bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 283: Reconstructed plate-based 3D screening assays that predict in vivo responses
Authors: Urs Sumithra , Steffey Michael , Qu Ying , Ryou Matthew , Kirshner Julia , Wise Scott 
Published: June 2022

Abstract
In preclinical drug development, there is an urgency to create models that are predictive and relevant at the same time. To support this effort, early drug development emphasizes establishing multiple strategies that address treatment response, resistance, and combination effects, all with rapid turnover. Given the ever-increasing relevance of 3D in vitro models, Labcorp employs 3D model systems co-developed with zPREDICTA. These organ-specific models can support tumor cell growth and mimic the composition and architecture of both solid tumors and hematological malignancies. While 2D in vitro assays are preferred for screening efforts of chemical libraries, mainly because of cost, they do not recapitulate the tumor architecture and the microenvironment that is more comparable to in vivo models. This can result in differences in pharmacological potencies of standard of care (SoC) agents when compared to the 3D and in vivo models. zPREDICTA 3D assays serve as a tool for in vitro screening of tumor cell lines, which in long term cultures develop similar characteristics to in vivo disease states. Specifically, this in vitro system correlates well with breast and lung carcinoma in vivo models when matching rank order of potencies of known SoC agents. zPREDICTA tumor-specific 3D systems as well as 2D cultures and in vivo models were used to compare and contrast the activity of a set of anticancer agents. Human MDA-MB-231 cells were sensitive to paclitaxel both in 2D and in the 3D r-Breast (IC50 of 7.9nM and 6.1nM, respectively) as well as in vivo, with complete growth inhibition at the dose of 15mg/kg. Paclitaxel was cytotoxic in 2D cultures of murine 4T1 breast tumor cells (IC50=59nM), but not in the 3D reconstructed mouse breast model (r-mBreast) or in vivo, where the syngeneic 4T1 model was refractory to paclitaxel up to 10mg/kg. Similarly, NCI-H460 cells were sensitive to paclitaxel in 2D (IC50=2.3nM), while minimal response was seen in the 3D r-Lung model, and in vivo there was minimal response seen at a 20mg/kg treatment. These same cells were refractory to erlotinib in 2D, 3D, and in vivo. Additional SoC agents were profiled in these models and will also be discussed. Taken together these data demonstrate that zPREDICTA’s organ-specific 3D models mimic in vivo response with a higher fidelity than the standard 2D cultures. Additional in vitro reconstructed 3D histotype models are being developed and validated with the goal of providing faster and more predictive in vivo results.
Citation Format: Sumithra Urs, Michael Steffey, Ying Qu, Matthew Ryou, Julia Kirshner, Scott Wise. Reconstructed plate-based 3D screening assays that predict in vivo responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 283.
Abstract 2838: Antigen-independent expansion enhances efficacy of CAR-T cells against solid tumor
Authors: Cao Zhiyuan , Pu Chengfei , Jiang Xianyang , Han Guiting , Peng Yuzhe , Wang Wensheng , Ding Wei , Shen Xiaogang , chen Dongqi , Jia Beibei , Xu Xiaoqiang , Huang Zhipeng , Huang Xi , Liu Wenbi , Zhu Ruihong , Tian Lee , Ballas Christopher , Lu Victor.X , Wu Zhao , Xiao Lei 
Published: June 2022

Abstract
One key hurdle for the CAR-T cell treatment of solid tumors is the limited accessibility of solid tumor antigens outside the tumor microenvironment, which prohibits the expansion of solid tumor-targeting CAR-T cells in patients. Here, we report the characterization of prostatic acid phosphatase (PAP) as a feasible CAR-T target for prostate cancer and a novel approach, named CoupledCAR, to expand solid tumor-targeting CAR-T cells lacking solid tumor antigens based on the observation of non-transduced T cells proliferating together with CD19 CAR-T cells during the treatment of acute lymphocyte leukemia. We demonstrated that CoupledCAR can significantly enhance the expansion and antitumor efficacy of PAP CAR-T cells both in vitro and in vivo. Furthermore, we showed that the expansion of solid tumor-targeting CAR-T cells does not depend on CAR/CD3ζ stimulation through direct antigen binding with CAR but enhances the memory status of CAR-T cells and causes little exhaustion. Since the CoupledCAR system does not rely on solid tumor antigens, we propose that it can be utilized in all CAR-T and T cell therapies for the treatment of solid tumors.
Citation Format: Zhiyuan Cao, Chengfei Pu, Xianyang Jiang, Guiting Han, Yuzhe Peng, Wensheng Wang, Wei Ding, Xiaogang Shen, Dongqi chen, Beibei Jia, Xiaoqiang Xu, Zhipeng Huang, Xi Huang, Wenbi Liu, Ruihong Zhu, Lee Tian, Christopher Ballas, Victor.X Lu, Zhao Wu, Lei Xiao. Antigen-independent expansion enhances efficacy of CAR-T cells against solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2838.
Abstract 2858: Development of a first-in-class humanized antibody targeting CXCL1 in bladder cancer
Authors: Murakami Kaoru , Sasaki Yuka , Furuya Hideki , Rosser Charles 
Published: June 2022

