bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB115: Blocking p27Kip1phosphorylation with a liposomal:peptide drug induces Reactive Oxygen Species,necroptosis and tumor regression in breast cancer cells
Authors: Blain Stacy Wister , Jilishitz Irina , Quinones Jason L. , Patel Priyank , Chen Grace , Pavetsky Jared , VanInwegen Allison VanInwegen , Schoninger Scott , Jogalekar Manasi P. , Tsiperson Vladislav , Yan Lingyue , Wu Yun , Gottesman Susan R. , Somma Jonathan 
Published: July 2021

Abstract
Resistance to cyclin D-cdk4/6 inhibitors (CDK4/6i) represents an unmet clinical need and is frequently caused by compensatory CDK2 activity. Here we describe a novel strategy to prevent CDK4i resistance by using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. We find that NP-ALT blocks proliferation in HR+ breast cancer (BC) cells, as well as CDK4i-resistant cell types, including Triple Negative (TN) BC. The peptide ALT is not as stable in primary mammary epithelium, suggesting that NP-ALT has little effect in non-tumor tissues. In HR+ BC cells specifically, NP-ALT treatment induces ROS and RIPK1-dependent necroptosis. Estrogen signaling and ERα appear required. Significantly, NP-ALT induces necroptosis in MCR7 ESRY537S cells, which contain an ER gain of function mutation frequently detected in metastatic patients, which renders them resistant to endocrine therapy. Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance. Because the RAS/MAPK axis is the target of many therapies, NP-ALT, with its ability to target p27, can deal with the backend drug resistance seen in the presence of other inhibitors, extending the addressable market of this line of therapy.
Citation Format: Stacy Wister Blain, Irina Jilishitz, Jason L. Quinones, Priyank Patel, Grace Chen, Jared Pavetsky, Allison VanInwegen VanInwegen, Scott Schoninger, Manasi P. Jogalekar, Vladislav Tsiperson, Lingyue Yan, Yun Wu, Susan R. Gottesman, Jonathan Somma. Blocking p27Kip1phosphorylation with a liposomal:peptide drug induces Reactive Oxygen Species,necroptosis and tumor regression in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB115.
Abstract LB119: VRN08, a Selective Mps1 Kinase Inhibitor Induces Mitotic Catastrophe and Apoptosis Efficiently in Advanced Cancers Including Rb1-Deficient
Authors: Jung Hong Ryul , Kim Yeonsil , Kim Haelee , Kwon Ji-Hye , Seo Dong-hyuk , Son Jung Beom , Kim Nam Doo , Kim Daekwon , Kim Sunghwan 
Published: July 2021

Abstract
Spindle assembly checkpoint (SAC) prevents mis-segregation of chromosome and allows accurate division in mitosis. Mps1 (also known as TTK) is one of the essential kinases for recruitment of SAC proteins after chromosome segregation. Failure of SAC induces chromosome instability, mitotic catastrophe, and ultimately apoptotic cell death and Mps1 is induced or activated in rapidly dividing tumor cells. Therefore, Mps1 has been considered an attractive anti-cancer drug target. VRN081569 is a potent type I kinase inhibitor of Mps1, which stabilizes Mps1 kinase domain in a closed conformation by forming a tight interface with its kinase domain. This structural stabilization appears to increase cellular potency for the induction of aneuploidy and apoptosis (~ 10 nM or less GI50 value). The loss of retinoblastoma tumor suppressor gene (Rb1), which is prevalent in advanced cancers, dysregulates cell cycle and promotes cell division. In particular, the resistance to CDK4/6 inhibitors has been reportedly mediated by loss of the Rb1 gene. We found that Rb1-negative cells express higher level of Mps1 than Rb1-positive cells and VRN081569 efficiently induce apoptosis of Rb1-negative Triple Negative Breast Cancer (TNBC) cell line MDA-MB-468 than Rb1-positive TNBC MDA-MB-231. Especially we confirmed that VRN081569 induces caspase 3/7 activity faster in Rb1-negative cells (~50-fold EC50 of caspase 3/7 activity compared to Rb1-positive cells), and cell cycle analysis has shown that our compound induces a dose-dependent dysregulation of mitosis, resulting in a decrease in the frequency of the G0/G1 phase, and also induces aneuploidy and apoptosis. Finally, we confirmed a combination effects with anti-microtubule agents BCL-2 inhibitor and PARP-1 inhibitor, suggesting that modulation of two different cellular processes may overcome the lack of single agent activity for TNBC.
Citation Format: Hong Ryul Jung, Yeonsil Kim, Haelee Kim, Ji-Hye Kwon, Dong-hyuk Seo, Jung Beom Son, Nam Doo Kim, Daekwon Kim, Sunghwan Kim. VRN08, a Selective Mps1 Kinase Inhibitor Induces Mitotic Catastrophe and Apoptosis Efficiently in Advanced Cancers Including Rb1-Deficient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB119.
Abstract LB134: The rexinoid MSU-42011 enhances dendritic-T cell cross talk in a HER2 positive model of breast cancer
Authors: Leal Ana Sofia , Carapellucci Sarah , Liby Karen T. 
Published: July 2021

