bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3971: Developing cancer cell based in vitro and in vivo models with CRISPR-mediated knock-in technology for anti-tumor drug discovery
Authors: Xu Nengwei , Wang Reifeng , Xiang Jian , Gu Qingyang , Qiang Xiangnan 
Published: April 2023

Abstract
Human cancer cell lines have long been applied for anti-tumor drug discovery considering their acquired genomic diversity of different carcinomas. Genetic engineering based on cancer cell lines is no doubt a useful and promising approach in induction of new therapeutic targets/elements while maintaining intrinsic characteristics of original cell in parallel. Recently, the emergence of CRISPR knock-in technology has accelerated precise editing across whole genome, from gene depletion, small fragment insertions to site-direct mutations, thereby prompting our understanding of the influence of a specific oncotarget in given tumor genetic background. Herein, by employing CRISPR/Cas9 system, two human cancer cell line-based, inheritable drug resistance models were established where the mutation site C481S of BTK in REC-1 conferred resistance to Ibrutinib and the mutation site R537S/D538G of ESR1 exerted resistance to Fulvestrant in MCF-7. In addition, the engineered cell models also enable the mechanism characterization and development of viable therapeutic agents targeting those oncogenic-driver mutations in a subtype of cancers. The murine colon cancer cell line CT26, which harbors KRASG12D mutation, was genetically modified to express KRASG12C protein to allow for an expandable pocket providing opportunities for compound recruitment. The resultant KRASG12C CT26 cell line showed pronounced inhibitory effect after treatment with AMG510. More interestingly, the therapeutic combination involving both AMG510 and anti-PD1 antibodies demonstrated more effective anti-tumor activities when compared to monotherapy. Moreover, CRIPSR-mediated engineered knock-in cells with a traceable tag linked to endogenous oncotarget also exhibit capability in new therapeutic modality discovery. Based on HiBiT protein tagging technology, we generated a series of HiBiT knock-in cell lines for real-time cell-based protein degradation analysis on various compelling targets, such as ESR1, KRAS, and BRD4, et al. Thereby, the construction of these in vitro and in vivo models with the ease of CRISPR KI technology is indispensable in new generation of therapeutic drug exploration.
Citation Format: Nengwei Xu, Reifeng Wang, Jian Xiang, Qingyang Gu, Xiangnan Qiang. Developing cancer cell based in vitro and in vivo models with CRISPR-mediated knock-in technology for anti-tumor drug discovery. [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 3971.
Abstract 4023: Inhitibing GRP78 in non-small cell lung cancer with acquired resistance to EGFR-TKI
Authors: Park Jaewoo , Purushothaman Baskaran , Hong Sera , Choi Munkyung , Song Joon Myong , Kang Keon Wook 
Published: April 2023

Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have improved the survival of non small cell lung cancer (NSCLC) patients with active mutation of EGFR. However, some of the patients who received EGFR-TKIs showed the acquired resistance, and eventually relapsed within several months. In the TCGA data sets, gene expression of glucose-related protein 78 (GRP78), an ER chaperone, was upregulated in NSCLC tissues. We also confirmed that protein level of GRP78 was increased in HCC827-GR, H1993-GR and H1993-ER NSCLC cell lines with acquired resistance to EGFR-TKIs. Since GRP78 modulates ER stress level which induces ROS and apoptosis, Ru(II) complex 1 and HA15, both the known GRP78 inhibitors induced higher ER stress and ROS generation accompanying more remarkable anti-proliferative and apoptotic effects in EGFR-TKI-resistant NSCLC cell lines. GRP78 level was also found to be higher in H1975, EGFR-TKI-resistant T790M-mutant cell line than other NSCLC cell lines. Blockade of GRP78 also led to apoptosis in H1975, which is consistent with the results found in the acquired EGFR-TKI-resistant cell lines. In summary, we suggest GRP78 targeting as a potential therapeutic strategy for the acquired EGFR-TKI-resistant NSCLC patients.
Citation Format: Jaewoo Park, Baskaran Purushothaman, Sera Hong, Munkyung Choi, Joon Myong Song, Keon Wook Kang. Inhitibing GRP78 in non-small cell lung cancer with acquired resistance to EGFR-TKI. [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 4023.