Abstract
Introduction and Objectives: Chemokine (C-X-C motif) ligand 1 (CXCL1) plays a crucial role in tumor initiation, promotion, and progression in bladder cancer (BCa) development. Previously, we reported on a monoclonal murine antibody (HL2401) towards CXCL1 which was capable of inhibiting growth in both in vitro and in vivo models. Herein, we have developed a first-in-class humanized monoclonal antibody neutralizing CXCL1 (NTC-001). This study is final step in pre-clinical stage. In this study, we aimed to evaluate efficacy and safety of the antibody to move into phase 1 clinical trials in near future.
Methods: We humanized mouse anti-human CXCL1 antibody resulting in NTC-001, and then tested for the following: molecular weight and pH, specificity, binding affinity to ligand and to albumin, ability to inhibit in vitro angiogenesis, ability to inhibit cellular proliferation alone or with chemotherapy, and pharmacokinetics and pharmacodynamics.
Results: NTC-001 had a molecular weight of 150kD, and was an acidic antibody (pH5.1). NTC-001 specifically bound human CXCL1 in both WB and ELISA. NTC-001 was bound to albumin and had minimal hepatic metabolism. NTC-001 significantly inhibited tube formation in HUVEC, and more efficiently with the formulation. NTC-001 significantly inhibited T24 cell proliferation (p&lt;0.001). Inhibitory effect of NTC-001 on cell proliferation was correlated with the levels of CXCL1 expression in BCa cell lines. Compared to CXCL1 expression-low group (RT112 and UMUC-14), CXCL1 expression-high group (T24, 5637, 253J, 253J-BV) tended to show low IC50. Synergistic combination efficacy was observed in NTC-001 in combination with gemcitabine (combination index&lt;1) though not with cisplatin. PK study demonstrated a half-life of 324 hours and 18 hours in CD-1 and NSG-SGM3, respectively.
Conclusions: NTC-001 is a first in class humanized neutralizing monoclonal antibody towards CXCL1, and could be a promising therapeutic agent in BCa. We are going to proceed to complete our investigational new drug enabling studies in both small and large animals.
Citation Format: Kaoru Murakami, Yuka Sasaki, Hideki Furuya, Charles Rosser. Development of a first-in-class humanized antibody targeting CXCL1 in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2858.
Abstract 2896: DLL3-targeted T cell engager therapy (HPN328) for neuroendocrine prostate cancer
Authors: Ku Sheng-Yu , Yamada Yasutaka , Ng Patrick , Sun Laura , Beltran Himisha 
Published: June 2022

