bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5644: Claudin 18.2 X 4-1BB bispecific antibody induced potent tumor inhibition through tumor-specific 4-1BB activation
Authors: Jiang Wenqing , Fang Lei , Wang Zhengyi , Guo Taylor B. , Park Eunyoung , Sung Eunsil , Jung Jaeho 
Published: September 2020

Abstract
Background
Claudin 18.2 (CLDN18.2) is a gastric-specific membrane protein. In the healthy tissue, CLDN18.2 expression is restricted to the short-lived differentiated cells of gastric mucosa as a component of tight junction with limited accessibility of antibody treatment. However, it was ectopically expressed at significant levels in a variety of primary lesion and metastases of epithelial tumor entities, including gastric, pancreatic, esophageal, and lung adenocarcinoma cells. Taken together, CLDN18.2 was believed to be an ideal tumor antigen for immunotherapy. Here, we generated and described a bispecific antibody TJ-CD4B which could redirect and activate T cells to CLDN18.2 positive tumor cells by engaging 4-1BB antigen, thus positioned as a potential novel therapy for gastric cancer and other CLDN18.2 positive tumors.
Methods
TJ-CD4B was evaluated for its antigen binding through protein-based binding and cell based binding assay. The cell-based function of TJ-CD4B was further evaluated in a 4-1BB signaling reporter assay and primary human T cell assay. The in vivo efficacy was validated in 4-1BB humanized C57BL/6 mice transferred with colon cancer cell line MC38 overexpressed with human CLDN18.2. Percentage of tumor infiltrating and peripheral CD8+ T cells was evaluated by FACS analysis.
Results
TJ-CD4B showed stronger binding capability to CLDN18.2 when compared with benchmark monoclonal antibody against CLDN18.2 (IMAB362). Functional evaluation of TJ-CD4B indicated the activation of 4-1BB signaling was solely dependent on CLDN18.2 expression on the cell. Furthermore, TJ-CD4B showed superior 4-1BB activity than benchmark 4-1BB monoclonal antibody (Urelumab) in the presence of cells expressing a wide range of CLDN18.2 level including CLDN18.2-low cells. Using a humanized 4-1BB mouse model, TJ-CD4B showed strong tumor growth inhibition (TGI) of CLDN18.2 expressing tumor cells. Meanwhile, we also observed TJ-CD4B increased tumor infiltrating lymphocytes while it had no impact on peripheral lymphocytes. Drug developability assessment indicated that TJ-CD4B was a reasonably developable molecule to be taken forward.
Conclusions
Our data showed that CLDN18.2-targeted 4-1BB bispecific antibody, TJ-CD4B, displayed potent anti-tumor activity only in tumor microenvironment, possibly minimizing the risk of peripheral toxicity. These compelling data supported the further development of TJ-CD4B, which aims to enter clinical phase in early 2021.
Citation Format: Wenqing Jiang, Lei Fang, Zhengyi Wang, Taylor B. Guo, Eunyoung Park, Eunsil Sung, Jaeho Jung. Claudin 18.2 X 4-1BB bispecific antibody induced potent tumor inhibition through tumor-specific 4-1BB activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5644.
Abstract 5666: A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer
Authors: Nabet Barzin Y. , Esfahani Mohammad S. , Hamilton Emily G. , Chabon Jacob J. , Moding Everett J. , Rizvi Hira , Steen Chloe B. , Chaudhuri Aadel A. , Liu Chih Long , Hui Angela B. , Stehr Henning , Goljenola Linda , Jin Michael C. , Jeon Young-Jun , Tseng Diane , Merghoub Taha , Neal Joel W. , Wakelee Heather A. , Padda Sukhmani K. , Ramchandran Kavitha J. , Das Millie , Bonilla Rene F. , Yoo Christopher , Chen Emily L. , Ko Ryan B. , Newman Aaron M. , Hellmann Matthew D. , Alizadeh Ash A. , Diehn Maximilian 
Published: September 2020

Abstract
Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICI) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we analyze 211 samples from 99 patients and demonstrate that pre-treatment circulating tumor DNA (ctDNA) and circulating immune profiles are independently associated with DCB. We further show that ctDNA dynamics after a single ICI infusion can identify the majority of patients who will achieve DCB. Integrating these determinants, we describe an entirely noninvasive multi-analyte assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA- On-treatment) that robustly predicted DCB, and that was validated in two independent cohorts (AUC = 0.89-0.93, PPV = 92-100%, HR = 0.04-0.11). Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICI.
Citation Format: Barzin Y. Nabet, Mohammad S. Esfahani, Emily G. Hamilton, Jacob J. Chabon, Everett J. Moding, Hira Rizvi, Chloe B. Steen, Aadel A. Chaudhuri, Chih Long Liu, Angela B. Hui, Henning Stehr, Linda Goljenola, Michael C. Jin, Young-Jun Jeon, Diane Tseng, Taha Merghoub, Joel W. Neal, Heather A. Wakelee, Sukhmani K. Padda, Kavitha J. Ramchandran, Millie Das, Rene F. Bonilla, Christopher Yoo, Emily L. Chen, Ryan B. Ko, Aaron M. Newman, Matthew D. Hellmann, Ash A. Alizadeh, Maximilian Diehn. A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5666.
Abstract 5678: Novel glucocorticoid receptor degrading bifunctional molecules as therapeutics in castration-resistant prostate cancer
Authors: Link James T. , Blazanin Nicholas , Deribe Yonathan Lissanu 
Published: September 2020