Abstract 4024: Overcoming ALK resistance with covalent cysteine-reactive inhibitors in lung cancer
Authors: Yang Diane , Harry Stefan , Zhang Edwin , Oppong-Holmes Zavontae , Carlin Alexander Daniel , Yang Wenxin , Smith Abigail , Onozato Maristela , Bar-Peled Liron , Iafrate Anthony J. 
Published: April 2023

Abstract
The EML4-ALK fusion gene is the main oncogenic driver in 5% of non-small cell lung cancer and has been effectively targeted using ALK-specific tyrosine kinase inhibitors. While survival rates have improved steadily with each new generation of ALK TKI, resistance generally develops, including second site ALK kinase mutations as well as by-pass track activation. Since almost all anti-ALK approaches have focused on kinase domain inhibition, we sought to develop novel inhibitors with alternative mechanisms of action against ALK to overcome current drug resistance. Cysteine-reactive small molecule drugs may enable new mechanisms of target inhibition, and clinically successful examples of recent FDA-approved drugs in NSCLC include afatinib, osimertinib, sotorasib, and adagrasib.We aimed to explore and uncover novel cysteine-reactive covalent inhibitors of EML4-ALK. Using cysteine druggability mapping (CDM), a proteome-wide mass spectrometry target engagement assay, we first determined the landscape of reactive cysteines in ALK-positive cell lines and identified various targetable cysteines within the MAPK pathway and within the EML4-ALK fusion protein itself. To identify small molecules that modulate ALK activation, degradation, and downstream signaling, we conducted a high-content phosphorylated protein screen by testing 4,400 reactive cysteine compounds and found 20 potential hits that impacted ALK phosphorylation or expression. Using proteomic analysis, we have determined the comparative specificity of these compounds, and have ranked them based on p-ALK reduction efficiency and on their off-target binding patterns. We have initiated hit-to-lead development on a compound that binds to the EML4 portion of the fusion and we are performing a detailed analysis of its mechanism of action. To further optimize the potency of the compound, we designed, synthesized, and are testing several hundred analog compounds. By applying the hit compounds from the screen in ALK TKI-resistant models, we will be able to evaluate the ability of these compounds to overcome ALK resistance. To our knowledge, we have identified the first EML4-ALK covalent binder targeting the EML4 domain. Using the unique mechanism of action of the current ALK kinase inhibitor, we have uncovered a potential compound to overcome ALK resistance.
Citation Format: Diane Yang, Stefan Harry, Edwin Zhang, Zavontae Oppong-Holmes, Alexander Daniel Carlin, Wenxin Yang, Abigail Smith, Maristela Onozato, Liron Bar-Peled, Anthony J. Iafrate. Overcoming ALK resistance with covalent cysteine-reactive inhibitors in lung 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 4024.
Abstract 4043: Stimulation of the mapk and pi3k/akt pathways in pancreatic cancer cells by polyisoprenylated cysteinyl amide inhibitors
Authors: Ofosu-Asante Kweku , Lazarte Jassy M. , Burra Amarendar G. , Lamango Nazarius S. 