Abstract
Breast cancer (BC) was considered an immunologically silent tumor, however recent findings suggest that immune cells present in the tumor microenvironment play important roles in tumor growth. Retinoid X receptors (RXRs) are a subclass of nuclear receptors that act as ligand-dependent transcription factors that regulate a variety of cellular processes including proliferation and differentiation. Rexinoids are synthetic molecules that bind and activate RXRs. Bexarotene (Targretin®) is the only rexinoid approved by the FDA and is used for the treatment of refractory cutaneous T-cell lymphoma. Other more potent rexinoids have been synthesized, such as LG100268 and LG101506, which will not be tested in clinical trials because of intellectual property issues. Because recent studies have suggested that RXRs are involved in immune regulation, we synthesized novel rexinoids and selected MSU-42011 as a lead compound. MMTV-neu mice with tumors approximately 32 mm3 in volume were treated with control diet or MSU-42011 (100 mg/kg diet) for 10 days. Rexinoid treatment significantly (p=0.0069) reduced tumor fold change normalized to initial volume from 8.33 in controls to 4.80 on treatment. Analysis of the tumor by flow cytometry showed no significant differences in the major immune populations, such as T cells, macrophages and dendritic cells. However, expression of PDL1 was increased in CD11c+, MHC-II+ dendritic cells (5484 vs 7140 MFI, p=0.0456), suggesting engaged dendritic cells in activating cytotoxic T cells. To further elucidate the cross talk between dendritic and T cells, cytokines associated with T cell recruitment and activation were analyzed by RT-PCR. Tumor treated with MSU42011 had a 38.5 fold increase in IL12a expression (p=0.011, n=4), and a 20.8 fold increase in CCL9 (p=ns, n=4), suggesting that dendritic cells are actively recruiting and activating T cells. The activation of cytotoxic T cells was confirmed by a 75.5 fold increase in interferon gamma (p=0.0026, n=4) and a decrease of FOXP3 expression (p=ns, n=4). To test if the effects seen in tumor reduction were dependent on the presence of T cells, CD4 and CD8 were depleted. Depletion of CD4 alone, but not CD8, reversed the tumor reduction induced by MSU-42011. These results show that RXR agonists can be used to modulate immune cell populations in the tumor microenvironment, specifically by recruiting and activating dendritic cells that then activate cytotoxic T cells. We thank the Breast Cancer Research Foundation for support of these studies.
Citation Format: Ana Sofia Leal, Sarah Carapellucci, Karen T. Liby. The rexinoid MSU-42011 enhances dendritic-T cell cross talk in a HER2 positive model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB134.
Abstract LB139: VRN10, Discovery of Potent Irreversible HER2 Kinase Inhibitors with Intracranial Activity
Authors: Kim Hwan , Lee Younho , Park Jinhee , Lee Youngyi , Choi Jieun , Yoo Jihye , Park Chanmi , Lee Somi , Ko Eunhwa , Son Jung Beom , Choi Hwan Geun , Kim Nam Doo , Kim Daekwon , Kim Sunghwan 
Published: July 2021