Abstract
Background: Neuroendocrine Prostate Cancer (NEPC) is an aggressive variant of prostate cancer that can arise de novo or emerge during prostate cancer progression as a mechanism of therapy resistance. The development of effective therapies for patients with NEPC is a clinical unmet need. Delta-Like Ligand 3 (DLL3) is a negative regulator of Notch signaling and aberrantly expressed on the cell surface in the majority of NEPC and other small cell carcinomas. HPN328 is a DLL3-targeted Tri-specific T cell Activating Construct (TriTAC) that binds to DLL3 on tumor cells, CD3 on T cells, and human serum albumin. Here, we evaluated the specificity and anti-tumor activity of HPN328 in NEPC preclinical models.
Methods: Immunohistochemistry (IHC) was used to evaluate DLL3 expression in prostate cancer preclinical models. We co-cultured DLL3-positive and DLL3-negative tumor cells in vitro with either human PBMCs or T cells and used CellTiter-Glo and live-cell imaging to examine tumor cell viability after the exposure to HPN328. We conducted flow cytometry to examine T cell activation. Patient-derived organoid xenografts were used to determine the anti-tumor activity of HPN328 in vivo and we applied digital spatial profiling (Nanostring) to examine effects on immune cell infiltration.
Results: HPN328 suppressed cell growth and induced cell death in DLL3-positive prostate cancer organoid cell line models at a range of 0.7nM - 10nM with the presence of human T cells. Flow cytometry analysis illustrated that T cell activation markers, such as CD25, were upregulated in a dose- and time-dependent manner. In vivo studies demonstrated robust anti-tumor activity of HPN328 in causing tumor regression and stable disease after stopping the treatment in DLL3-positive models, but not in DLL3-negative models. Sustained anti-tumor effects were observed without adverse events in mice.
Conclusions: The DLL3-targeted TriTAC HPN328 demonstrates robust and specific anti-tumor activity in DLL3-positive NEPC preclinical models in vitro and in vivo. T cell engagers targeting DLL3 represent a promising therapeutic strategy for NEPC.
Acknowledgements: This research is funded by a Helen Trailblazers Award from the Helen Gurley Brown Foundation/DFCI Presidential Initiative (H.B.).
Citation Format: Sheng-Yu Ku, Yasutaka Yamada, Patrick Ng, Laura Sun, Himisha Beltran. DLL3-targeted T cell engager therapy (HPN328) for neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2896.
Abstract 2999: Activation of NFKB is responsible for defective autophagy in cadmium-induced transformation of prostate cells
Authors: Shukla Vaibhav , Tyagi Ashish , Kolluru Venkatesh , Saran Uttara , Chandrasekaran Balaji , Ankem Murali K. , Damodaran Chendil 
Published: June 2022

Abstract
Background: Evidence from the epidemiological, laboratory and clinical studies suggest that chronic exposure to cadmium (Cd) leads to the development and progression of prostate cancer (CaP). Previously, we reported defective autophagy due to upregulation of Placenta Specific 8 (Plac8) (a phagosome and lysosome fusion regulator) is responsible for Cd-induced transformation of normal prostate epithelial cells. This study mechanistically dissects the upstream signaling that regulates Plac8 function, which drives defective autophagy during Cd-induced transformation.
Methods: To examine the molecular interaction between NFκB and Plac8, we developed NFκB/Plac8 overexpression and knockdown in normal prostate epithelial cells (RWPE-1) and cadmium transformed prostate epithelial cells lines (CTPE). In addition, we performed phenotypic, and molecular analysis including promoter-based studies, western blot, and in vivo analysis to determine the interaction between Plac8 and p65 in Cd-exposed prostate epithelial cells.
Results: Our results confirmed that overexpression of Plac8 in normal prostate epithelial cells mimics Cd-transformed prostate cells (CTPE) and induces defective autophagy by regulating autophagy-related genes (ATGs) and an enhanced autophagic flux. Conversely, either NFκB or Plac8 knockdown in CTPE cells abrogates autophagy signaling. Further, Cd-exposure failed to induce defective autophagy signaling in transformed cells. Silencing p65 either by genetically or pharmacological inhibitors downregulated Plac8 expression and its survival function in CTPE cells. Hence, we investigated the interaction between NFκB and Plac8 by promoter-based analysis. We found NFκB binding site in the Plac8 promoter, and mutating NFκB binding sites in the Plac8 promoter showed a decline in luciferase activity confirming our hypothesis that NFκB activation is necessary for Plac8 activation and autophagy signaling in CTPE cells. Finally, we confirmed that silencing Plac8 significantly inhibited the tumor growth of CTPE cells compared to vehicle control. Our ongoing studies on xenotransplanted stably knockdown of p65 in CTPE cells may confirm that NFκB activation is responsible for Plac8 function and tumor growth in mice models.
Conclusion: In conclusion, our results suggest that NFκB transcriptionally regulates Plac8 function, which drives pro-survival autophagy signaling in Cd-transformed prostate epithelial cells.
Citation Format: Vaibhav Shukla, Ashish Tyagi, Venkatesh Kolluru, Uttara Saran, Balaji Chandrasekaran, Murali K. Ankem, Chendil Damodaran. Activation of NFKB is responsible for defective autophagy in cadmium-induced transformation of prostate cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2999.
Abstract 301: Repurposing engineered thymoquinone nanoparticles to inhibit drug-resistant prostate cancer
Authors: Singh Santosh Kumar , Mishra Manoj Kumar , Singh Rajesh 
Published: June 2022

