bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2475: Visualization of cell to cell and cell to matrix interactions in the disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T cells
Authors: Xiao Zebin , Hopper Leslie A. , Kopp Meghan C. , McMillan Emily , Li Yue , Barrett Richard L. , Puré Ellen 
Published: June 2022

Abstract
The efficacy of chimeric antigen receptor (CAR) T-cell therapy in solid tumors is limited by inefficient T-cell infiltration, localization and hypofunctionality within the tumor microenvironment. Prior studies demonstrated that stromal cell targeted CAR T cells, in particular CAR T cells that target fibroblast activation protein (FAP), can effectively infiltrate, and inhibit tumor growth in mouse models of pancreatic ductal adenocarcinomas (PDAC) due to their capacity to deplete stromal cells and extracellular matrix (ECM) that otherwise present a barrier to adoptive cell therapies. However, the kinetics of tumor infiltration by FAP-CAR T cells, and the cell-cell and cell-matrix interactions that contribute to their anti-tumor activity are poorly understood. A better understanding FAP-CAR T-cell kinetics and intratumoral interactions should provide insights into the requirements for successful adoptive cell therapies in solid tumors. By combining immunostaining and real-time two-photon microscopy in tumor fragments of PDAC, we found that stromal cell targeted FAP-CAR T cells can efficiently traffic into tumors. Initially (days 1-3) FAP-CAR T cells were enriched in the stroma surrounding tumor nests but excluded from the tumor nests per se. While associated with the stroma rich region, the CAR T cells appeared activated and T cell motility was observed in loose collagen regions, but T cells migrated poorly in dense matrix areas. Aligned collagen fibers in the tumor boarder dictated the migratory trajectory of T cells and restricted them from entering tumor nests. By day 5 we observed depletion of immunosuppressive stromal cells, dissolution of the fibrillar collagen network surrounding tumor nests and infiltration of FAP-CAR T cells into tumor nests. Treatment with hyaluronidase increased the ability of T cells to infiltrate the tumor nest. Thus, FAP-CAR T cell-mediated ablation of immunosuppressive FAP+ stromal cells and disruption of the desmoplastic stroma they generate, can enhance accumulation and functionality of CAR-T cell therapy in the context of highly desmoplastic solid tumors.
Citation Format: Zebin Xiao, Leslie A. Hopper, Meghan C. Kopp, Emily McMillan, Yue Li, Richard L. Barrett, Ellen Puré. Visualization of cell to cell and cell to matrix interactions in the disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T 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 2475.
Abstract 2544: Preoperative exercise inhibits hepatic metastasis by suppressing PMN-MDSC formation of NETs
Authors: Cheng Xiang , Zhang Hongji , Tsung Allan , Huang Hai 
Published: June 2022

Abstract
Introduction: Under surgical trauma, the pathological amplification and activation of neutrophils with potent immunosuppressive functions, also known as polymorphonuclear myeloid-derived suppressive cells (PMN-MDSCs), can promote metastasis by forming neutrophil extracellular traps (NETs) that are web-like structures consisting of nuclear DNA, histones, and granule proteins. Preoperative exercise (PEx) reduces postoperative complications with improved clinical outcomes in cancer patients undergoing surgeries. are. Our preliminary data show that PEx suppresses liver ischemia/reperfusion (I/R)-induced colorectal cancer (CRC) liver metastasis. Our recent studies have shown I/R-induced NETs promote liver CRC metastasis by capturing tumor cells and preventing infiltration and cytotoxicity of CD8+ T cells in tumor microenvironment (TME). We hypothesize that PEx remodels the TME by suppressing PMN-MDSCs formation of NETs.
Methods: Male mice were subjected to exercise for 4 weeks, before MC38 colorectal cancer cells were injected through portal vein, and then subjected to 70% partial liver warm I/R as surgical stress. The single-cell RNA sequencing (scRNA-seq) was performed on CD45+leukocytes from TME 3 weeks after surgery. Immunofluorescence staining and Western Blot were used to determine NETs formation in the TME. Flow cytometry was used to determine the infiltration of PMN-MDSCs and CD8+ T lymphocytes in the tumors.
Results: Our scRNA-seq data reveal that PEx leads to a remarkable transcriptomic shift in most immune cells types, such as PMN-MDSCs, M-MDSCs, T cells, Kupffer cells, B cells, NK and NKT cells, in the TME. PEx decreases the percentages of PMN-MDSCs in the TME and inhibits theNETs formation by PMN-MDSCs. scRNA-seq shows a significant increase of the chemokines CXCL10 in PEx-trained PMN-MDSCs obtained 3 weeks after I/R-induced hepatic metastasis, compared with sedentary controls. In addition, PEx increases the number of CD8+ T lymphocytes infiltrating the TME.
