bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1440: Identification of a novel EGFR sparing brain penetrant ErbB2 inhibitor with activity against oncogenic ErbB2 mutations
Authors: Chicarelli Mark J , Bouhana Karyn , Brizendine Richard K. , Cable LouAnn , Crow Michelle , Fell Brad , Fischer John , Fulton Jennifer , Guarnieri Anna , Jalluri Ravi , Knox Hailey , Koch Keith A. , Rieger Rob , Robinson John , Stunkard Lee M. , Sullivan Francis , Turton Roy , Winski Shannon , Zhou Yeyun 
Published: June 2023

Abstract
Oncogenic driver mutations in ErbB2 (e.g., S310F/Y, L755S, V777L, V842I) are present in a variety of tumor types including gastric, uterine, urothelial carcinoma, non-small cell lung, breast, and colorectal, some of which are also known to metastasize to the CNS. These mutations can also emerge as mechanisms of acquired resistance to targeted therapies and as such represent a novel and actionable target mutation set across solid tumor indications. Current therapies that target ErbB2 have poor potency against these mutations or are limited in their utility due to inhibition of wild type epidermal growth factor receptors (WT EGFR). The inhibition of WT EGFR is associated with debilitating clinical effects that include diarrhea, stomatitis, and hepatotoxicity. Additionally, treatment of CNS metastases is especially challenging since the potential therapy must also cross the blood brain barrier to have a therapeutic effect. Next generation ErbB2 inhibitors that are active against ErbB2 mutations, spare WT EGFR, and that can penetrate the brain would provide improved target coverage with the potential for fewer off target side effects compared to current therapies and as well as the potential to exhibit superior clinical efficacy. Herein, we describe the pre-clinical in vitro and in vivo activity of a novel, brain penetrant ErbB2 inhibitor which retains potency against prevalent mutations while sparing WT EGFR.
Citation Format: Mark J Chicarelli, Karyn Bouhana, Richard K. Brizendine, LouAnn Cable, Michelle Crow, Brad Fell, John Fischer, Jennifer Fulton, Anna Guarnieri, Ravi Jalluri, Hailey Knox, Keith A. Koch, Rob Rieger, John Robinson, Lee M. Stunkard, Francis Sullivan, Roy Turton, Shannon Winski, Yeyun Zhou. Identification of a novel EGFR sparing brain penetrant ErbB2 inhibitor with activity against oncogenic ErbB2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1440.
Abstract 1468: MYC-C interacts with Aurora kinase A in Ewing sarcoma cells
Authors: McNae Molly , Burgess Selena G. , Bayliss Richard , Burchill Susan A. 
Published: June 2023

Abstract
EWSR1-ETS fusion genes result in upregulation and high expression of the oncogene MYC-C in Ewing sarcoma (ES). MYC-C is therefore an attractive therapeutic target in these aggressive cancers with limited treatment options. Unsuccessful efforts to target MYC-C proteins directly have resulted in the development of inhibitors to associated stabilizing proteins, such as Aurora kinase A (AURKA), to induce proteasomal degradation1. In this study we test the hypothesis that MYC-C and AURKA interact in ES. Peptide pull-down assays were performed using Strep-Tactin Sepharose beads and N-biotinyl MYC-C peptides. After incubation with AURKA, eluted proteins were analyzed by SDS-PAGE. Intracellular colocalization of proteins was examined by immunofluorescence of TC-32 and SK-N-MC cell lines using confocal microscopy (Zeiss LSM880) and high content imaging (CD7). Cells were stained with anti-MYC-C and anti-AURKA antibodies, and DAPI used to visualize nuclei. DuoLink® proximity ligation assays (PLA; Sigma) were performed on TC-32 and SK-N-MC cell lines. Images were captured on the confocal microscope and the number of nuclear foci quantified.MYC-C binds AURKA through its transcriptional activation domain (residues 1-155). Residues 10-34 of MYC-C are sufficient for binding with AURKA (residues 122-403) in cell-free peptide assays. Colocalization of MYC-C and AURKA was visualized in mitotic SK-N-MC cells, but not in TC-32 cells. The proteins colocalize at the spindle poles. PLA confirmed an interaction between MYC-C and AURKA in TC-32 and SK-N-MC ES cells. The number of foci per nucleus was significantly higher in the SK-N-MC p53-null cells compared to the wild-type p53 TC-32 cells (p&lt;0.0001). In conclusion, MYC-C and AURKA colocalize and interact in the nucleus of ES cells. The frequency of interactions is greater in p53-null cells compared to cells with wild-type p53. Peptide pull-down assays identified residues 10-34 of MYC-C as the minimal AURKA interacting region. Disruption of this interaction by AURKA inhibitors may provide a mechanism for MYC-C degradation in ES, which could be exploited to develop novel therapeutic combinations to improve outcomes. 1Richards MW, Burgess SG, Poon E, Carstensen A, Eilers M, Chesler L, Bayliss R. Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. Proc Natl Acad Sci U S A. 2016 ;113(48):13726-13731.
Citation Format: Molly McNae, Selena G. Burgess, Richard Bayliss, Susan A. Burchill. MYC-C interacts with Aurora kinase A in Ewing sarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1468.
Abstract 1474: Hippo-mediated control of the mutant TERT promoter via MYC and GABP
Authors: Stevers Nicholas O. , Mancini Andrew , Costello Joseph F. 
Published: June 2023

