bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 959: C/EBPβ antagonist peptide, ST101, as a therapeutic approach in breast cancer
Authors: Rotolo Jim A. , Koester Mark , Ramirez Ricardo , Ghamsari Lila , Leong Siok , Gallagher Erin , Merutka Gene , Kappel Barry J. 
Published: July 2021

Abstract
Breast cancer (BC) is the most common invasive cancer in women, with more than 2.1 million cases and over 626,000 deaths occurring worldwide annually. Although age-adjusted mortality from BC has been declining since 1990, the median survival for patients with metastatic disease remains at 2-3 years, and 5-year survival approximates 25%. Thus, the medical need for more effective agents in this clinical setting remains very high. CCAAT/Enhancer Binding Protein Beta (C/EBPβ) is a transcription factor overexpressed in many cancers that regulates expression of factors that promote tumor survival, proliferation and inhibit differentiation. C/EBPβ dimers, such as with Jun/Fos and CREB/ATF family members, form via basic leucine zipper (bZIP)-driven coiled-coil interactions and are necessary for its association with DNA and transcriptional activity. Due in part to the difficulty in therapeutically targeting transcription factors, no effective C/EBPβ inhibitors are clinically available. ST101 is a novel peptide antagonist of C/EBPβ currently being evaluated in a Phase 1/2 clinical study in patients with advanced unresectable and metastatic solid tumors. ST101 was designed to bind the C/EBPβ bZIP domain, thereby preventing dimer formation and inhibiting its transcriptional activity. Here we describe ST101 non-clinical anti-tumor activity to support further development as a therapeutic approach in BC. In vitro studies in 4T1-luc triple-negative breast cancer (TNBC) and MCF7 HRPOS breast adenocarcinoma cells demonstrate ST101 dose-dependent impact of cell viability (EC50 of 4.8 and 2.1 µM, respectively), accompanied by significant impact on C/EBPβ-mediated gene expression as determined by qPCR analysis. In contrast, normal human mammary epithelial cells were not sensitive to ST101 (EC50 &gt;100 µM). In vivo experiments indicate dose-dependent tumor growth inhibition in an orthotopic 4T1-luc model following ST101 exposure, with significant tumor growth delays observed following 25 mg/kg ST101 (p&lt;0.05 vs. controls). Mice treated with 25 mg/kg ST101 via subcutaneous injection demonstrated significant tumor growth delay and decrease in tumor volume vs. controls. These data emphasize the potential of ST101 as a potent peptide therapeutic for HRPOS and TN BC.
Citation Format: Jim A. Rotolo, Mark Koester, Ricardo Ramirez, Lila Ghamsari, Siok Leong, Erin Gallagher, Gene Merutka, Barry J. Kappel. C/EBPβ antagonist peptide, ST101, as a therapeutic approach 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 959.
Abstract 962: Small-molecule NSC58874 releases and activates p73 via induction of mutant p53 degradation in cancer cells
Authors: Zhang Shengliang , El-Deiry Wafik S. 
Published: July 2021