Abstract
Despite advanced treatment strategies and therapeutics for prostate cancer (PCa), the metastatic castration-resistant prostate cancer (mCRPC) mechanism remains obscure. Although docetaxel (DTX) and other anti-mitotic chemotherapeutic drug are considered the first line drugs for PCa patients; the resulting side effects and drug resistance increase the demand for an alternative such as natural compounds for effective treatment. However, the natural compounds that achieved remarkable height to overcome drug resistance, their bioavailability and targeted delivery during treatment has become a new challenge. As prostate-specific membrane antigen (PSMA) receptors are expressed on the surface of most PCa cells, we anticipated that these receptors may provide the potential target for effective therapy. Considering these, we employed the natural compound, thymoquinone (TQ)-encapsulated planetary ball-milled nanoparticles (PBM-NPs) formulated with starch (FDA approved, natural polysaccharides) inner core and biocompatible and biodegradable co-polymers poly (ε-caprolactone)/poly (ethylene glycol), functionalized with a PSMA aptamer (A10), which can selectively recognize and bind to PSMA membrane. The functionalities of this strategy were analyzed by targeting A10-TQ-PBM-NP in DTX-resistant cells (C4-2B-R and LNCaP-R), which overexpresses PSMA protein and multidrug resistance (MDR) gene ABCB1, and validated through flow cytometry, immunofluorescence, qRT-PCR, and western blot techniques. The results showed that the aptamer-based nano delivery of a TQ can modulate the cellular and molecular pathways responsible for DTX resistance in PCa cells through the EGFR and ZEB1 dependent mechanism. The A10-TQ-PBM-NPs counteract ATP-binding cassette (ABC)-transporter-mediated chemoresistance in PCa cells. In both cell lines, these NPs rapidly internalized and induced significant cell death at five times lower concentrations than non-conjugated PBM-TQ-NP. Further, A10-TQ-PBM-NPs have high selectivity to the PSMA receptor and downregulated the EGFR dependent pathway, Akt-1, ERK1/2, NF-kB, STAT3, and epithelial-mesenchymal transition (EMT) markers in both C4-2B-R and LNCaP-R cells, thus constraining cell survival, proliferation, and migration. The A10-TQ-PBM-NP bioconjugates also reveal remarkable efficacy and reduced toxicity as measured by body weight loss in the LNCaP-R cells xenograft mice. Altogether, our findings demonstrate that targeting PCa cells with PBM-NPs may reverse the MDR and could be used as potential therapeutic options for patients.
Citation Format: Santosh Kumar Singh, Manoj Kumar Mishra, Rajesh Singh. Repurposing engineered thymoquinone nanoparticles to inhibit drug-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 301.
Abstract 3015: Serine starvation silences estrogen receptor signaling through histone hypoacetylation
Authors: Li Albert M. , Li Yang , He Bo , Jiang Haowen , Lu Chao , Gruber Joshua J. , Rankin Erinn B. , Ye Jiangbin 
Published: June 2022

Abstract
Estrogen receptor (ER) plays important roles in regulating normal development and female reproductive system function. Loss of ER pathway activity is a hallmark of breast cancer progression, associated with accelerated tumor proliferation and resistance to endocrine therapy. How ER loss occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in solid tumors, downregulates estrogen receptor alpha (ERα) expression, represses transcriptional targets such as progesterone receptor (PR), and reduces sensitivity to antiestrogens, suggesting a transition of ER-positive (ER+) breast cancer cells to an ER/PR-negative (ER-/PR-) state. ER downregulation under serine starvation is accompanied by a global loss of histone acetylation. These chromatin changes are driven by metabolic reprogramming triggered by serine starvation, particularly lower glucose flux through glycolysis and the TCA cycle, leading to reduced acetyl-CoA levels and histone hypoacetylation. Supplementation with acetate or glycerol triacetate (GTA), precursors of acetyl-CoA, restores H3K27 acetylation and ERα expression under serine starvation. Therefore, a major consequence of serine starvation in breast cancer could be global chromatin changes that influence lineage-specific gene expression.
Citation Format: Albert M. Li, Yang Li, Bo He, Haowen Jiang, Chao Lu, Joshua J. Gruber, Erinn B. Rankin, Jiangbin Ye. Serine starvation silences estrogen receptor signaling through histone hypoacetylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3015.
Abstract 3019: The epigenetic factor KDM2B alters the serine-glycine synthesis pathway and the one-carbon metabolism (SGOC) in triple-negative breast cancer
Authors: Chavdoula Evangelia , Anastas Vollter , La Ferlita Alessandro , Aldana Julian , Sircar Anuvrat , Freitas Michael A. , Sehgal Lalit , Tsichlis Philip N. 
Published: June 2022

