bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3603: Optimizing combination therapy against antiestrogen-resistance in estrogen receptor positive breast cancer
Authors: Gutgesell Lauren M. , Xiong Rui , Zhao Jiong , Tonetti Debra A. , Thatcher Gregory R. 
Published: July 2017

Abstract
Approximately 75% of breast cancer incidences are Estrogen Receptor positive (ER+). Treatment of ER+ breast cancer with antiestrogen endocrine therapy targets the proliferative mechanisms of ER using selective ER modulators (SERMs), such as tamoxifen, and selective ER downregulators (SERDs), such as fulvestrant. The resistance to endocrine therapy, either innate or acquired, is clinically diagnosed in up to 50% of patients within 5 years of treatment. Antiestrogen therapy of ER+ mammary cancer cells in vitro and in xenografts does not cause complete cell death or regression. Through the use of combination therapy to target the remaining sub-population of cells, complete regression can be predicted. Our lab has developed endocrine tamoxifen-resistant models through prolonged exposure to tamoxifen, estrogen deprivation, and overexpression of PKCα, a pro-survival pathway component, in addition to a fulvestrant-resistant model through prolonged exposure to fulvestrant. Investigation of the resistance mechanisms will provide insight into potential, combinatorial targets for overcoming endocrine resistance in ER+ breast cancer. Use of spheroidal 3D cell culture provides a physiologically relevant model with sufficient throughput for drug discovery. Establishing spheroids and subsequent treatment predicts the efficacy of combination treatment on tumor regression. Targeting pathways associated with increased prevalence of resistance, such as CDK 4/6, can be employed for clinical therapy. Using both novel in-house and clinical SERMs and SERDs, we have used these multiple cell lines to discover combinatorial targets using both mechanistic and unbiased screening approaches. The use of combination endocrine therapy in tamoxifen-resistant models has shown antiproliferative synergy, and is able to enhance tumor regression in xenografts. By optimizing combinatorial endocrine treatment against both fulvestrant- and tamoxifen-resistance, novel therapeutic approaches are being developed for ER+ breast cancer.
Citation Format: Lauren M. Gutgesell, Rui Xiong, Jiong Zhao, Debra A. Tonetti, Gregory R. Thatcher. Optimizing combination therapy against antiestrogen-resistance in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3603. doi:10.1158/1538-7445.AM2017-3603
Abstract 3605: The role of androgen receptor in invasive lobular breast carcinoma
Authors: Stires Hillary , Riggins Rebecca B. 
Published: July 2017

Abstract
The leading problem for women with estrogen receptor α (ER) breast cancer – approximately 70% of all breast cancers – is that while the majority of tumors initially respond to anti-estrogen treatment including Tamoxifen and aromatase inhibitors, they will develop endocrine resistance. A histological subset of breast cancer called invasive lobular carcinoma (ILC) accounts for 15% of all breast cancer cases and approximately 90% of ILC are ER-positive. Despite clinical markers suggesting a better prognosis for ILC compared to the more common invasive ductal carcinoma (IDC), recent data suggests women with ILC develop Tamoxifen resistance at a higher rate than IDC. New strategies for treating hormone refractory tumors are needed that not only overcome anti-estrogen resistance, but also present a more tolerable side effect profile and have fewer dose-limiting toxicities than adjuvant chemotherapy. The majority of ER-positive breast cancers also express androgen receptor (AR) and while AR presence in breast cancer is controversial, increased expression of AR leads to Tamoxifen resistance in IDC cell lines. Since ILC has more AR expression than IDC, the role of AR in ILC was studied by treating cells with the non-aromatizable androgen dihydrotestosterone (DHT) and the synthetic androgen R1881 as well as the anti-androgen Enzalutamide. We have previously begun to characterize a Tamoxifen resistant variant of the ILC cell line Sum44PE termed LCCTam cells. In both Sum44PE and LCCTam cells, AR protein expression increases in response to androgens, an action that is blocked by Enzalutamide. Interestingly, androgens do not promote growth in ILC cells, but Enzalutamide is still able to inhibit growth. These results suggest Enzalutamide may be an effective alternative therapy for women with ILC. Future studies will focus on whether regulation of nuclear receptor co-factors influences differences in AR signaling in ILC.
Citation Format: Hillary Stires, Rebecca B. Riggins. The role of androgen receptor in invasive lobular breast carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3605. doi:10.1158/1538-7445.AM2017-3605
Abstract 3612: Combination FGFR4 and ER-targeted therapy for invasive lobular carcinoma
Authors: Levine Kevin , Chen Jian , Sikora Matthew , Tasdemir Nilgun , Tseng George , Puhalla Shannon , Jankowitz Rachel , Dabbs David , McAuliffe Priscilla , Lee Adrian , Oesterreich Steffi 
Published: July 2017