Abstract
Most cancers achieve replicative immortality through reactivation of telomerase reverse transcriptase (TERT), the rate limiting subunit in telomerase activity. Tumors from more than 50 distinct cancer types reactivate TERT expression via mutations in the TERT promoter. Understanding how the mutations lead to activation and immortality is a central question in cancer research. Oncogenic signaling pathways including EGFR/AMPK, MAPK, and C-MYC/ASL, have been linked to telomere maintenance via their regulation of the mutant TERT promoter. Two mutually exclusive point mutations in the TERT promoter generate a de novo E26 Transformation Specific (ETS) binding motif that recruits the GA-Binding Protein (GABP) multimeric complex to reactivate TERT expression (Bell et al, Science 2015). Recruitment of GABP to the mutant TERT promoter facilitates the recruitment of C-MYC to the promoter (Shi et al, Mol. Cell 2022), which aids in transcriptional activation. The Hippo pathway plays a key role in development, organ size determination, and homeostasis, and has been found dysregulated in numerous cancer types. GABP is a member of the Hippo pathway, with GABP activating the promoter of the Hippo transcriptional effector Yes-associated protein (YAP1) and the Hippo pathway core kinases stimulating GABP nuclear exit (Wu et al., Cell Reports 2013). We have found that YAP and its paralogue transcriptional coactivator with PDZ-binding motif (TAZ) are linked to mutant TERT promoter activation in glioblastoma via transcriptional activation of both GABPA and MYC. These observations suggest the Hippo pathway supports tumor immortality in glioblastoma. While immortality has proven to be an elusive target, further investigations of the signaling networks that converge on the activation of the mutant TERT promoter may reveal therapeutic targets that block tumor growth and have secondary benefit by their impact on tumor immortality.
Citation Format: Nicholas O. Stevers, Andrew Mancini, Joseph F. Costello. Hippo-mediated control of the mutant TERT promoter via MYC and GABP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1474.
Abstract 1483: Development of FUBP1 inhibitors to reprogram pancreatic cancer cells into an anti-cancer phenotype
Authors: Bunea Alexandra , Polera Christopher , Dobrovolskaite Aiste , Moots Holly , Phanstiel Otto 
Published: June 2023