Abstract
The tumor suppressor p53 is the most frequently mutated gene in cancer. Mutant p53 is a challenge to target in cancer therapy due to its many mutations and the fact that it is an inactivated transcription factor. p73 is a member of the p53 family but very rarely mutated in cancer cells. Therefore, activation of p73 is one of the promising strategies to restore the p53 pathway signaling in cancer therapy. Our laboratory has reported that p73 can be activated by small molecules to restore p53 pathway signaling via induction of p73 expression or interruption of p73 interaction with mutant p53. In the present study, we explored a strategy for releasing p73 from a mutant p53 inhibitory complex by induction of mutant p53 degradation using small molecule NSC59984. We previously reported that NSC59984 induces mutant p53 degradation and restores p53 pathway signaling through p73 in p53-mutant cancer cells. To address the mechanism of whether p73 is released from a mutant p53 inhibitory complex to transcriptionally regulate p53 targets, we performed p53-RE-luc reporter assays and Chromatin Immunoprecipitation (ChIP)-PCR in cancer cells with overexpression of p73. We found NSC59984 enhances p73-mediated signaling based on p53 target (such as p21 and noxa) induction at the protein level and p53-RE-luc reporter assay. Further ChIP-PCR analysis showed that NSC59984 treatment increases p73-binding to the p21 and Noxa promoters. These results taken together suggest that NSC59984 enhances p73 transcriptional activity to restore the p53 pathway signaling. It is also well known that p73 activity is regulated through a complex mechanism such as post-translational modifications and protein-protein interactions. We found that NSC59984 can stimulate the ERK2 signaling pathway. The MEK1 inhibitor U0126 partially blocked p73 binding to the p21 and Noxa promoters and their gene expression in cells treated with NSC59984, and this correlated with the rescue of mutant p53 stabilization. These results suggest that p73 is released from mutant p53 inhibitory complex and further stimulated through ERK2 signaling, as a mechanism of tumor suppression in tumors with mutant p53.
Citation Format: Shengliang Zhang, Wafik S. El-Deiry. Small-molecule NSC58874 releases and activates p73 via induction of mutant p53 degradation in 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 962.
Abstract 964: β-catenin antagonist peptide attenuates Wnt-dependent oncogenic activity
Authors: Rotolo Jim A. , Gallagher Erin , Ghamsari Lila , Leong Siok , Ramirez Ricardo , Koester Mark , Merutka Gene , Kappel Barry J. 
Published: July 2021

Abstract
β-catenin is an oncogenic transcription factor that has an essential role in cell development and biology. Increased β-catenin expression or activity has been implicated in many cancers, including breast and colorectal, and is associated with poor prognosis. Despite extensive ongoing research, β-catenin is conventionally considered ‘undruggable', and there are no current drugs available to target Wnt/β-catenin signaling. B-cell CLL/lymphoma 9 protein (BCL9) is a positive regulator of β-catenin transcriptional activity that is overexpressed in tumors. Disruption of β-catenin interaction with BCL9 has been shown genetically to suppress oncogenic Wnt/β-catenin transcription and represents a powerful approach to inhibit this previously undruggable target. Here, we describe the anti-tumor activity of a β-catenin antagonist peptide (BCAP), designed to disrupt the association of β-catenin with co-activator BCL9. Target engagement of BCAP with recombinant β-catenin was demonstrated in biophysical studies by circular dichroism spectroscopy, and inhibition of the β-catenin/BCL9 interaction was demonstrated in transiently transfected A549 cells by NanoBRET assay. Administration of BCAP to HEK293 cells stably transfected with TOPFlash reporter plasmid resulted in dose-dependent inhibition with an EC50 of 1.7 µM. Further, BCAP attenuated oncogenic gene transactivation in colorectal cancer cells (HCT116 and COLO320DM) and HRPOS breast cancer cells (MCF7), significantly decreasing the expression of Axin2 and CDK4 (p&lt;0.05), while not impacting Axin2 or CDK4 gene expression in Wnt-independent RKO and NCI-H460 cells. Administration of BCAP to 4T1-luc triple-negative breast cancer, HCT116 and COLO320DM cells resulted in dose-dependent in vitro cytotoxicity 48 hours post exposure, with EC50 values of 1.4, 4.4 and 1.2 µM, respectively. In in vivo orthotopic 4T1-luc tumor models, administration of BCAP via subcutaneous injection resulted in dose-dependent inhibition of tumor growth and significantly reduced tumor volume compared to control tumors (p&lt;0.05). These data demonstrate the significant in vitro and in vivo anti-cancer activity of BCAP and emphasize it's potential as a potent therapeutic for Wnt/β-catenin-dependent cancers.
Citation Format: Jim A. Rotolo, Erin Gallagher, Lila Ghamsari, Siok Leong, Ricardo Ramirez, Mark Koester, Gene Merutka, Barry J. Kappel. β-catenin antagonist peptide attenuates Wnt-dependent oncogenic 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 964.
Abstract 968: Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation
Authors: Tao Ran , Fang Douglas D. , Li Yuanbao , Zhang Kaixiang , Xu Chunhua , Fang Xu , Wang Qixin , Yang Dajun , Zhai Yifan 
Published: July 2021