Abstract
Human epidermal growth factor receptor 2 (HER2) amplification is one of oncogenic drivers most found in breast cancer but also occurs in multiple other tumor types. Approximately 10-30% of patients with breast cancer develop brain metastases (BCBM), a devastating cause of morbidity and mortality. To address this unmet medical need, VRN10s, brain penetrant, orally bioavailable, and irreversible small molecule inhibitors were designed to target HER2 while sparing EGFR wild type. In biochemical assays VRN10s had low nanomolar potency to inhibit catalytic activity of HER2. In cell viability assays using HER2+ breast and gastric cancer cell lines, VRN10s inhibited proliferation with single-digit nanomolar potency and exhibited an exceptional selectivity for HER2 over EGFR, with an enhancement of &gt; 30-fold. Neuregulin-1 (NRG-1) has been suggested to decrease the anti-tumor activity of HER2 kinase inhibitors by induction of HER3 in brain microenvironment. Two FDA-approved HER2 kinase inhibitors tucatinib and lapatinib are not only less brain permeable, but they also show significantly decreased activity in the presence of NRG-1. However, the addition of NRG-1 did not rescue the proliferation of HER2+ breast cancer cell lines treated with VRN10s. Western blot confirmed that VRN10s inhibit signal transduction downstream of HER2 and HER3 through the AKT and ERK pathways. Inhibition of HER2 is reported to cause cytotoxicity on cardiomyocytes. In spite of potent inhibition of HER2 catalytic inhibition, VRN10s did not show cardiomyocyte cytotoxicity more than other HER2 kinase inhibitors, including tucatinib and neratinib. We confirm VRN10s to have high brain exposure in several preclinical models. Consistent with our in vitro results, potent activity was observed in the xenograft and intracranial models using once daily oral administration with strong tumor growth inhibition. Based on in vitro assay, brain permeability and in vivo efficacy, VRN10s may be promising therapeutic candidates for patients with HER2+ tumors including BCBM.
Citation Format: Hwan Kim, Younho Lee, Jinhee Park, Youngyi Lee, Jieun Choi, Jihye Yoo, Chanmi Park, Somi Lee, Eunhwa Ko, Jung Beom Son, Hwan Geun Choi, Nam Doo Kim, Daekwon Kim, Sunghwan Kim. VRN10, Discovery of Potent Irreversible HER2 Kinase Inhibitors with Intracranial Activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB139.
Abstract LB140: CNS penetrant, irreversible inhibitors potently inhibit the family of allosteric oncogenic EGFR mutants expressed in GBM and demonstrate efficacy in patient-derived xenograft models
Authors: O'Connor Matthew , Lucas Matt , Romashko Darlene , Rasmussen Sara , Lin Tai-An , Waters Nigel , Fiorenza Raffaele , Wrona Iwona , Chen Deborah , Nicolaides Theodore , Raleigh David R. , Ozawa Tomoko , Trainor George , Arista Luca , Flohr Alexander , Ottaviani Giorgio , Roberts Chris , Buck Elizabeth 
Published: July 2021

Abstract
Oncogenic EGFR mutations occur in approximately 50% of glioblastomas (GBM) and largely reside in the extracellular domain. Prior attempts to reposition current generation EGFR inhibitors to treat GBM likely failed due to poor brain penetration and an inability to potently target the full spectrum of oncogenic mutations. As EGFR oncogenic mutations are found to be co-expressed in many GBMs, it is important that an inhibitor be broadly active against the entire family of relevant EGFR mutants. Additionally, a successful inhibitor would require a pharmacokinetic (PK) profile that allows for sufficient penetration of the blood brain barrier to elicit robust target engagement of the brain tumor. Using these design principles, we designed a series of highly potent molecules exemplified by BDTX-507. This molecule is an irreversible inhibitor of EGFR with antiproliferative IC50's less than 10 nM against the spectrum of GBM-relevant EGFR mutations. PK/PD studies demonstrated sustained pERK suppression exceeding 24 hours following a single QD dose. Furthermore, when dosed in GBM xenografts, including an intracranial Viii PDX (GBM6), robust tumor regressions and improved survival were observed. Emerging from this series were two advanced compounds, BDTX-700 and BDTX-1535, which also demonstrated potent inhibition of the GBM EGFR spectrum, selectivity v. wild-type EGFR, and an excellent CNS PK profile. BDTX-1535 is currently being evaluated in IND-enabling studies for future clinical evaluation in GBM patients.
Citation Format: Matthew O'Connor, Matt Lucas, Darlene Romashko, Sara Rasmussen, Tai-An Lin, Nigel Waters, Raffaele Fiorenza, Iwona Wrona, Deborah Chen, Theodore Nicolaides, David R. Raleigh, Tomoko Ozawa, George Trainor, Luca Arista, Alexander Flohr, Giorgio Ottaviani, Chris Roberts, Elizabeth Buck. CNS penetrant, irreversible inhibitors potently inhibit the family of allosteric oncogenic EGFR mutants expressed in GBM and demonstrate efficacy in patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB140.
Abstract LB166: Evaluation of CAR-T anti-tumor response in a novel immunocompromised NOD-Prkdcem26Cd52Il2rgem26Cd22/NjuCrl mouse model
Authors: Bankoti Rashmi , Joshi Amit , Jorgensen Lasse , Kongsgaard Andreas , Adorno Maddalena , Nicolis di Robilant Benedetta 
Published: July 2021