Abstract
Background Invasive Lobular Carcinoma (ILC) is an understudied subtype of breast cancer. Distinctive properties of ILC include growth patterns, metastatic behavior, receptor status (almost universally estrogen receptor (ER) positive), and survival outcomes (Long-term survival is lower in patients with ER+ ILC compared to the other main histological subtype, invasive ductal carcinoma). Our lab recently generated six long-term estrogen deprivation (LTED) models of ILC cells. We performed RNA-Sequencing on these six LTED cell lines and identified differentially expressed genes compared to their parental cells cultured with estrogen. We overlapped these results with a previously published analysis of a tamoxifen-resistant ILC cell line and found that FGFR4 is the most consistently overexpressed gene in the setting of acquired resistance to endocrine therapy in ILC cells.
Hypothesis FGFR4 is an important mediator of resistance to endocrine therapy in ILC.
Methods To study the role of FGFR4 in acquired resistance to endocrine therapy, we used siRNA, multiple shRNAs, and specific small molecule inhibition for growth assays of ILC cells. To study the role of FGFR4 in de novo resistance to endocrine therapy, we collected 129 well curated ER+ ILC tumor specimens. We performed gene expression analysis on the pre-treatment samples using a custom NanoString panel.
Results FGFR4 inhibition decreases parental and LTED ILC cell growth in classic 2D growth conditions, in the setting of ultra-low attachment, and in colony formation assays. Mechanistically, FGFR4 and estrogen signaling are antagonistic in parental ILC cells. In our clinical samples, increased expression of FGFR4 is predictive of shorter time to distant recurrence.
Conclusion FGFR4 may play an important role in both acquired and de novo resistance to endocrine therapy in ILC. Future studies will assess the efficacy of combining FGFR4 inhibitors with ER-targeted therapy for patients with ILC.
Citation Format: Kevin Levine, Jian Chen, Matthew Sikora, Nilgun Tasdemir, George Tseng, Shannon Puhalla, Rachel Jankowitz, David Dabbs, Priscilla McAuliffe, Adrian Lee, Steffi Oesterreich. Combination FGFR4 and ER-targeted therapy for invasive lobular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3612. doi:10.1158/1538-7445.AM2017-3612
Abstract 3613: Development of chemically modified peptide inhibitor ERAP targeting BIG3-PHB2 complex on hormone-resistant breast tumor
Authors: Katagiri Toyomasa , Yoshimaru Tetsuro 
Published: July 2017