Published: April 2023

Abstract
Pancreatic cancer is the third deadliest cancer with a 5-year survival rate of less than 10%. Over 90% of reported cases are driven by KRAS mutations. KRAS signals through the MAPK and PI3K pathways. Targeting mutant KRAS has been a decades-long challenge until recently whereby drugs that react with specific mutant proteins have been developed. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) are potential anticancer agents with an alternative design strategy targeting polyisoprenylation-dependent processes of hyperactive mutant or overexpressed G-proteins. The effect of PCAIs on the viability and downstream mediators of KRAS signaling was determined on PANC-1 and MIAPaCa-2 cells. Of the 16 different analogs tested, NSL-YHJ-2-45 and NSL-YHJ-2-27 were the most potent with EC50 values of 3.6 and 3.8 against PANC-1 cells, respectively. For MIAPaCa-2 cells, NSL-YHJ-2-27 was the most potent with an EC50 value of 2.2. Western blotting analysis of PCAIs-treated PANC-1 cells revealed that phosphorylated BRAF, MEK 1/2, ERK 1/2 and p90RSK increased by 64, 129, 152 and 79%, respectively, while phosphorylated CRAF levels decreased by 27%. Moreover, monomeric G-proteins, CDC42, RHOA and RAC 1/2/3 protein levels decreased by 20, 58 and 13%, respectively. NSL-YHJ-2-27 (5 µM) also increased the levels of pAKT (Ser 473) and pAKT (Thr 308) by 72 and 192%, respectively. When MIAPaCa-2 cells were treated with 0-5 µM NSL-YHJ-2-27, MEK 1/2, ERK 1/2 and p90RSK phosphorylation increased by 78, 270 and 260%, respectively. However, at 5 µM NSL-YHJ-2-27, there were no significant changes in protein levels of the monomeric G proteins RAC 1/2/3 and RHOA, but protein levels of CDC42 increased by 132%. NSL-YHJ-2-27 (5 µM) increased the levels of pAKT (Ser 473) and pAKT (Thr 308) of MIAPaCa-2 cells by 97 and 82%, respectively. The results indicate the effect of PCAIs on the phosphorylation of important kinases involved in MAPK and AKT pathways. These effects on these signaling pathways strongly indicate the potential of the PCAIs against RAS-driven cancers.
Citation Format: Kweku Ofosu-Asante, Jassy M. Lazarte, Amarendar G. Burra, Nazarius S. Lamango. Stimulation of the mapk and pi3k/akt pathways in pancreatic cancer cells by polyisoprenylated cysteinyl amide inhibitors. [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 4043.
Abstract 4064: PD-1 blockade therapy enhances the antitumor effects of lymphodepletion and adoptive T cell transfer
Authors: Watanabe Satoshi , Takahashi Miho , Suzuki Ryo , Arita Masashi , Sato Ko , Fujisaki Toshiya , Ohtsubo Aya , Shoji Satoshi , Shono Kunihiro , Masuda Takaaki , Sekiya Tomoki , Nozaki Koichiro , Tanaka Tomohiro , Kondo Rie , Saida Yu , Hokari Satoshi , Koya Toshiyuki , Kikuchi Toshiaki 
Published: April 2023

Abstract
Background: Lymphodepleting cytotoxic regimens, such as chemotherapy and radiotherapy, have shown the ability to enhance antitumor immunity. Although the mechanisms of antitumor effects augmentation in tumor-bearing hosts after lymphodepletion and T cell transfer have been intensively investigated, the influence of lymphodepletion followed by T cell transfer on immune checkpoint molecules (ICMs) expressed on tumor cells and immune cells remains to be elucidated. In the current study, we evaluated the effects of lymphodepletion and adoptive T cell transfer on ICMs in the tumor microenvironment. In addition, we investigated whether lymphodepletion and adoptive transfer of T cells augments antitumor effects of anti-PD-1 blockade therapy.
Methods: B6 mice were inoculated subcutaneously with the MCA205 murine fibrosarcoma. On day 7, mice were lymphodepleted by sublethal irradiation with 500 cGy and were reconstituted intravenously with spleen cells from normal mice as a source of naïve T cells. These mice were injected intraperitoneally with anti-PD-1 mAb on days 7 and 14. On day 21, tumor tissues were harvested, and single cell suspensions were labeled with fluorophore-conjugated antibodies for FACS analyses.
Results: The expressions of ICMs, including PD-L1, PD-1, TIGIT, TIM-3 and LAG-3, were upregulated on recipient CD4+ and CD8+ T cells in the tumor microenvironment. In contrast, these ICMs were significantly reduced in transferred donor T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Furthermore, transfer of both donor CD4+ and CD8+ T cells was responsible for this augmentation of antitumor effects.
Conclusions: Our observations suggest that a possible mechanism of the antitumor effect augmentation mediated by lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. Blockade of PD-1 significantly enhanced the antitumor effects of lymphodepletion and T cell transfer.