Abstract
Background: The development of immunocompromised mice revolutionized the field of cancer and stem cell research. Due to the lack of mature B and T lymphocytes, SCID (severe combined immunodeficiency disease) mice are ideal for xenoengraftment of human cells and tissue, including patient-derived tumor cells, hematopoietic stem cells and T cells. Over the years, the SCID models have been implemented to increase the efficiency of engraftment and NSG (NOD-SCID;IL2Rgammanull) has become the most reliable in vivo human cancer model. Here we compared NSG with the novel mouse strain NCG for immune-oncology applications, in particular for CAR-T therapy. NCG (NOD-Prkdcem26Cd52Il2rgem26Cd22/NjuCrl) is a recently developed triple immunodeficient mouse strain, created by sequential CRISPR/Cas9 editing of the PRKDC and IL2rg loci in the NOD/Nju strain. For this purpose, we engrafted NALM-6 and CHLA-55 tumor cell lines and treated them with CD19 and GD2.CAR T cells, respectively. Results: Four different operators generally considered NCG mice to be easier to handle. NCG mice were a bit smaller and have a much smaller spleen compared to age-matched NSG mice. Tumor engraftment was particularly rapid in NCG while the dissemination to organs was comparable. Generally, NCG showed signs of sickness earlier and upon lower tumor burden. When treated with CAR-T cells, in vivo anti-tumor response was comparable, both in a leukemia mouse model (96.6% NSG vs 97.7% NCG) and in a disseminated neuroblastoma model (67.3% NSG vs 57.8% NCG).Conclusion: Our preliminary data show that NCG mice are a suitable immunocompromised host for CAR-T pre-clinical studies.
Citation Format: Rashmi Bankoti, Amit Joshi, Lasse Jorgensen, Andreas Kongsgaard, Maddalena Adorno, Benedetta Nicolis di Robilant. Evaluation of CAR-T anti-tumor response in a novel immunocompromised NOD-Prkdcem26Cd52Il2rgem26Cd22/NjuCrl mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB166.
Abstract LB199: Trafficking of Semaphorin4D is regulated by endoplasmic reticulum chaperone GRP78
Authors: Carlos Anthony , Tsai Yuan-Li , Ma Yan , Lee Amy 
Published: July 2021

Abstract
Localization of endoplasmic reticulum (ER) chaperones to the cell surface is an adaptive mechanism for cells to expand the functionality of these proteins in response to stress by activating signaling pathways distinct from their ER functions, thereby impacting cell survival and signaling. In cancer, cell-surface ER chaperones have been reported to regulate oncogenic signaling pathways, proliferation and cell adhesion through interactions with other cell surface proteins. The emerging role of peripheral cell surface GRP78 (csGRP78), traditionally regarded as an ER luminal chaperone, as a multifunctional co-receptor for many different types of cell surface proteins presents novel opportunities for therapeutic interventions. One such cell surface protein is Semaphorin4D (Sema4D). Sema4D was originally discovered as a cell surface cleavable ligand and neuronal axon guidance cue that mobilizes the actin cytoskeleton to facilitate neuronal growth cone homing during development. In cancer, cell surface Sema4D expression is pro-metastatic and pro-angiogenic. Sema4D has been shown to be highly expressed in the breast cancer and epidemiological studies have demonstrated that Sema4D expression in breast cancer patients confers a poor prognosis and high probability of metastatic organotropism. Our recent advances have preliminarily identified a critical role for GRP78 in facilitating Semaphorin4D (Sema4D) trafficking. We show that Sema4D forms a direct protein-protein interaction with GRP78 and that GRP78 may facilitate membrane trafficking of Sema4D to the cell surface, where it exerts pro-angiogenic and metastatic effects. Furthermore, csGRP78 may interact with and facilitate many of the functions of Sema4D. Understanding the conditions by which GRP78 contributes to surface expression of Sema4D and the downstream effects may lead to novel therapeutics that abrogate the effects of Sema4D in cancer and to the elucidation of novel mechanisms by which Sema4D trafficking in cancer is regulated by GRP78.
Citation Format: Anthony Carlos, Yuan-Li Tsai, Yan Ma, Amy Lee. Trafficking of Semaphorin4D is regulated by endoplasmic reticulum chaperone GRP78 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB199.
Abstract LB202: Biphosphorylated Src at Y416/527 is active in triple-negative breast cancer cell lines and a subset of patient samples
Authors: Razorenova Olga V. , Nelson Luke , Wright Heather , Dinh Nguyen , Nguyen Kevin , Heinemann Scott 
Published: July 2021