Abstract
Approximately 70% of breast cancer cells express estrogen receptor alpha (ERα), and depend on estrogen (E2) for proliferative and metastatic activity. The current endocrine therapies for breast cancer are mainly based on targeting ERα signaling using selective ERα modulators, ERα downregulators, and aromatase inhibitor. However, up to 50% of patients with ERα-positive tumors either initially do not respond or become resistant to these drugs. The precise molecular mechanisms for the endocrine resistance contributes to be an active area of research. Therefore, identifying the factors and pathways responsible for resistance and defining ways to overcome it lead to develop novel molecular-target therapies to endocrine resistance. Recent findings support that the Brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ERα signaling modulation in these cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using ERα activity-regulator synthetic peptide (ERAP: 165-177 amino acids) derive from a helical BIG3 sequence, a dominant-negative peptide inhibitor leads to the significant anti-tumor effect. However, duration of its effect is very short for clinical use. Here, we report the development of the chemically modified ERAP using stapling methods (stapled ERAP) to improve duration of its antitumor effects. The stapled ERAP specifically inhibited the BIG3-PHB2 interaction, thereby exhibiting the long-lasting suppressive activity and their intracellular localization without membrane-permeable polyarginine sequence supposedly through the formation of stable α-helix structure induced by the stapling. Importantly, a combination of stapled ERAP and tamoxifen caused a synergistic inhibitory effect in breast cancer cell growth. Tumor bearing mice treated with every 7 days with stapled ERAP treatment effectively prevented the BIG3-PHB2 interaction as well as daily treatment, leading to the complete regression of E2-dependent tumor in vivo. Our findings suggest that the stapled ERAP may be a promising anti-tumor drug to suppress the growth of luminal-type breast cancer in clinical use.
Citation Format: Toyomasa Katagiri, Tetsuro Yoshimaru. Development of chemically modified peptide inhibitor ERAP targeting BIG3-PHB2 complex on hormone-resistant breast tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3613. doi:10.1158/1538-7445.AM2017-3613
Abstract 3620: RARalpha interactome in breast cancer, the S100 calcium binding protein A3 binds tothe retinoid receptor
Authors: Terao Mineko 
Published: July 2017

Abstract
All-trans-retinoic acid (ATRA) is used in the treatment of acute promyelocytic leukemia. ATRA is endowed with promising anti-tumor activity in other tumor types, including breast cancer. In breast cancer, the anti-tumor activity of ATRA is mediated by the retinoid nuclear receptor, RARα (EMBO Mol Med. 2015 7:950-972). RARα is a ligand-dependent transcriptional factor, which is part of nuclear complexes regulating the expression of target genes. To define the RARα interactome in breast cancer cells we took a proteomic approach. We performed mass-spectrometric analysis of RARα immuno-precipitates from nuclear extracts of an ATRA-sensitive breast cancer cell line over-expressing the receptor. We identified 30 proteins differentially interacting with RARα in the absence/presence of ATRA. Three of these proteins FABP5, HSP27 and S100A3 interact with RARα in the absence of ATRA and their binding to the receptor is dramatically reduced upon addition of the retinoid ligand. Binding of the three proteins to RARα was validated by different types of immuno-precipitation experiments. We focused our attention on S100A3, a calcium binding protein whose function is largely unknown. Pull-down and Far-Western experiment indicated that S100A3 binds directly to RARα. Binding is specific to this nuclear receptor isotype as similar interactions with S100A3 are not observed with RARβ, RARγ or RXRα. S100A3 over-expression inhibited RARα ligand-dependent transcriptional activity, suggesting that the calcium-binding protein is a co-repressor. We designed specific shRNAs targeting S100A3 and we are in the process of evaluating their functional effects on ATRA-dependent anti-tumor activity in retinoid sensitive breast cancer cell lines.
Citation Format: Mineko Terao. RARalpha interactome in breast cancer, the S100 calcium binding protein A3 binds tothe retinoid receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3620. doi:10.1158/1538-7445.AM2017-3620
Abstract 3631: Delivery of a CD20 transferrin receptor VNAR bispecific antibody to the brain for CNS lymphoma
Authors: Walsh Frank S. , Wicher Krzysztof , Szary Jaroslaw , Stocki Pawel , Demydchuk Michael , Rutkowski Lynn 
Published: July 2017