Summary: Our study shows that PEx downregulates NETs formation and increases the CXCL10 expression in PMN-MDSCs, thus promoting the recruitment more cytotoxic CD8 T lymphocytes to suppress tumor metastasis.
Citation Format: Xiang Cheng, Hongji Zhang, Allan Tsung, Hai Huang. Preoperative exercise inhibits hepatic metastasis by suppressing PMN-MDSC formation of NETs [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 2544.
Abstract 2568: ARTS-021 is a potent and selective CDK2 inhibitor that demonstrates anti-cancer activity in preclinical cancer models with CCNE1 amplification
Authors: Liang jiaqi , Cheng Dai , Guo Yali , zhang xiaobin , Liu Xipan , Fu Jia , Ding Qiang , Xiong Wen , Li Fang , Chen Yaoyu , Sheng Qing 
Published: June 2022

Abstract
Cyclin E1 amplification is prevalent in cancers with high unmet medical need such as high grade serous ovarian cancer, stomach cancer and esophageal cancer. Cancer cell lines with high expression level of cyclin E1 gene exhibited profound sensitivity to CDK2 gene depletion, suggesting CDK2 selective inhibitors have the potential to treat patients harboring Cyclin E1 alterations. Here we report the development and preclinical characterization of ARTS-021, an orally bioavailable small molecule CDK2 selective inhibitor. In enzymatic assay against a panel of different CDKs, ARTS-021 potently inhibits the activity of CDK2/CyclinE1 complex with 50% inhibitory concentration (IC50) in the sub-nanomolar range, displaying superior selectivity against other CDKs (CDK1,4,6,7,9). Very low hit rate (S(10)=0.022, at 1uM) is observed when ARTS-021 is assessed in whole Kinome profiling, further revealing the selectivity of this compound. ARTS-021 also demonstrates potent CDK2 inhibition and selectivity against other CDK family members (CDK1,4,6,9) in a series of cellular assays. Consistent with genetic CDK2 dependence data, cell lines with CCNE1 amplification are particularly sensitive to ARTS-021. Double nanomolar ARTS-021 inhibits Rb phosphorylation and blocks G1/S transition, leading to cell growth arrest specifically in CCNE1 amplified cell lines. This CDK2 dependent anti-tumor activity is further validated in vivo, where daily ARTS-021 administration leads to tumor stasis in CCNE1 amplified but not wild type xenograft models. Taken together, these data demonstrate ARTS-021 as a promising CDK2 selective inhibitor with strong potential towards the development of effective therapies for CCNE1 altered cancer.
Citation Format: jiaqi Liang, Dai Cheng, Yali Guo, xiaobin zhang, Xipan Liu, Jia Fu, Qiang Ding, Wen Xiong, Fang Li, Yaoyu Chen, Qing Sheng. ARTS-021 is a potent and selective CDK2 inhibitor that demonstrates anti-cancer activity in preclinical cancer models with CCNE1 amplification [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 2568.
Abstract 257: Normalization of tumor stroma improves the anti-tumor activity of anti-PD-L1 peptides in pancreatic cancer
Authors: Lin Chien-Yu , Cheng Kun 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by the abundant fibrotic stroma surrounding malignant epithelial cells. The tumor stroma is composed of extracellular matrix proteins, myofibroblasts, stellate cells, and immune cells, and comprises up to 80% of the tumor mass. The stroma promotes the progression and metastasis of tumors and the development of chemoresistance. However, the strategies of completed depletion of the stroma resulted in a more aggressive tumor and a poor survival rate in clinical trials. We discovered that silencing the RNA binding protein αCP2, which is encoded by the poly(rC)-binding protein 2 (PCBP2) gene, could destabilize the type I collagen mRNA in human pancreatic stellate cells and mouse NIH/3T3 fibroblasts, leading to the normalization of the tumor stroma. We recently discovered an anti-PD-L1 peptide that effectively blocks the PD1/PD-L1 pathway. We hypothesize that silencing αCP2 modulates the PDAC stroma, thus improving the therapeutic efficacy of immunotherapy. Therefore, the objective of this study is to develop a combination therapy strategy to treat PDAC with PCBP2 siRNA nanoparticles and the anti-PD-L1 peptide. A mixture of 1×106 PANC02 tumor cells and NIH/313 fibroblast cells was subcutaneously implanted into C57BL/6 mice to establish the desmoplastic PDAC model. The mice were treated with saline, PCBP2 siRNA nanoparticles, the anti-PD-L1 peptide, and PCBP2 siRNA nanoparticles plus the anti-PD-L1 peptide. The results showed that the combination of PCBP2 siRNA nanoparticles with the anti-PD-L1 peptide reduced tumor growth. PCBP2 siRNA decreased type I collagen expression in the tumor. The normalized stroma showed increased infiltration of effective immune cells. This approach provides a new strategy to improve the therapeutic efficacy of immunotherapy in PDAC by normalizing the tumor stroma with the PCBP2 siRNA nanoparticle.