Abstract
The purpose of this project was to identify small molecules which reprogram tumor cells into an anticancer phenotype. Far upstream binding protein 1 (FUBP1) has been identified as a master regulator of a panel of genes involved in tumor survival including c-Myc and p21. FUBP1 controls gene expression by binding to specific far upstream element (FUSE) DNA sequences of the promoters of key tumor survival genes to regulate their transcription to provide a pro-tumor phenotype (high c-Myc, low p21). This makes FUBP1 a novel therapeutic target as its inhibition reprograms tumors to an anti-cancer phenotype (low c-Myc, high p21). This report describes the development of novel anthranilic acid derivatives which bind to FUBP1 (as shown by ChIP and gel shift assays) and modulate the mRNA and protein expression (qRT-PCR and Western) of FUSE-controlled genes (e.g., c-Myc and p21). The lead compound UCF699 was shown to reprogram pancreatic ductal adenocarcinoma (PDAC) cells into an anti-cancer phenotype in a dose-dependent manner and inhibit pancreatic cancer cell growth. In summary, the ability of UCF699 to control the expression of multiple FUSE-controlled genes and to reprogram tumor cells into an anti-cancer phenotype provides an exciting new way to treat pancreatic tumors.
Citation Format: Alexandra Bunea, Christopher Polera, Aiste Dobrovolskaite, Holly Moots, Otto Phanstiel. Development of FUBP1 inhibitors to reprogram pancreatic cancer cells into an anti-cancer phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1483.
Abstract 1537: DRIVE-Biologics: All the steps from discovery to development of novel biological entities
Authors: Fang Emily , Bunce Campbell , Payne Philip , Teran Rafael , Duchamp Olivier , Mignard Caroline , Bichat Francis , Viviani Fabrice 
Published: June 2023

Abstract
Biologics first revolutionized cancer treatment in the late 1900s with the approval of rituximab and trastuzumab, two monoclonal antibodies targeting antigens expressed on tumor cells. Another milestone was achieved in the early 2010s with the approval of antibodies targeting immune checkpoints. Nowadays, the discovery and development of new biological entities and biological therapeutic products represent a rapidly growing market in various therapeutic areas, with about 10 to 15 biologics being approved each year. We have built a premium expert ecosystem services - DRIVE-Biologics - to support and accelerate biologics drug discovery and development in oncology, immuno-oncology, and inflammatory diseases. The DRIVE-Biologics consortium provides a unique integrated solution with specialist services from strategic partners, to access market analysis, establish the ability to design, optimize, and develop novel biological entities addressing the therapeutic target of interest. DRIVE-Biologics supplies the high-level, IND-focused discipline to rigorously manage the integrated programs integrating CMC, manufacturing, regulatory affairs and clinical trial.
We will present the lead optimization and multiparameter preclinical evaluation process to select and assess biological candidates for downstream development and clinical studies:
-Custom cellular model development for discovery and potency analysis;
-In vitro screening, target engagement, and mechanism of action elucidation with cellular models ranging from tumor cell lines, immune cells or primary patient samples;
-In vivo efficacy and safety studies using refined and highly characterized syngeneic, xenogeneic, patient-derived xenograft or humanized mouse models up to non-human primates;
-DMPK capabilities to develop and validate bioanalytical methods (including GLP-compliancy) such as LBA and qPCR/RT-qPCR and also assess immunogenicity;
-Biodistribution and tumor specificity analysis of bioconjugated and radiolabeled biologics.
Herein, we provide DRIVE-BIO optimization and preclinical evaluation process to select promising biologics and list the key parameters to be checked.
We will present our recent results which highlight the importance to optimize these parameters to improve the efficacy of biologics.
Citation Format: Emily Fang, Campbell Bunce, Philip Payne, Rafael Teran, Olivier Duchamp, Caroline Mignard, Francis Bichat, Fabrice Viviani. DRIVE-Biologics: All the steps from discovery to development of novel biological entities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1537.
Abstract 1586: The potential therapeutic effect of the Rac/Cdc42 inhibitor MBQ-167 in glioblastomain vitro
Authors: Almedina Derealise Garcia , Grafals-Ruiz Nilmary , Dharmawardhane Suranganie , Torres-Sanchez Anamaris 
Published: June 2023