Abstract
Ovarian cancer is one of the deadliest malignancies in women, and up to 70% of patients with epithelial ovarian cancer have FAK overexpression, amplification, or activation. FAK plays an important role in cellular migration, growth factor signaling, cell cycle progression, cellular survival and chemoresistance. This biomarker is also significantly associated with higher tumor stage, metastasis, and shorter overall survival in patients with ovarian cancer. Inhibition of FAK is therefore emerging as a promising treatment target.
APG-2449 is a clinical stage FAK/ALK/ROS1 multi-kinase inhibitor. In this study we investigated antitumor activity of APG-2449 combined with standard-of-care chemotherapeutics in ovarian cancer in the preclinical setting. In a mouse xenograft tumor model derived from ovarian cancer cell line OVCAR-3, which was resistant to platinum-based therapies, APG-2449 combined with paclitaxel, and paclitaxel plus carboplatin, synergistically enhanced antitumor activity, whereas the chemotherapeutics showed no activity. Synergistic antitumor activity was also observed in multiple patient-derived xenograft (PDX) models derived from women with chemoinsensitive ovarian cancer, which also frequently expresses high levels of FAK.
By comparing gene expression profiles of PDX tumors obtained from responders and nonresponders to the combined therapy, we identified CD44 (a marker for cancer stem cells) as a potentially predictive biomarker. Western blot analysis confirmed higher protein levels of CD44 in pretreated tumors of responders. Interestingly, downregulation of CD44 levels was observed in combination-treated tumors, suggesting that these combinations reduced cancer stem cell populations in ovarian cancer. Accordingly, in ovarian cancer cells exposed to APG-2449 alone or combined with paclitaxel, numbers of cells positive for CD44 or aldehyde dehydrogenase 1 (ALDH1; another marker for cancer stem cells) decreased in a dose-dependent manner.
In summary, our data suggest that FAK inhibition by APG-2449 sensitizes ovarian tumors to chemotherapeutics in preclinical tumor models of ovarian cancer. The synergistic antitumor activity was mediated by downregulation of CD44+ or ALDH1+ cancer stem cell populations. These findings encourage clinical development of APG-2449 in combination with chemotherapies for treatment of ovarian cancer.
Citation Format: Ran Tao, Douglas D. Fang, Yuanbao Li, Kaixiang Zhang, Chunhua Xu, Xu Fang, Qixin Wang, Dajun Yang, Yifan Zhai. Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation [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 968.
Abstract 975: Antitumor effect of cyclin- dependent kinase inhibitor flavopiridol in c-Myc overexpressing esophageal cancer
Authors: Hassan Md Sazzad , Awasthi Niranjan , Li Jun , Schwarz Margaret A. , von Holzen Urs 
Published: July 2021

Abstract
Tumors with elevated c-Myc expression often exhibit highly aggressive phenotype and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting a synthetic-lethal approach dependent on elevated c-Myc signaling is effective in treating esophageal cancer with a CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth without association with improved overall survival in esophageal cancer patients. c-Myc expression was enhanced by Wnt signaling activator (6-bromoindirubin-3′ -oxime (BIO) or pcDNA3-cMyc and c-Myc expression was depleted by c-Myc siRNAs. Interestingly, esophageal cancer cells with elevated c-Myc expression were preferentially more sensitive to induction of apoptosis by CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combinations with chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth with significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to CDK inhibitor flavopiridol and flavopiridol alone or in combination with cytotoxic or targeted agents can be a potential therapy for c-Myc overexpressing esophageal cancer.
Citation Format: Md Sazzad Hassan, Niranjan Awasthi, Jun Li, Margaret A. Schwarz, Urs von Holzen. Antitumor effect of cyclin- dependent kinase inhibitor flavopiridol in c-Myc overexpressing esophageal 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 975.
Abstract 986: Induction of lytic cycle of Epstein-Barr virus by a novel organic compound through activation of the c-Jun N-terminal kinase pathway
Authors: Dorothea Mike , Yiu Stephanie PT , Hui Kwai Fung , Chiang Alan K. S. 
Published: July 2021

