bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1728: Single cell RNA-seq analysis reveals a role of pro-inflammatory tumor-associated macrophages in driving prostate cancer progression
Authors: Zhao Jimmy L. , Chan Joseph , Land Max , Smith Perianne , Gopalan Anuradha , Haffner Michael , Pe'er Dana , Sawyers Charles 
Published: June 2022

Abstract
Genomic amplification and increased expression of C-MYC are found in high-grade intraepithelial neoplasm (HGPIN) and primary prostate adenocarcinoma. What role C-MYC plays in the initiation and progression of prostate cancer remains unclear. A genetically engineered mouse model with a high level of human C-MYC protein expression under a probasin promoter (Hi-Myc model) was developed that captures prostate cancer progression from hyperplasia at 6-week-old, to HGPIN at 3-6 month-old, and ultimately to invasive adenocarcinoma at 8-month-old. Applying single-cell RNA sequencing (scRNA-seq) technology, we have carefully studied the temporal transcriptional change in MYC-expressing tumor-initiating cells and the tumor-infiltrating immune cells to understand the cell-intrinsic and -extrinsic mechanisms by which C-MYC promotes the transition from HGPIN to invasive prostate cancer. We have identified a particular type of luminal cells, Prom1+ L1 cells, as the likely tumor initiating cells in the Hi-Myc model. The MYC-expressing L1 tumor initiating cells were more abundant and cycling more often in the invasive cancer at 8-month-old, compared to the pre-invasive stage. Interestingly, significant infiltration of novel M1-like tumor-associated macrophages (TAMs) correlated with the histologic tumor progression from HGPIN to invasive cancer. Targeting TAMs with anti-CSF1R antibody delayed prostate cancer progression and invasion, which appears to be independent of CD8 T-cells. Mechanistically, TAMs expressed a high level of IL-1b, which stimulated Hi-Myc prostate cell proliferation in an organoid co-culture system. More importantly, depleting IL-1b with a neutralizing antibody slowed prostate cancer progression in Hi-Myc mice. Lastly, we found that increased macrophage gene expression was associated with higher Gleason scores and worse disease-free survival in a TCGA clinical patient cohort. In summary, we have identified a molecular mechanism involving pro-inflammatory TAMs and IL-1b in driving early prostate cancer progression in a MYC-driven prostate cancer model, opening a potential therapeutic avenue to target TAMs and pro-inflammatory cytokine in preventing early prostate cancer progression.
Citation Format: Jimmy L. Zhao, Joseph Chan, Max Land, Perianne Smith, Anuradha Gopalan, Michael Haffner, Dana Pe'er, Charles Sawyers. Single cell RNA-seq analysis reveals a role of pro-inflammatory tumor-associated macrophages in driving prostate cancer progression [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 1728.
Abstract 1758: The preclinical pharmacology of PRO1102, a novel exatecan-based HER2-directed antibody-drug conjugate with robust anti-tumor activity
Authors: Wang Lei , Liu Haidong , Shang Xiao , Han Tae H. , Zhao Baiteng 
Published: June 2022

Abstract
PRO1102 is an antibody-drug conjugate (ADC) directed toward HER2, a validated protein target that is overexpressed in multiple cancers, including breast and gastrointestinal cancer. PRO1102 is comprised of 1) trastuzumab, a clinically and commercially validated HER2-directed antibody, 2) a cleavable, hydrophilic linker, and 3) exatecan, a topoisomerase 1 inhibitor. The mechanism of action and the clinical potential of PRO1102 was evaluated in a series of experiments. PRO1102 maintained the same binding attributes of the parent antibody, trastuzumab, in vitro. In mouse xenograft studies, PRO1102 demonstrated robust anti-tumor activity across multiple HER2-expressing cell lines that was generally better than ADCs with alternative drug-linker technologies, such as those associated with monomethyl auristatin E, mertansine (DM1) and deruxtecan. In addition, PRO1102 retained activity in cancer cells with moderate and low HER2 expression, suggesting the potential to benefit a broader range of patients of HER2-expressing cancers. The pharmacokinetics of PRO1102 was evaluated in rats and PRO1102 was stable in circulation with disposition similar to the parent antibody. Tolerability was evaluated in mice and at PRO1102 dose levels associated with robust anti-tumor activity, PRO1102 was well tolerated. PRO1102 exhibits the attributes needed for an effective ADC with robust activity in a broad selection of HER2-expressing cancers.
Citation Format: Lei Wang, Haidong Liu, Xiao Shang, Tae H. Han, Baiteng Zhao. The preclinical pharmacology of PRO1102, a novel exatecan-based HER2-directed antibody-drug conjugate with robust anti-tumor activity [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 1758.
Abstract 1781: Up284, a novel inhibitor to treat quadruple negative breast cancer
Authors: Karanam Balasubramanyam , Yates Clayton , Anchoori Ravi 
Published: June 2022