Abstract
Glioblastoma is a highly aggressive astrocytoma known to form the most lethal type of primary brain tumor. Therapeutic options are limited because 94% of diagnosed patients survive less than five years. Glioblastoma malignancy is attributed to uncontrolled cellular proliferation, increased angiogenesis, apoptosis resistance, and local invasion. The Homologous small GTPases of the Rho family, Rac1 and Cdc42, are critical regulators of the invasion and migration of glioblastoma cells. Previous studies have found a correlation between the high expression of Rac and CDC42 and the highly invasive characteristics of GBM in vivo. Our group characterized the small molecule compound MBQ-167 as a potent dual inhibitor of Rac and Cdc42 in breast and pancreatic cancer and have shown its utility in cell and mouse models of metastasis. In this project, we tested the hypothesis MBQ-167 is also a valid therapy option for glioblastoma. The T98G glioblastoma cell line was treated with varying concentrations (62 nM to 1000 nM) of MBQ-167 for 24 hrs, and effects on Rac/PAK activation (at 24 hours) was determined through active GTP bound Rac pulldowns, cell viability (at 48 and 96 hours) through MTT assays, and cellular migration (at 12, 24, and 48 hours) through wound healing assays. Results show that 250 nM of MBQ-167 inhibits Rac and PAK activation by 50% as well as cell viability at both time points (48 and 96 hours). MBQ-167 (150 nM-500 nM) also blocked glioblastoma cell migration at 12, 24, and 48 hours. Taken together, these results confirm that MBQ-167 is a viable inhibitor in glioblastoma.
Citation Format: Derealise Garcia Almedina, Nilmary Grafals-Ruiz, Suranganie Dharmawardhane, Anamaris Torres-Sanchez. The potential therapeutic effect of the Rac/Cdc42 inhibitor MBQ-167 in glioblastomain vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1586.
Abstract 1670: Sabizabulin shows anti-cancer efficacy in HER2+ breast cancer and novel sabizabulin derivatives overcome paclitaxel-resistance in triple negative breast cancer
Authors: Hartman Kelli L. , Krutilina Raisa I. , Oluwalana Damilola , Parke Deanna N. , Chen Hao , Miller Duane D. , Li Wei , Seagroves Tiffany N. 
Published: June 2023

Abstract
Of the four breast cancer molecular subtypes, the HER2 overexpressing subtype (HER2+) accounts for 15% of all breast cancer cases. Preferred frontline treatment relies on anti-HER2 therapies, such as trastuzumab and pertuzumab, combined with microtubule inhibitors, such as taxanes. However, the clinical efficacy of taxanes is limited by development of chemoresistance and hematological and neurotoxicities. Other agents that target tubulin, such as colchicine-binding site inhibitors (CBSIs) are a class of promising alternatives to taxane therapy due to their ability to overcome P-gp-mediated taxane resistance. Sabizabulin (formerly known as VERU-111) is a potent CBSI that is orally bioavailable, overcomes paclitaxel resistance, and inhibits tumor growth and distant metastases in triple negative breast cancer (TNBC). Here, we demonstrate sabizabulin’s anti-cancer efficacy in HER2+ breast cancer. We report that sabizabulin inhibits proliferation of HER2+ breast cancer, maintains a low nanomolar IC50 value, inhibits colony formation, and causes apoptosis in HER2+ breast cancer cell lines. Sabizabulin inhibits the primary tumor growth in an orthotopic HER2+ in vivo model, BT474, and in a patient-derived xenograft model, HCI-12. While sabizabulin shows promising results for treatment in HER2+ breast cancer, we further optimized the structure of sabizabulin to create a new class of anti-cancer molecules: 40a, CH-2-77, and 60c. Based on in vitro data, 60c showed higher potency in HER2+ breast cancer cell lines and was chosen as the lead compound to further study in a paclitaxel-resistant triple negative breast cancer in vivo study where it was able to effectively inhibit primary tumor growth compared to the vehicle group.
Citation Format: Kelli L. Hartman, Raisa I. Krutilina, Damilola Oluwalana, Deanna N. Parke, Hao Chen, Duane D. Miller, Wei Li, Tiffany N. Seagroves. Sabizabulin shows anti-cancer efficacy in HER2+ breast cancer and novel sabizabulin derivatives overcome paclitaxel-resistance in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1670.
Abstract 1671: Discovery of ETS-003, a potent and selective YAP/TAZ-TEAD PPI inhibitor with broad anti-tumor activity in Hippo-YAP aberrant cancers
Authors: Lu Jiajun , Gao Ming , He Hao , Feng Lijian , Gao Zhenting , Cui Wenqi , Yang Kun , Lu Jiting , Zheng Qiangang , Zhu Jidong , Guo Xin 
Published: June 2023