Abstract
Penetration of the blood brain barrier (BBB) remains a significant hurdle in the development of biologic therapeutics for CNS-related cancers. Antibody-based molecules typically do not cross the BBB in amounts required for therapeutic efficacy. Receptor-mediated transporters in the luminal membrane of brain capillary endothelium, which normally transport circulating endogenous peptides and proteins, offer a non-invasive approach for the delivery of therapeutic molecules to the brain.Using a combination of in vitro and in vivo phage display technology, we isolated a panel of cross species (rodent, primate and human) binders to the transferrin receptor 1 (TfR1) from synthetic libraries of shark variable antigen receptors (VNARs). Initially, the anti-TfR1 VNARs were fused to an immunoglobulin Fc backbone for testing in mice. At therapeutic (2 mg/kg) doses delivered by tail vein injection, high levels of the VNAR-Fc antibodies were found in the brain after 18 hours, which exceeded 5% of the plasma levels. Brain fractionation studies showed that the VNAR-Fc antibodies to TfR1 translocated to the brain parenchyma and were not retained in the capillaries. The lead anti-TfR1 VNAR was then used to target aberrant B cells in the brain for conditions such as cerebral lymphoma where existing CD20 therapies to not penetrate the CNS at therapeutic doses. A family of anti-CD20/TfR1 bispecific molecules were produced by linking the small VNAR to either the N- and C- terminus of heavy and light chains to create both monovalent and bivalent fusions . We used rituxan as the CD20 agent. The bispecifics were assessed for binding to the two cognate antigens and then tested for brain penetration after tail vein injection. At least 4 different formats gave excellent brain penetration 18 hours after dosing at 3.75mg/kg. Unmodified rituxan had a brain plasma ratio of 0.25 in line with published data while the best anti-TfR1-rituximab bispecific formats were between 2 to 5%. The bispecific formats also retain antibody-dependent cell-mediated cytotoxicity and will be further tested for brain penetration in non-human primates and in rodent models of CNS lymphoma. If these results successfully translate from rodents to larger animals, the peripheral delivery of a brain penetrant CD20/TfR1 bispecific antibody would provide a safer and more effective alternative to CD20 antibody delivery by the intrathecal route and could have broad utility in B cell driven brain cancer.
Citation Format: Frank S. Walsh, Krzysztof Wicher, Jaroslaw Szary, Pawel Stocki, Michael Demydchuk, Lynn Rutkowski. Delivery of a CD20 transferrin receptor VNAR bispecific antibody to the brain for CNS lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3631. doi:10.1158/1538-7445.AM2017-3631
Abstract 3635: Improved T Cell activation bioassays to advance the development of bispecific antibodies and engineered T cell immunotherapies
Authors: Somberg Richard L. , Stecha Pete , Garvin Denise , Hartnett Jim , Fan Frank , Cong Mei , Cheng Jey 
Published: July 2017

Abstract
T cells play a central role in cell-mediated immunity and can mediate long-term, antigen-specific, effector and memory responses. In recent years, a variety of immunotherapy strategies aimed at inducing, strengthening or engineering T cell responses have emerged as promising approaches for the treatment of diseases such as cancer and autoimmunity. Current methods used to measure TCR-mediated T cell proliferation and cytokine production rely on primary PBMCs as a source of T cells, which must be stimulated via co-culture with APCs or anti-TCR/CD3 antibodies. These assays are laborious and highly variable due to their reliance on donor primary cells, complex assay protocols and unqualified assay reagents. As a result, these assays are difficult to establish in quality-controlled drug development settings. To overcome this barrier, we developed two reporter-based bioluminescent T cell activation bioassays that can be used for the development of bispecific antibodies and engineered T cell immunotherapies. The assays consist of Jurkat T cells genetically engineered to express luciferase downstream of either NFAT or IL-2 response elements. The T cell activation bioassays reflect the mechanisms of action of biologics designed to induce TCR and/or CD28-mediated T cell activation, as demonstrated using anti-CD3 and/or anti-CD28 antibodies as well as blinatumomab, a bispecific antibody that simultaneously binds CD3 expressed on T cells and CD19 expressed on malignant B cells. The bioassays are pre-qualified according to ICH guidelines and show assay specificity, precision, accuracy and linearity required for routine use in potency and stability studies. Finally, our data illustrate the use of reporter-based T cell activation bioassays for characterizing and measuring the activity of engineered chimeric antigen receptor T cells.
Citation Format: Richard L. Somberg, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Jey Cheng. Improved T Cell activation bioassays to advance the development of bispecific antibodies and engineered T cell immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3635. doi:10.1158/1538-7445.AM2017-3635
Abstract 3648: Targeting glypican-2 in neuroblastoma via single domain antibody-based immunotoxins and chimeric antigen receptor T cells
Authors: Li Nan , Fu Haiying , Hewitt Stephen , Dimitrov Dimiter , Khan Javed , Ho Mitchell 
Published: July 2017