Abstract
Epigenetic and metabolic alterations in cancer cells are intertwined. The concentration of metabolites can influence the activity of chromatin modifiers, which in turn can act as metabolic sensors that translate changes in cellular metabolism to transcriptional reprogramming. In the present study, we investigated the role of histone demethylase KDM2B in the metabolic reprogramming of the triple-negative breast cancer (TNBC), in which KDM2B is selectively expressed at high levels. Knockdown of KDM2B in TNBC cell lines reduced their proliferation rate and tumor growth in vivo. Transcriptomic, proteomic, and metabolomic profiling demonstrated that the Serine-Glycine pathway and One Carbon metabolism (SGOC) and other amino acid biosynthetic and catabolic processes are downregulated by the knockdown of KDM2B. Additionally, we see reduction of metabolites produced via these pathways (purines, pyrimidines, formate, glutathione and NADPH). Importantly, the expression of the enzymes involved in the SGOC metabolic pathway (e.g. PHGDH, PSAT1, PSPH, SHMT2, MTHFD1L, MTHFD2 and DHFR) depends on c-MYC, NRF2, and ATF4 which our data show that they are under the positive regulatory control of KDM2B. The epistatic relationship between these factors, with the expression of the enzymes of the SGOC pathway and the effects of the KDM2B knockdown on chromatin occupancy and accessibility of the promoters of these factors is in progress and will be presented. Analysis of TCGA data showed positive and statistically significant correlations between KDM2B and the SGOC gene signature in TNBC patients. In addition, the metabolic pathway signature that distinguishes control and shKDM2B-transduced cells corresponds to the metabolic signature of a subset of TNBCs, which have been reported to carry poor prognosis. The present study highlights the role of the epigenetic factor KDM2B as an upstream regulator of the metabolic reprogramming of TNBC.
Citation Format: Evangelia Chavdoula, Vollter Anastas, Alessandro La Ferlita, Julian Aldana, Anuvrat Sircar, Michael A. Freitas, Lalit Sehgal, Philip N. Tsichlis. The epigenetic factor KDM2B alters the serine-glycine synthesis pathway and the one-carbon metabolism (SGOC) in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3019.
Abstract 302: MEKi-FGFRi combination nanoparticles for use against KRASmt/FGFR-compensatory lung tumors
Authors: Izawa-Ishiguro Arianna R. , Sridharan Ramya , Wun Christopher , Sami Tabassum J. , Heller Daniel A. 
Published: June 2022

Abstract
Targeting oncogenic signaling in the MAPK pathway can be achieved with small molecules such as trametinib, a MEK inhibitor (MEKi). Trametinib-induced MEK inhibition in KRAS-mutant (KRASmt) lung cancer, however, results in compensatory MAPK pathway re-activation through fibroblast growth factor receptor 1 (FGFR1). Combining MEK inhibition with FGFR1 inhibition should thereby combat this compensation; nonetheless, systemic administration of combination therapy faces its own set of challenges. Such challenges include delivering appropriate kinase inhibitor concentrations to target tumor tissue while avoiding dose-limiting additive toxicities.
Although previous work has identified that combination therapy involving trametinib and FGFR inhibitor (FGFRi) ponatinib synergistically inhibits growth and proliferation of KRASmt cells, ponatinib interacts with a variety of targets and may mediate its synergistic effects via mechanisms not specific to FGFR1. To improve the efficacy at which we target KRASmt/FGFR-compensatory lung tumors, we encapsulated trametinib with a variety of FGFR1-specific inhibitors to form P-selectin-targeted nanoparticles. By formulating these nanoparticles, compensatory MAPK pathway activation through FGFR1 can be more efficaciously inhibited. Concurrently, greater concentrations of kinase inhibitor combinations can be locally delivered to lung tumors while mitigating toxic side effects that occur from systemic free drug. Here we show that these MEKi-FGFRi combination nanoparticles can be formulated to efficaciously inhibit growth and proliferation in KRASmt/FGFR-compensatory cancer cells.
Citation Format: Arianna R. Izawa-Ishiguro, Ramya Sridharan, Christopher Wun, Tabassum J. Sami, Daniel A. Heller. MEKi-FGFRi combination nanoparticles for use against KRASmt/FGFR-compensatory lung tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 302.