Citation Format: Chien-Yu Lin, Kun Cheng. Normalization of tumor stroma improves the anti-tumor activity of anti-PD-L1 peptides in pancreatic 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 257.
Abstract 2630: Heterogeneity inducible tumor stem cells relate distant metastasis and the treatment resistance
Authors: Miyoshi Norikatsu , Fujino Shiki , Sekido Yuki , Hata Tsuyoshi , Ogino Takayuki , Takahashi Hidekazu , Uemura Mamoru , Yamamoto HIrofumi , Doki Yuichiro , Eguchi Hidetoshi 
Published: June 2022

Abstract
Regarding metastatic potential of cancer cells and the refractory status, regulatory and epigenetic factors underlie the cancer treatment resistance by inducing cellular heterogeneity. Circulating tumor cells (CTCs) and their stemness are critical for metastases formation associated with poor survival rates. In colorectal cancer (CRC), several stem-cell markers, such as CD44v9 and LGR5, the positive cells cause intertumoral heterogeneity and promote refractory potential. However, the mastermind of the cells which is critical for the treatment resistance remains unknown. Here, we aimed to identify the mechanisms of the treatment resistance of the CRC by focusing on typical stem cells. We selected several stem cell-related genes such as pluripotency related genes, based on the expression profile analysis of CRC patients along with drug susceptibility assays using patient-derived organoids. Despite the small number of cancer stem cells, the single cell produced heterogeneous cell populations in vitro and in vivo, expressing various differentiation and stem biomarkers, and confirmed by the knockdown analysis. Single-cell trajectory analysis suggested that heterogeneous populations including cancer stem and some persister cells were derived from the stem cells following administration of anti-cancer drugs. Furthermore, the stem cells formed heterogeneous liver metastases at a high rate, and these unique cells were observed in the bloodstream of CRC patients. This present study unveils a mechanism of CRC treatment resistance and highlights the potential of stem marker-expressing cells as CTCs.
Citation Format: Norikatsu Miyoshi, Shiki Fujino, Yuki Sekido, Tsuyoshi Hata, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, HIrofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi. Heterogeneity inducible tumor stem cells relate distant metastasis and the treatment resistance [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 2630.
Abstract 2680: PCAI-induced phosphorylation of MAP kinase pathway enzymes is associated with cell death of black American lung adenocarcinoma cell line NCI-H23
Authors: Gregory Matthew D. , Tawfeeq Nada , Lazarte Jassy M. , Jin Yonghao , Puente Pablo , Belony Nadine , Offringa Ite A. , Huang Yong , Lamango Nazarius S. 
Published: June 2022

Abstract
Lung cancer is a leading cause of cancer-related mortality accounting for 23% of cancer deaths in the US. Non-small cell lung cancer (NSCLCs) comprises 84% of all lung cancer cases, and of these, 40% are lung adenocarcinoma (LUAD). Moreover, black Americans are underrepresented in scientific clinical trials but have a lung cancer incidence rate that is 37% higher than their white counterparts. To address this disparity and lack of effective treatment options, we determined the potency of polyisoprenylated cysteinyl amide inhibitors (PCAIs) on cell viability and its effects on KRAS and its downstream mediators in NCI-H23, a black American cell line that harbors a KRAS mutation. Among the 17 PCAIs that were tested, compound NSL-YHJ-2-27 showed the most potency with an EC50 of 2.7 µM. Western blot analysis was performed to determine the effect of the PCAIs on the levels of Mitogen-Activated Pathway Kinase (MAPK)-related proteins. After 48 h of exposure to 5 μM of NSL-YHJ-2-27, we observed increases of 150, 64.5, and 77% in phosphorylation levels of ERK1/2, MEK1/2, and 90RSK. While the particular 90RSK enzymes whose phosphorylation is/are elevated are not known at this time, 90RSK 3 and 4 are known to be proapoptotic. These findings suggest that the PCAIs may be used to target cancers with KRAS mutations that currently lack effective therapies. In the future, we will use a collection of isogenic cell lines to examine the potency of the PCAIs in LUAD driven by other RAS and related monomeric G-proteins, epidermal growth factors, and their receptors as well as RAS-GAPs. Therapies emanating from these studies have the potential to contribute to mitigating the lung cancer therapeutic inequities.