Abstract
While the majority of men with prostate cancer will experience modest morbidity, advanced castration-resistant prostate cancer (CRPC) remains a devastating disease with significant mortality and limited treatment options. Recently approved anti-androgen therapies such as enzalutamide have shown promising clinical responses. Unfortunately, patients frequently develop resistance to these therapies. Signaling through the glucocorticoid receptor (GR) has emerged as a primary mechanism of resistance to enzalutamide in CRPC suggesting that GR is an attractive therapeutic target. However, existing small molecule antagonists of GR suffer from partial agonist activity leading to activation of a subset of GR target genes which limits their anti-tumor efficacy. To overcome this problem, we have developed bifunctional small molecules or proteolysis targeting chimeras (PROTACs) that induce potent and specific degradation of GR. Using iterative structure-activity relationship (SAR) studies, we have developed a novel chemical linker that imparted superior properties to PROTACs. These novel GR PROTACs induce profound degradation of GR. Using proteomic analysis and quantification of more than 8000 proteins, we show that our GR PROTAC is highly selective for GR. GR PROTACs inhibited proliferation of enzalutamide-resistant prostate cancer cells, have favorable pharmacokinetic properties and are active in vivo. Importantly, GR PROTACs work synergistically with enzalutamide to inhibit growth of prostate cancer xenografts in a castration-resistant mouse model of prostate cancer. Mechanistically, we identified improved suppression of AR and GR target genes in the combination of GR PROTAC and enzalutamide. More importantly, the combination was able to suppress crucial developmental pathways implicated in prostate cancer resistance to therapy and tumor dormancy. Our novel GR PROTACs highlight the power of targeted protein degradation to deliver excellent chemical probes and potentially impactful cancer therapeutics.
Citation Format: James T. Link, Nicholas Blazanin, Yonathan Lissanu Deribe. Novel glucocorticoid receptor degrading bifunctional molecules as therapeutics in castration-resistant prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5678.
Abstract 5698: Novel conditionally active bispecific T cell engagers targeting solid tumors
Authors: Cugnetti Ana Paula G. , Liu Haizhen , Wang Jing , Xing Charles , Wheeler Christina , Lucas Matthew , Chang Cathy , Frey Gerhard , Boyle William J. , Short Jay M. 
Published: September 2020

Abstract
The use of CD3/target bispecific molecules has great therapeutic potential in oncology. This potential, however, is diminished due to serious on-target drug-related toxicities, restricting the development of bispecific T cell engagers to targets that have limited expression in normal tissues. Conditionally Active Biologic (CAB) technology is a proprietary platform that generates antibodies which have no or very little binding to the target antigen in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (including Warburg effect). Using our CAB technology, we have developed CD3/target bispecific antibodies that bind to recombinant CD3 and to CD3 expressing cells under in vitro tumor microenvironment conditions, but not in physiologic conditions (CAB CD3). CAB CD3 bispecific antibodies were generated against various well-established tumor associated antigens (TAA), including EpCAM, B7-H3, HER-2 and EGFR. All of these molecules play important roles in cancer biology and are attractive targets for the development of therapeutic bispecific antibodies. In addition, we have also developed CAB TAA / CAB CD3 bispecific antibodies. In vitro and in vivo efficacy data as well as toxicology studies in non-human primates for CAB-T cell engagers will be presented. Our data demonstrates that CAB bispecific antibodies are efficacious in vivo and have lower toxicity comparing to non-CAB bispecific antibodies. The CAB technology will allow the generation of a new class of T-cell engagers with increased safety margin and therapeutic index in the clinic.
Citation Format: Ana Paula G. Cugnetti, Haizhen Liu, Jing Wang, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active bispecific T cell engagers targeting solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5698.
Abstract 5708: Deciphering Warburg effect: hypoxia inhibits tumor cell differentiation through reducing acetyl-CoA generation and chromatin accessibility
Authors: Ye Jiangbin , Li Yang , Gruber Joshua J. , Litzenburger Ulrike M. , Zhou Yiren , Miao Yu R. , LaGory Edward L. , Li Albert M. , Hu Zhen , Hart Lori S. , Maris John M. , Chang Howard Y. , Giaccia Amato J. 
Published: September 2020