Citation Format: Satoshi Watanabe, Miho Takahashi, Ryo Suzuki, Masashi Arita, Ko Sato, Toshiya Fujisaki, Aya Ohtsubo, Satoshi Shoji, Kunihiro Shono, Takaaki Masuda, Tomoki Sekiya, Koichiro Nozaki, Tomohiro Tanaka, Rie Kondo, Yu Saida, Satoshi Hokari, Toshiyuki Koya, Toshiaki Kikuchi. PD-1 blockade therapy enhances the antitumor effects of lymphodepletion and adoptive T cell transfer. [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 4064.
Abstract 4133: OncoTAM, a comprehensive preclinical platform to explore macrophages as key drivers of cancer progression and develop new therapies against tumor-associated-macrophages
Authors: Mignard Caroline , France Damien , Bichat Francis , Legrand Nicolas , Duchamp Olivier 
Published: April 2023

Abstract
Tumor-Associated Macrophages (TAMs) play an important role in the development of tumors, modulation of neoangiogenesis, immune suppression, and metastasis. A high infiltration of macrophages in the tumor is also correlated with a poor prognosis in several cancer types. Therefore, they became an attractive target for cancer immunotherapies. Several macrophage-targeting approaches in anticancer therapy are under development, including TAM depletion, inhibition of new TAM differentiation, or re-education of TAM activation for cancer cell phagocytosis. In this presentation, we will share different examples of in vitro assays and in vivo models we are implementing to support preclinical development of novel TAM-targeting strategies. Antibody-dependent cellular phagocytosis (ADCP) has been used to demonstrate one crucial mechanism of action of different antibody (Ab) therapies targeting macrophages. Some of these Ab (including anti-CSF1) have then been tested in syngeneic in vivo tumor models. To reach this goal, we demonstrated that the tumor implantation site in mice (subcutaneous vs orthotopic) could impact the polarization of macrophages (M1 vs M2). Differences in the ratio of M1 and M2 subtypes infiltrating the PAN-02 pancreatic murine tumors were observed, and anti-CSF1 antibodies increased the survival of mice bearing orthotopic Renca murine kidney tumor by eliminating TAMs. Additionally, in xenograft models of human breast tumors in NOD-SCID mice, the eradication of TAMs by anti-CSF1R clearly demonstrated the importance of macrophages in the tumor progression and in the anti-tumor efficacy of Abs mediated by macrophages. By using an orthotopic Hepa1-6 murine liver cancer model, we showed high antitumor efficacy of compounds targeting the STAT6 pathway by reprogramming immunosuppressive TAMs into an M1 phenotype that promotes the induction of a cytotoxic immune response. For compounds displaying no cross-reactivity with murine target, we developed models and characterized the TAMs in breast, colon, melanoma and head & neck PDX and CDX tumors in different huCD34-engrafted mouse models. Altogether, the panel of in vitro assays and in vivo tumor models in OncoTAM should be useful to provide insights on the mechanism of action and antitumor efficacy of novel immune-oncology strategies targeting macrophages.
Citation Format: Caroline Mignard, Damien France, Francis Bichat, Nicolas Legrand, Olivier Duchamp. OncoTAM, a comprehensive preclinical platform to explore macrophages as key drivers of cancer progression and develop new therapies against tumor-associated-macrophages. [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 4133.
Abstract 4175: Development of breast cancer risk assessment tool: The Korean decision aid for cancer screening (K-DACS) study
Authors: Jung Wonyoung , Mark Park Yong-Moon , Park Sang Hyun , Han Kyungdo , Park Junhee , Yeo Yohwan , Lee Jung Kwon , Sandler Dale P. , Shin Dong Wook 
Published: April 2023

Abstract
Purpose: Widely used breast cancer risk prediction tools are based on data from Western countries, but risk factors may differ for Asian women. Hence, we aimed to develop a risk assessment tool for breast cancer in Asian women, using a nationwide, population-based cohort in Korea. Methods: Women aged ≥ 40 years who participated in both breast cancer screening and general health examination in 2009 were eligible for this study. Age, body mass index (BMI), breast density, lifestyle and reproductive factors, and comorbidities were used to develop 5-year breast cancer risk prediction models in premenopausal (n=771,856) and postmenopausal (n=1,108,047) women at baseline. Backward stepwise selection in the Cox proportional hazards model was used to construct the best-fit risk prediction model, which was then converted into a risk score nomogram, representing an individual probability estimate of incident breast cancer. Model performance was evaluated by discrimination and calibration. Results: Among premenopausal women, high BMI, low parity, short breastfeeding period, early age at menarche, high breast density, history of benign breast mass, and family history of breast cancer contributed to breast cancer risk prediction. The appropriate predictors in postmenopausal women additionally included age, type 2 diabetes, dyslipidemia, late age at menopause, hormone replacement therapy use, except for number of parities. The concordant statistic of risk prediction model was 0.58 (95% confidence interval [CI] 0.57-0.59) for premenopausal women, and 0.64 (95% CI 0.63-0.65) for postmenopausal women. Our model correlated well in the calibration plot in both premenopausal and postmenopausal women.Conclusions: Our breast cancer risk prediction model showed good performance for postmenopausal women, providing the background for risk-based screening recommendations in Asian women.