Keywords: Polyisoprenylated Cysteinyl Amide Inhibitors (PCAIs), Mitogen Activated Pathway Kinases (MAPK), KRAS, Lung Adenocarcinoma (LUAD), Non-small cell lung cancer (NSCLCs)
Citation Format: Matthew D. Gregory, Nada Tawfeeq, Jassy M. Lazarte, Yonghao Jin, Pablo Puente, Nadine Belony, Ite A. Offringa, Yong Huang, Nazarius S. Lamango. PCAI-induced phosphorylation of MAP kinase pathway enzymes is associated with cell death of black American lung adenocarcinoma cell line NCI-H23 [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 2680.
Abstract 2687: The estrogenic activities of endocrine disruptors alter the extracellular matrix and tissue stiffness in the mammary gland
Authors: Wormsbaecher Clarissa , Hindman Andrea R. , Avendano Alex , Cortes-Medina Marcos , Song Jonathan W. , Burd Craig J. 
Published: June 2022

Abstract
In utero exposure to estrogenic endocrine disrupting compounds (EDCs) increases a woman’s lifetime risk of breast cancer. Similarly, mice exposed in utero to the estrogenic EDC bisphenol A (BPA) have increased susceptibility to mammary gland tumors. It is unclear which BPA-induced alterations predispose the mammary gland to cancer transformation. There is a critical need to understand the mechanisms that drive increased cancer risk in order to assess the impact of BPA and BPA alternatives that retain estrogenic activity. We have utilized in utero BPA exposure as a model system for in utero estrogenic endocrine disruption to study the long-term consequences to the mouse mammary stroma. We found that BPA exposed fibroblasts showed significant transcriptional deregulation, with the extracellular matrix being the most altered cellular component and multiple collagen genes being more highly expressed. The fibroblasts from the BPA exposed mice decreased fluid permeability of the extracellular matrix, indicative of an increased density in the extracellular matrix. Also, in utero BPA exposure increased mammary gland stiffness. Changes to breast density, stiffness, and collagen deposition are all associated with breast cancer risk. Further, we test BPA alternative compounds with varying affinities for the estrogen receptor in our in utero model to assess the phenotypes in the mouse mammary stroma which are associated with breast cancer risk. Additionally, we use a mesenchymal estrogen receptor alpha (ERα) knockout mouse model to dissect the in utero cellular target of EDCs.
Citation Format: Clarissa Wormsbaecher, Andrea R. Hindman, Alex Avendano, Marcos Cortes-Medina, Jonathan W. Song, Craig J. Burd. The estrogenic activities of endocrine disruptors alter the extracellular matrix and tissue stiffness in the mammary gland [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 2687.