Abstract
Hippo/YAP is a conserved signaling pathway controlling organ development, tissue regeneration and immune modulation. Cascade of tumor suppressor genes (NF2, LATS1/2) and multiple signals from cellular microenvironment (mechano-transduction) regulate YAP/TAZ phosphorylation and degradation. The stabilized YAP/TAZ translocate from cytoplasm to nucleus, where they bind with TEADs for transcriptional activation. YAP/TAZ regulate numerous genes expression which play central roles in cell proliferation, apoptosis, tumor microenvironment remodeling, and drug resistance, making them appealing targets for cancer treatment. Disruption of YAP/TAZ-TEAD protein-protein interaction (PPI) has been regarded as an effective approach to abolish YAP/TAZ oncogenic activity. Previously we have reported the discovery of YAP/TAZ-TEAD PPI hit compounds bound at the Ω loop site of TEAD1. Here we report that the CADD-guided optimization of the hit compounds has yielded an orally available and potent YAP/TEAD PPI inhibitor ETS-003 with favorable ADME properties and robust anti-tumor efficacy. ETS-003 could potently block YAP/TAZ-TEAD PPI both in vitro and in cells, and disrupt YAP/TAZ genome-wide chromatin binding, resulting in on-target inhibition of YAP transcriptome. ETS-003 exhibited broad anti-proliferative activity in a variety of solid tumor cell lines. In Hippo-YAP dysregulated mesothelioma models, ETS-003 showed profound anti-tumor activity and good PK/PD/efficacy correlation. Moreover, when combined with MAPK pathway inhibitors (Osimertinib, Sotorasib and MRTX1133), ETS-003 could significantly enhance the anti-proliferative activity, suggesting multiple combination opportunities for ETS-003 in clinical investigations. The non-GLP studies of ETS-003 showed favorable safety margin, and warranted further clinical studies of ETS-003 in solid tumors.
Citation Format: Jiajun Lu, Ming Gao, Hao He, Lijian Feng, Zhenting Gao, Wenqi Cui, Kun Yang, Jiting Lu, Qiangang Zheng, Jidong Zhu, Xin Guo. Discovery of ETS-003, a potent and selective YAP/TAZ-TEAD PPI inhibitor with broad anti-tumor activity in Hippo-YAP aberrant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1671.
Abstract 1690: Myc suppression permits entry into the cancer endocycle to evade toxic effects of chemotherapy
Authors: Loycano Michael , Pienta Kenneth J. , Amend Sarah R. 
Published: June 2023

Abstract
Recent advances in precision medicine and immunotherapy have made great strides in cancer treatment and care, but chemoresistance remains a major challenge. One method of chemoresistance employed by cancer cells is accession of the protective polyaneuploid cancer cell (PACC) state, in which cells enter a functionally dormant state upon environmental stress. Entry into the PACC state begins with a whole-genome duplication event followed by endocycling, where the cells are metabolically active and cycling through repeated G1, S and G2 phases of the cell cycle without dividing. While in this state, cells avoid the mitotic stress exerted by common chemotherapeutics and survive therapy, eventually undergoing a depolyploidization process to repopulate the tumor, driving cancer lethality. The mechanisms by which a cancer cell can switch between a mitotic cell cycle and an endocycle are unknown. Cancer is characterized by deregulated cell proliferation, often driven by mutation or amplification of genes that govern the cell cycle. C-myc, an oncogenic transcription factor, is dysregulated in roughly 70% of cancers and is clinically used as a negative prognostic factor for disease-free survival and metastasis. C-myc is responsible for the transcriptional activation of many cell cycle-related genes, and repression of cell cycle inhibitors. Our data indicate that endocycling cells in the PACC state downregulate c-myc expression. Transcriptomic analyses show repression of myc targets, along with supporting protein data that total c-myc protein levels are decreased. While myc downregulation is expected in non-proliferative cells, the compensatory mechanisms mediating the G1/S transition in the cancer endocycle remain unknown. These observations suggest the presence of underlying mechanisms to reprogram the mitotic cell cycle to access the PACC state. We hypothesize that myc downregulation is essential for cells to activate the cancer endocyle and enter the protective PACC state. Understanding the mechanisms that govern this transition is crucial to generate next-generation cancer therapeutics to block accession or disrupt this state.
Citation Format: Michael Loycano, Kenneth J. Pienta, Sarah R. Amend. Myc suppression permits entry into the cancer endocycle to evade toxic effects of chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1690.