Abstract
Neuroblastoma is the most common extracranial solid tumor in children. Approximately 45% of patients receiving standard therapy relapse and ultimately succumb to metastatic disease. One of the major challenges in the treatment of neuroblastoma and other pediatric cancers is the lack of effective targets. As such, there is an urgent need for a new therapeutic target. Here we demonstrate that glypican-2 (GPC2) protein is highly expressed in nearly half of neuroblastoma cases. High GPC2 expression has been correlated with poor overall survival when compared to patients with low GPC2 expression. The reduction of GPC2 expression inhibits neuroblastoma cell growth and induces tumor cell apoptosis through downregulation of Wnt/β-catenin signaling. We have discovered a group of human single domain antibodies specific for GPC2 and have used them to make two forms of antibody therapeutics, antibody-toxin conjugates (immunotoxins) and chimeric antigen receptor (CAR) T cells. Treatment with the immunotoxin inhibits proliferation of GPC2-positive neuroblastoma cells in vitro and mouse models. The CAR T cells targeting GPC2 suppress the growth of neuroblastoma xenograft tumors and eradicate disseminated neuroblastomas in mice. Our study establishes GPC2 as a new target of antibody-based cancer therapy and demonstrates that single domain-based antibody therapeutics can be used in the treatment of neuroblastoma.
Citation Format: Nan Li, Haiying Fu, Stephen Hewitt, Dimiter Dimitrov, Javed Khan, Mitchell Ho. Targeting glypican-2 in neuroblastoma via single domain antibody-based immunotoxins and chimeric antigen receptor T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3648. doi:10.1158/1538-7445.AM2017-3648
Abstract 3655: Biomarker strategy to guide the clinical development of ImmTACTM molecules, a novel class of bispecific T cell engaging biologic drugs
Authors: McAlpine Cheryl , Krige David , Herrero-Gonzalez Sandra , Franklin Sarah , Hurst Jacob , Shingler William , Patel Sanjay , Johnson Andy , Parker Debbie , Coughlin Christina M. , Hassan Namir J. , Jakobsen Bent K. 
Published: July 2017

Abstract
IMCgp100, a first in class immunotherapy, is a T cell redirecting bispecific biologic comprising an affinity enhanced T-cell receptor specific for gp100 and an anti-CD3 scFV. Phase I/IIa data has provided evidence of a favourable safety profile, and durable responses in both cutaneous and uveal melanoma have been observed. To complement the clinical studies we have developed a comprehensive biomarker strategy to aid our understanding of pharmacodynamics, patient response and potential mechanisms of resistance which includes analysis of markers in both the tumour and periphery. The data obtained to date provide evidence of the pharmacodynamic effects of the molecule including chemokine/cytokine release, in both the tumor and periphery, and lymphocyte infiltration into tumors. In addition, changes in the levels of certain chemokines following the first dose of IMCgp100 were associated with tumor shrinkage. The biomarker strategy we have developed forms the basis for the support of the on-going Ph II development of IMCgp100 in both cutaneous and uveal melanoma and for other ImmTAC molecules, as single agents and in combination, for the treatment of solid tumours.
Citation Format: Cheryl McAlpine, David Krige, Sandra Herrero-Gonzalez, Sarah Franklin, Jacob Hurst, William Shingler, Sanjay Patel, Andy Johnson, Debbie Parker, Christina M. Coughlin, Namir J. Hassan, Bent K. Jakobsen. Biomarker strategy to guide the clinical development of ImmTACTM molecules, a novel class of bispecific T cell engaging biologic drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3655. doi:10.1158/1538-7445.AM2017-3655