Abstract 2691: Expression pattern and prognostic significance of HER family members and EGFRvIII in pancreatic cancer
Authors: Khan Tanzeel , Khelwatty Said A. , Bagwan Izhar , Seddon Alan , Dalgleish Angus , Mudan Satvinder , Modjtahedi Helmout 
Published: June 2022

Abstract
Pancreatic cancer is one of the most aggressive, heterogeneous, and fatal types of human cancers. There is urgent need for discovery of biomarkers of prognostic significance, predictive value and as well as therapeutic targets in patients with pancreatic cancer. In this study, we examined the relative expression and prognostic significance of all HER family members and the type III EGFR mutant (EGFRvIII) in patients with pancreatic ductal adenocarcinoma (PDC). The expression levels of wild-type EGFR (wtEGFR), HER2, HER3, HER4 and EGFRvIII were determined in tumor specimens from 43 patients by immunohistochemistry using antibodies DAK-H1-WT, Neu 3B5, SP71, HFR1 and NBP2-50599 respectively. The staining was scored based on the percentage of positive tumor cells, the intensity (i.e. strong 3+, moderate 2+, weak 1+) and the cellular location of immunostaining (i.e. membranous, cytoplasmic or nuclear). The association between the expression level of the biomarkers and patient overall survival was evaluated using Chi-squared, Kaplan-Meier survival curves and log rank test. At cut-off value of above 5%, we found weak to moderate expression of wtEGFR, HER2, HER3, HER4 and EGFRvIII in 4.7%, 14%, 14%, 20.9% and 2.3% of the cases examined respectively. The cellular location of wtEGFR and HER2 was found to be predominantly cytoplasmic, HER-3 membranous and cytoplasmic whereas HER4 expression was found to be mainly nuclear. There was no statistically significant association between the expression level of these markers and patient overall survival. The expression levels of the above biomarkers were also evaluated in tissue microarrays (TMAs) from 40 cases of pancreatic ductal adenocarcinoma. Interestingly, at the same cut-off value, 62.5%, 75%, 0%, 55% and 5% of the TMAs were positive for wtEGFR, HER2, HER3, HER4 and EGFRvIII respectively. Overall, we found that the expression pattern of HER family members was heterogenous, and with EGFRvIII expression being very low in both whole tumor sections and TMAs from patients with pancreatic cancer. Taken together, our results provide support for more detailed studies of co-expression of all HER family members in a larger group of pancreatic cancer patients. Such studies should help to unravel their potential as targets for therapeutic interventions as well as their prognostic significance and predictive value for response to therapy.
Citation Format: Tanzeel Khan, Said A. Khelwatty, Izhar Bagwan, Alan Seddon, Angus Dalgleish, Satvinder Mudan, Helmout Modjtahedi. Expression pattern and prognostic significance of HER family members and EGFRvIII in pancreatic 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 2691.
Abstract 2826: Rewiring CAR T-cells for absolute solid tumor specificity and safety
Authors: Weist Michael R. , Sharbi-Yunger Adi , Yi Jason , Schnair Caitlin , Bassan David , Kim Tanya , Tabak Sarit , Lopesco Yael , Weinberger Leehee , Bujanover Nir , Chaim Neta , Vucci Kristina , Foord Orit , Calzone Frank J. , Kendall Rick , Adams Gregor B. 
Published: June 2022

Abstract
Translation of the unprecedented efficacy of chimeric antigen receptor (CAR) T-cell technology into solid tumors requires a solution to the problem of on-target damage of vital organs. We have developed an inhibitory CAR platform (iCAR) that imposes self-regulation in CAR T-cells to restrict inappropriate activation against normal cells without compromising tumor efficacy. The system consists of an iCAR that is co-expressed with a conventional activating CAR (aCAR) designed to activate T-cells. The iCAR and aCAR scFvs bind distinct cell-surface antigens that are ubiquitously expressed across all solid tumor histologies and normal tissues. The iCAR is allele-specific whereas the aCAR is pan-allelic. The iCAR technology was validated in functional assays and NSG models with cancer cell lines that mimic loss-of-heterozygosity (LOH) which is common in most human cancers due to increased chromosomal instability. In this context, loss of iCAR target expression due to LOH generates irreversible target specificity. Tumor-specific overexpression of aCAR and iCAR targets, a common barrier to the clinical translation of potent agents targeting the cell-surface proteins is not required. We have shown using in vitro and in vivo models that CAR T-cell activation and target killing are fully inhibited by dual iCAR + aCAR antigen engagement. This outcome validates the concept of iCAR-mediated protection of normal cells in vital organs. In contrast, tumors that mimic iCAR target LOH through CRISPR editing were fully eradicated with aCAR engagement alone. T-cell activation, proliferation, and cytotoxic activity after exposure to target cells lacking iCAR target antigen was found to be quantitatively indistinguishable from the results obtained with single input aCAR CAR T-cells. These results suggest that iCAR technology can enable treatment of cancer patients with solid tumors using CAR T-cells that maximize potency and efficacy by mitigating on-target CRS, neurotoxicity, and inevitable organ damage. The restriction of CAR T activation to the local tumor environment by iCAR-mediated self-regulation directly addresses a fundamental technology gap that cannot be solved by CAR T dosing or aCAR modification alone.
Citation Format: Michael R. Weist, Adi Sharbi-Yunger, Jason Yi, Caitlin Schnair, David Bassan, Tanya Kim, Sarit Tabak, Yael Lopesco, Leehee Weinberger, Nir Bujanover, Neta Chaim, Kristina Vucci, Orit Foord, Frank J. Calzone, Rick Kendall, Gregor B. Adams. Rewiring CAR T-cells for absolute solid tumor specificity and safety [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 2826.