abstract
Metastatic dissemination can already occur during early pre-invasive breast cancer stages. However mechanisms that control early cancer cell dissemination are unclear. Here we show that MMTV-HER2 early cancer lesions contain an invasive subpopulation of HER2+/E-cadherinlo cancer cells that disseminate by recruiting resident CD206+ mammary tissue resident macrophages (MTMs). This occurs months before monocyte-derived macrophages are recruited into advanced tumors. Early HER2+ lesions, but not healthy mammary tissue, produced CCL2 in an NFκB dependent manner and recruited intra-ductal MTMs, that secreted Wnt1 and thereby induced an epithelial to mesenchymal transition (EMT) in the early HER2+ cancer cells. Depletion of MTMs before overt tumors appeared prevented early cancer cells from undergoing an EMT and drastically reduced early dissemination. Surprisingly macrophage depleting therapy in MMTV-Her2 only during pre-malignant stages reduced alveolar metastases, even when mice went through invasive tumor stages and macrophages had repopulated the overt tumor tissue. Importantly, humans with DCIS lesions that contained macrophage+/E-Cadherinlo microenvironments frequently had disseminated cancer cell (DCCs) in the bone marrow. Taken together, we reveal that resident MTMs can promote early dissemination explaining how early cancer spread might proceed in breast cancer patients. We also propose that eDCCs play a long-term causal role in metastasis development.
Citation Format: Nina Linde, Arthur Mortha, Nicole Saenger, Maria Sosa, Ethan Tardio, Tanja Fehm, Thomas Karn, Miriam Merad, Julio Aguirre-Ghiso. Macrophages orchestrate early dissemination of HER2+ cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A59.
Abstract A63: IFNAR1 downregulation during melanoma progression upregulates αv expression and promotes metastasis
Authors: Ortiz Angelica , Katlinskaya Yuliya V. , Katlinski Kanstantsin V. , Fuchs Serge Y. 
Published: May 2019

Abstract
The anti-metastatic effects of type 1 interferon (IFN1) prompted its use for adjuvant therapy in malignant melanoma patients at high risk for developing metastasis. While IFN1 adjuvant therapy continues to be the preferred treatment, many patients fail to elicit response to IFN1 treatment and progress to develop distal metastases often resulting in a lethal outcome. We observed downregulation of the IFNAR1 chain of the IFN1 receptor and suppression of IFN1 signaling in genetically engineered mouse melanomas driven by melanocyte-specific activation of Braf and inactivation of Pten. Induction of melanoma in animals expressing IFNAR1 that is deficient in ubiquitination and degradation led to a delayed onset of the disease and decreased number of local metastases. Remarkably, no distant metastases were found in these mice despite substantial primary tumor burden. Gene set enrichment analysis demonstrated a dramatic loss of the αv integrin pathway signature in mice harboring stabilized IFNAR1. Conversely, melanomas induced in Ifnar1 knockout mice yielded transplantable cell lines that displayed high levels of αv expression. Restoring IFNAR1 expression in these cells led to the loss of αv expression. We discuss the role of these mechanisms in melanoma metastasis and refractoriness to IFN1-based therapy.
Citation Format: Angelica Ortiz, Yuliya V. Katlinskaya, Kanstantsin V. Katlinski, Serge Y. Fuchs. IFNAR1 downregulation during melanoma progression upregulates αv expression and promotes metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A63.