Abstract
Targeted therapeutics are needed for triple-negative breast cancer (TNBC). In this study, we investigated the activation of Src family of cytoplasmic tyrosine kinases (SFKs) and two SFK substrates: CUB-domain containing protein 1 (CDCP1) and protein kinase C delta (PKCd) in 56 formalin-fixed, paraffin-embedded (FFPE) TNBCs. Expression of SFK phosphorylated at Y416 (SFK_pY416+) in tumor cells was strongly associated with phosphorylation of CDCP1 and PKCd (CDCP1_ pY743+ and PKCd_pY311+), as assessed by immunohistochemistry, indicating increased SFK activity in situ. To enable biochemical analysis, protein extraction from FFPE tissue was optimized. Cleaved CDCP1 isoform (70 kDa) was expressed to a varying degree in all samples but only phosphorylated in TNBC tumor cells that expressed SFK_pY416. Interestingly, active SFK was found to be biphosphorylated (SFK_pY416+/pY527+). Biphosphorylated active SFK was observed more frequently in forkhead box protein A1 (FOXA1)-TNBCs. In addition, in SFK_pY416-samples, FOXA1+ TNBC tended to be SFK_pY527+ (classic inactive SFK), and FOXA1- TNBC tended to be SFK_pY527-(SFK poised for activation). Strong SFK_pY416 staining was also observed in tumor-infiltrating lymphocytes in a subset of TNBCs with high tumor-infiltrating lymphocyte content. This report will facilitate protein biochemical analysis of FFPE tumor samples and justifies the development of therapies targeting the SFK/CDCP1/PKCd pathway for TNBC treatment.
Citation Format: Olga V. Razorenova, Luke Nelson, Heather Wright, Nguyen Dinh, Kevin Nguyen, Scott Heinemann. Biphosphorylated Src at Y416/527 is active in triple-negative breast cancer cell lines and a subset of patient samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB202.
Abstract LB203: FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer
Authors: Tavares Sandra , Liv Nalan , Pasolli Milena , Opdam Mark , Ratze Max , Saornil Manuel , Sluimer Lilian , Hengeveld Rutger , van Es Robert , van Werkhoven Erik , Vos Harmjan , Rehmann Holger , Burgering Boudewijn , Oosterkamp Hendrika , Lens Susanne , Klumperman Judith , Linn Sabine , Derksen Patrick 
Published: July 2021

Abstract
To this day, targeted treatment options for patients with triple negative metastatic breast cancer (TNBC) are still virtually absent. Previously, we showed that elevated expression of the tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/TNBC patients. Here, we show that high FER levels are also associated with improved outcome after adjuvant taxane-based combination chemotherapy, in high-risk, HER2-negative patients. In TNBC cells, we observed a causal relation between high FER levels and sensitivity to taxanes. Our proteomics and mechanistic studies demonstrated that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identified DCTN2 as a novel FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for tubular recycling domains development in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.
Citation Format: Sandra Tavares, Nalan Liv, Milena Pasolli, Mark Opdam, Max Ratze, Manuel Saornil, Lilian Sluimer, Rutger Hengeveld, Robert van Es, Erik van Werkhoven, Harmjan Vos, Holger Rehmann, Boudewijn Burgering, Hendrika Oosterkamp, Susanne Lens, Judith Klumperman, Sabine Linn, Patrick Derksen. FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB203.