Abstract
The reactivation of lytic cycle of Epstein-Barr Virus (EBV) is an important component of the emerging lytic induction therapy to specifically target the virus in EBV-associated malignancies. The potency of the lytic induction is central to the effectiveness of the lytic induction therapy. It is hampered by cancer cells that are refractory to lytic induction. This study aims to elucidate novel pathways involved in inducing EBV lytic cycle in epithelial cancer cells using a small organic compound, E11 intermediate (E11.1), and develop new drug combinations to overcome the refractoriness of the cancer cells to lytic induction. E11.1 was found to be the active component in the original E11 compound which has a superior lytic induction capability in both gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC) cells. Timepoint and dose dependent studies were performed to characterize E11.1's lytic reactivation kinetics of EBV in AGS-BDneo cells. Reactive oxygen species (ROS) scavengers and chemical pathway inhibitors were used to investigate the involvement of ROS and major cellular pathways in inducing lytic cycle of EBV by E11.1. Concomitant drug treatment of E11.1 and histone deacetylase (HDAC) inhibitor (suberoylanilide hydroxamic acid or romidepsin) was tested for synergistic action in lytic induction and cell death. E11.1 elicited a rapid kinetics of lytic induction through the activation of c-Jun N-terminal kinase (JNK) pathway in GC and NPC cells and induced the production of ROS and cell death at later timepoints. The combination of E11.1 and HDAC inhibitor reactivated the lytic cycle of EBV synergistically in both GC and NPC lines at 48 hours of treatment. In conclusion, we provided the evidence of activation of JNK pathway in the induction of EBV lytic cycle by E11.1 in EBV-positive epithelial malignancies. E11.1 and HDAC inhibitor induced the lytic cycle of EBV in EBV-positive epithelial cancer cells synergistically resulting in enhanced cell death.
Citation Format: Mike Dorothea, Stephanie PT Yiu, Kwai Fung Hui, Alan K. S. Chiang. Induction of lytic cycle of Epstein-Barr virus by a novel organic compound through activation of the c-Jun N-terminal kinase pathway [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 986.
Abstract CT150: Humanized CD19 CAR-T cells in the treatment of relapsed and refractory diffuse large B-cell lymphoma: A case report
Authors: Li Tan , Wang Yi , Li Bin , Hu Xueying , Liu Liu , Bao Yangyi , Li Qiao , Yang Lin , Li Hongxia 
Published: July 2021

Abstract
The authors did not submit an updated abstract. The original abstract should be considered final.
Citation Format: Tan Li, Yi Wang, Bin Li, Xueying Hu, Liu Liu, Yangyi Bao, Qiao Li, Lin Yang, Hongxia Li. Humanized CD19 CAR-T cells in the treatment of relapsed and refractory diffuse large B-cell lymphoma: A case report [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 CT150.
Abstract CT155: Role of Time intensity & density curve for detecting early changes in pancreatic adenocarcinoma
Authors: Rahmanuddin Syed , Cridebring Derek , Korn Ron , Brase Jordyn , Motarjem Pejman , Kai Wenli , Chung Vincent , Borazanci Erkut , Goel Ajay , Von Hoff Daniel 
Published: July 2021