Abstract
The Warburg effect is a metabolic hallmark of all cancer cells, characterized by increased glucose uptake and glycolysis for lactate generation. The generation and excretion of lactate would appear be a waste of carbon backbone and energy that is needed for proliferation. It was proposed by Warburg that the cause and consequence of the Warburg effect were the injury of respiration and cell dedifferentiation, respectively. One common factor that damages mitochondrial respiration is hypoxia, which is a metabolic stress that blocks cell differentiation and promotes cancer progression. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma (NB) differentiation model, we have discovered that hypoxia represses the differentiation induced by retinoic acid (RA) as demonstrated by loss of neuron differentiation markers and changes in cell morphology, associated with reduction of global histone acetylation, that are caused by the induction of pyruvate dehydrogenase kinases (PDKs). PDKs phosphorylate pyruvate dehydrogenase (PDH), thereby blocking pyruvate entry into the TCA cycle, reducing acetyl-CoA generation, and promoting the Warburg effect. Genetic and pharmaceutical inhibition of PDK restores histone acetylation and NB cell differentiation morphology. Acetate supplementation restores histone acetylation, along with differentiation markers expression and neuron differentiation. In addition, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduces chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. These findings suggest that (1) combining RA and acetate supplementation represents a potentially effective therapeutic strategy for neuroblastoma treatment; (2) diverting pyruvate away from acetyl-CoA generation is a key mechanism by which the Warburg effect blocks cell differentiation.
Citation Format: Jiangbin Ye, Yang Li, Joshua J. Gruber, Ulrike M. Litzenburger, Yiren Zhou, Yu R. Miao, Edward L. LaGory, Albert M. Li, Zhen Hu, Lori S. Hart, John M. Maris, Howard Y. Chang, Amato J. Giaccia. Deciphering Warburg effect: hypoxia inhibits tumor cell differentiation through reducing acetyl-CoA generation and chromatin accessibility [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5708.
Abstract 5712: Nutrient scarcity confers breast cancer brain metastasis sensitivity to serine synthesis pathway inhibition
Authors: Ngo Bryan , Kim Eugenie , Doll Sophia , Bustraan Sophia , Luengo Alba , Davidson Shawn M. , Ali Ahmed , Ferraro Gino , Kang Diane , Ni Jing , Liang Roger , Plasger Ariana , Kastenhuber Edward R. , Eskandari Roozbeh , Bacha Sarah , Sriram Roshan , Stein Benjamin D. , Bakhoum Samuel F. , Mullarky Edouard , Snuderl Matija , Mainolfi Nello , Suri Vipin , Friedman Adam , Manfredi Mark , Sabatini David M. , Jones Drew , Yu Min , Zhao Jean J. , Jain Rakesh K. , Heiden Matthew G. Vander , Mann Matthias , Cantley Lewis C. , Pacold Michael E. 
Published: September 2020

Abstract
The metabolic milieu of the brain is severely deprived of nutrients, including the amino acids serine and its catabolite glycine. The metabolic rewiring required for tumor cells to survive in the nutrient-limited environment of the brain and the metabolic vulnerabilities this confers are poorly understood.
Here we demonstrate that cell-intrinsic de novo serine synthesis is a major determinant of triple-negative breast cancer (TNBC) brain metastasis. Whole proteome comparison of TNBC cells that differ in their capacity to colonize the brain reveals that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is the most significantly upregulated protein in cells that efficiently metastasize to the brain. Expression of catalytically active PHGDH in a non-brain trophic cell line promoted brain metastasis. Furthermore, genetic silencing or pharmacological inhibition of PHGDH attenuated brain metastasis burden in mice.
These findings indicate that nutrient availability determines serine synthesis pathway dependence in brain metastasis, and suggest that PHGDH inhibitors may be useful in the treatment of patients with cancers that have spread to the brain.
Citation Format: Bryan Ngo, Eugenie Kim, Sophia Doll, Sophia Bustraan, Alba Luengo, Shawn M. Davidson, Ahmed Ali, Gino Ferraro, Diane Kang, Jing Ni, Roger Liang, Ariana Plasger, Edward R. Kastenhuber, Roozbeh Eskandari, Sarah Bacha, Roshan Sriram, Benjamin D. Stein, Samuel F. Bakhoum, Edouard Mullarky, Matija Snuderl, Nello Mainolfi, Vipin Suri, Adam Friedman, Mark Manfredi, David M. Sabatini, Drew Jones, Min Yu, Jean J. Zhao, Rakesh K. Jain, Matthew G. Vander Heiden, Matthias Mann, Lewis C. Cantley, Michael E. Pacold. Nutrient scarcity confers breast cancer brain metastasis sensitivity to serine synthesis pathway inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5712.
Abstract 5713: Reprogramming of serine metabolism during breast cancer progression
Authors: Li Albert Mao , Ducker Gregory S. , Li Yang , Seoane Jose A. , Xiao Yiren , Melemenidis Stavros , Zhou Yiren , Liu Ling , Vanharanta Sakari , Graves Edward E. , Rankin Erinn B. , Curtis Christina , Massague Joan , Rabinowitz Joshua D. , Thompson Craig B. , Ye Jiangbin 
Published: September 2020