Citation Format: Wonyoung Jung, Yong-Moon Mark Park, Sang Hyun Park, Kyungdo Han, Junhee Park, Yohwan Yeo, Jung Kwon Lee, Dale P. Sandler, Dong Wook Shin. Development of breast cancer risk assessment tool: The Korean decision aid for cancer screening (K-DACS) study. [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 4175.
Abstract 4191: Assessing performance of biomarker extraction from electronic health records: Data augmentation methods for a hierarchical self-attention network (HiSAN)
Authors: Priya Shalini , Peluso Alina , Shekhar Mayanka Chandra , Danciu Ioana , Miller Jordan , Hanson Heidi A. 
Published: April 2023

Abstract
Background: Extraction of HER2 status from electronic health records (EHR) may expedite clinical trials matching and be used for survivorship research. Deep learning (DL) algorithms have potential to extract this data; however, inherent class imbalance leads to reduced model performance. We compare state of the art strategies to handle class imbalance in models trained to extract HER2 status. This comparative analysis may be used as a guideline for HER2 extraction.
Methods: 680,117 pathology reports collected from 2017-2021 by the National Cancer Institutes’ Surveillance, Epidemiology, and End-Results (SEER) program were used for this study. Pathology reports are manually labelled by cancer registrars as HER2 -, HER2+, or Unknown (class ratio 65%, 11%, 24% respectively). We compare six data augmentation (DA) methods: balanced frequency weighting, ROS while up-sampling HER2+ by 595%, RUS while down-sampling HER2- by 83%, SMOTE, ADASYN, and SMOTE-Tomek. As a comparison we consider the HiSAN model i.e., a DL architecture currently used by SEER for automatic classification of reports.
Result: Applying DA strategies did not improve the performance of the HiSAN model (Table 1). Frequency based class-weighting (Acc=0.78), ROS (Acc=0.81), and RUS (Acc=0.80) perform worse than the baseline model, suggesting simple data augmentation methods do not boost performance for this task. Advanced oversampling with SMOTE (Acc=0.88) and ADASYN (Acc=0.88) perform better than simple approaches, but do not improve the predictive accuracy of the baseline HiSAN.
Conclusion: Common DA methods do not improve the performance of the HiSAN biomaker method. While the overall accuracy of the baseline HiSAN model is quite high, other methods for improved accuracy should be explored.
Table 1. Method Accuracy (Acc) Sensitivity Specificity Precision HiSAN (Baseline) 0.8898 0.7583 0.8944 0.8507 Frequency class weighting 0.7826 0.8033 0.8932 0.7040 Random Over Sampling (ROS) 0.8057 0.7672 0.8883 0.7130 Random Under Sampling (RUS) 0.8042 0.7883 0.8930 0.6902 Synthetic Minority Oversampling Technique (SMOTE) 0.8796 0.7341 0.8827 0.8340 Adaptive Synthetic Sampling (ADASYN) 0.8764 0.7467 0.8863 0.8142 SMOTE-Tomek 0.8823 0.7620 0.8956 0.8200
Citation Format: Shalini Priya, Alina Peluso, Mayanka Chandra Shekhar, Ioana Danciu, Jordan Miller, Heidi A. Hanson. Assessing performance of biomarker extraction from electronic health records: Data augmentation methods for a hierarchical self-attention network (HiSAN). [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 4191.