Abstract
Purpose: Pancreatic cancer has limited options for early detection and this study tried to tackle that issue using TIDC (Time Intensity Density Curve), 3D volumetric and perfusion imaging. Experimental Design: This quantitative study was done by analyzing multi-phase CT images of patients undergoing treatment of different stages of pancreatic ductal adenocarcinoma (PDAC). Using advanced 3D imaging software we identified the perfusion and radiodensity of tumors at different stages. This analysis was done using 41 adult patients with unresectable treatment-naïve PDAC who were either enrolled in a clinical trial at HonorHealth Research Institute (Scottsdale, AZ) or treated at the City of Hope Comprehensive Cancer Center (Duarte, CA) as standard of care non study patients between 2015-2019. All patients were over the age of 18 and had been diagnosed with PDAC. We divided the participant sample into two groups, labeled Cohort 1 and Cohort 2. For image acquisition in both groups, we required to have multiphase CT images for the collection of images at both locations. Results: TIDC, 3D volumetric measurements and perfusion imaging proved useful in the quantification of tumor aggressiveness. Our results showed that perfusion in PDAC displayed delays in the venous phase which may be linked to vascular growth related activity and exhibits the active and viable part of the tumor. 3D volumetric analysis of the patient's multi-phase CT scan showed clear changes in arterial and venous perfusion and correlated with how rapidly patients progressed (e.g. tumor aggressiveness). Conclusion: TIDC and 3D volumetric analysis could play a significant role in defining the aggressiveness of the pancreatic ductal adenocarcinoma.
Citation Format: Syed Rahmanuddin, Derek Cridebring, Ron Korn, Jordyn Brase, Pejman Motarjem, Wenli Kai, Vincent Chung, Erkut Borazanci, Ajay Goel, Daniel Von Hoff. Role of Time intensity & density curve for detecting early changes in pancreatic adenocarcinoma [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 CT155.
Abstract CT213: NEON-1: a first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies
Authors: Voskoboynik Mark , Moser Justin C. , Lakhani Nehal , Millward Michael , Davar Diwakar , Harb Wael A. , Yang Jing , Means Gary , Manjarrez Kristi , Tercero Almudena , Zayed Hany , Hillson Jan , Dela Cruz Christine , Perez Graciela , Peng Stanford L. 
Published: July 2021

Abstract
BACKGROUND: Checkpoint inhibitors (CPI) targeting the PD-1 and CTLA-4 pathways have demonstrated significant clinical benefit in multiple tumors, but the majority of patients exhibit or develop resistance, at least in part due to insufficient activation and/or excessive exhaustion of tumor-specific T cells. Strong preclinical rationale exists to combine CPIs with T cell costimulatory agonists, but such approaches have not yet translated into significantly improved clinical benefit. The majority of these approaches, though, have not targeted CD28, a critical T cell costimulator recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. As monotherapy, ALPN-202 has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating a favorable safety profile in preclinical toxicology studies.
METHODS: This is a cohort-based, open-label dose escalation and expansion study in adults with advanced solid tumors or lymphoma (NCT04186637). The objectives of this study are to evaluate the safety, efficacy, pharmacokinetics, anti-drug antibodies, and pharmacodynamics of ALPN-202. Subjects who are refractory or resistant to standard therapy (including approved CPIs), or without available standard or curative therapy are eligible. ALPN-202 is administered by IV infusion. After two single-subject cohorts (0.001 mg/kg, 0.01 mg/kg), a standard 3+3 dose escalation (0.1-20 mg/kg) has been implemented with two dose schedules in parallel, Q1W and Q3W. Thereafter, expansion cohorts are planned to enroll subjects at a selected dose regimen(s) in selected indications. Biomarkers include tumor measurements of PD-L1, CD28, CD80 and CD86 to explore the possible relationship between baseline expression and outcomes. Other pharmacodynamic analyses include target saturation, inflammatory cytokines and immunophenotyping of circulating leukocytes. As of January 2021, the trial is continuing as planned; no DLTs have been observed through the 0.3 mg/kg cohorts (dose level 4).
Citation Format: Mark Voskoboynik, Justin C. Moser, Nehal Lakhani, Michael Millward, Diwakar Davar, Wael A. Harb, Jing Yang, Gary Means, Kristi Manjarrez, Almudena Tercero, Hany Zayed, Jan Hillson, Christine Dela Cruz, Graciela Perez, Stanford L. Peng. NEON-1: a first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies [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 CT213.