Abstract
The causes and consequences of metabolic reprogramming during human breast cancer metastasis remain largely unknown. We performed metabolomics in the human triple-negative breast cancer cell line MDA-MB-231 (231-Parental) and its metastatic subclones that display tissue-tropism towards the brain (831-BrM), the bone (1833-BoM), and the lung (4175-LM). Using molecular and metabolic flux analysis, we uncovered that the mitochondrial serine and one-carbon (1C) unit pathway is upregulated in the metastatic subclones. Inhibition of the first rate-limiting enzyme of the pathway, serine hydroxymethyltransferase (SHMT2), potently suppresses proliferation of metastatic subclones in culture and impairs growth of lung metastatic subclones at both primary and metastatic sites in mice. In addition to breast cancer, a few other cancer types, such as adrenocortical carcinoma (ACC) and kidney chromophobe cell carcinoma (KICH), also display increased SHMT2 expression during disease progression. Moreover, we found that metastatic cells are exquisitely adapted to low serine conditions by synthesizing serine de novo from glucose to generate 1C units, and blocking serine catabolism abrogates metastatic growth under serine deprivation.
How do metastatic breast cancer cells acquire new metabolic properties such as de novo serine synthesis? We observed that 231-Parental cells grown in media lacking serine for up to ten passages exhibited metastatic cell-like metabolic properties. Subsequent RNA-sequencing revealed dramatic global gene expression changes during serine starvation in more primary tumor-like cells. Several pathways involved in metastasis such as TNFα signaling, mTOR1 signaling, and Ras signaling were modulated upon serine starvation. These data suggest that the availability of the nonessential amino acid serine may play a key regulatory role in breast cancer progression and metastasis, and highlight the potential for metabolite supplementation to block or halt these transformations.
Citation Format: Albert Mao Li, Gregory S. Ducker, Yang Li, Jose A. Seoane, Yiren Xiao, Stavros Melemenidis, Yiren Zhou, Ling Liu, Sakari Vanharanta, Edward E. Graves, Erinn B. Rankin, Christina Curtis, Joan Massague, Joshua D. Rabinowitz, Craig B. Thompson, Jiangbin Ye. Reprogramming of serine metabolism during breast cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5713.
Abstract 5725: Epigenetic and transcriptional profiling reveal endosomal protein sorting as a glioblastoma cancer stem cell dependency
Authors: Gimple Ryan C. , Zhang Guoxin , Rich Jeremy N. 
Published: September 2020

Abstract
Glioblastoma is a highly lethal primary intrinsic brain tumor for which current standard-of-care therapies are merely palliative. Functionally defined glioblastoma stem cells (GSCs) contribute to this poor prognosis by driving therapeutic resistance, maintenance of cellular heterogeneity, and disease recurrence. A deeper appreciation for the specific features that distinguish normal from neoplastic stem cells may inform selective therapeutic targeting. To further understand the molecular processes essential for maintaining cancer stem cell populations, we interrogated the active enhancer landscapes and transcriptional output of GSCs and normal neural stem cells (NSCs) through H3K27ac ChIP-seq and RNA-seq respectively. GSC-specific targets that held prognostic significance in patient datasets and which were essential in whole genome CRISPR screening data implicated endosomal protein sorting as a key feature in GSC biology. Targeting endosomal sorting impaired GSC viability and proliferation and contributed to apoptosis, while NSCs displayed a reduced cell proliferation deficit. Impaired endosomal protein sorting led to a reduction in the mRNA and protein levels of the stem and neuro-developmental transcription factors SOX2 and OLIG2 and reduced self-renewal capacity of GSCs, suggesting a role in the maintenance of stemness. Mechanistically, regulation of endosomal sorting may impact localization and stability of receptor tyrosine kinases and WNT signaling elements to control GSC maintenance. High expression of this endosomal sorting factor is associated with poor glioblastoma patient prognosis, suggesting its clinical importance. Thus, targeting the endosomal sorting pathway may represent a novel therapeutic approach for glioblastoma treatment.
Citation Format: Ryan C. Gimple, Guoxin Zhang, Jeremy N. Rich. Epigenetic and transcriptional profiling reveal endosomal protein sorting as a glioblastoma cancer stem cell dependency [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5725.