Abstract
Quadruple negative breast cancer (QNBC), lacking the expression of ER (estrogen receptor), PR (progesterone receptor), HER2 (human epidermal growth factor receptor 2) and AR (androgen receptor), is the breast cancer subtype with the worst prognosis, and QNBC disproportionately afflicts African Americans. It has no standard-of-care treatment targets and thus efficacious and safe treatments are urgently sought for this unmet medical need, and to address the disparity in breast cancer outcomes. The current proposal is motivated by data showing elevated expression of proteasome subunit RPN13 is associated with both African American race and lower survival in QNBC patients, that RPN13 selectively targeted by a small molecule Up284 developed by Up Therapeutics. Both triple negative breast cancer and QNBC cell lines show evidence of greater vulnerability to proteasome inhibitors. However, licensed 20S proteasome inhibitors, e.g. bortezomib, have proven ineffective against solid tumors, with emergence of resistance, and dose limiting toxicities including thrombocytopenia and neutropenia. Up284 has a target and structure designed to overcome the limitations of the licensed drugs with respect to drug resistance. Up284 blocks substrate recognition and deubiquitination rather than just one of the three 20S catalytic activities), poor activity against solid tumors (Up284 has a novel spiro structure with evidence of improved drug access to tumor as compared to peptide-based 20S inhibitors), key toxicities of thrombocytopenia and neutropenia (unlike 20S inhibitors, Up284 does not target the immunoproteasome expressed by hematopoietic cells and does not show these toxicities). Up284 shows broad anticancer activity in vitro, including against QNBC lines with a robust therapeutic index, a promising safety profile and pharmacodynamics, and the ability to control xenograft tumor. By inhibiting proteasome ubiquitin receptor RPN13 function and its associated deubiquitinase activity, Up284 triggers more rapid accumulation and increased molecular weight polyubiquinated protein aggregates than is induced by 20S inhibitors. These toxic misfolded protein aggregates produce an unresolved ER stress, activate the canonical Unfolded Protein Response (UPR) signaling cascade and more rapidly triggers apoptosis than 20S inhibitor. The safety parameters and promising efficacy of Up284 against breast cancer lines encourages us to validate Up284 efficacy in more QNBC lines and animal models. We discuss Up284 efficacy and pharmacological analysis in our presentation.
Citation Format: Balasubramanyam Karanam, Clayton Yates, Ravi Anchoori. Up284, a novel inhibitor to treat quadruple 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 1781.
Abstract 1862: Naphthoquinone analogues inhibit Wnt/β-catenin signaling and colorectal cancer tumorigenesis
Authors: Hoyle Rosalie G. , Morris Andrew , Pagare Piyusha , Zaman Shadid Uz , Ma Zhikun , Zhang Yan , Li Jiong 
Published: June 2022

Abstract
In this study, we performed a structure-activity-relationship study of seven previously identified chloro-naphthoquinone analogs and evaluated their abilities to inhibit the Wnt/β-catenin signaling pathway. The Wnt/β-catenin signaling pathway plays essential roles in colorectal cancer (CRC) initiation, proliferation, and development. While targeting the Wnt/β-catenin pathway has been validated as a very promising approach for CRC treatment, developing a therapeutic for inhibition of this elusive pathway has been very challenging for researchers. Of the seven chloro-naphthoquinone analogues, we found that two compounds, Compound 3 and Compound 6, significantly inhibited Wnt target gene transcription and Wnt-induced colorectal tumorigenesis in vitro. Chromatin immunoprecipitation binding assays and computational modeling analysis revealed that Compound 3 and Compound 6 inhibit the Wnt/β-catenin pathway through disruption of the TCF4-DNA binding, a crucial step for the activation of the Wnt/β-catenin signaling pathway. Lastly, using a patient-derived organoid model and xenograft mouse model, we showed that these compounds inhibit CRC tumorigenesis. Taken together, this study demonstrates a novel mechanism of action for these chloro-naphthoquinone analogs, which can be further explored in future drug design and discovery efforts for small molecules targeting the TCF family proteins for inhibition of the Wnt/β-catenin signaling pathway.
Citation Format: Rosalie G. Hoyle, Andrew Morris, Piyusha Pagare, Shadid Uz Zaman, Zhikun Ma, Yan Zhang, Jiong Li. Naphthoquinone analogues inhibit Wnt/β-catenin signaling and colorectal cancer tumorigenesis [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 1862.
Abstract 1864: Baicalein attenuates endometrial cancer growth by suppressing the ARF6
Authors: Mcglorthan Latoya , Syed Viqar 
Published: June 2022

Abstract
Using mass spectrometry-based proteomics, we have previously shown enhanced expression of the Adenosine diphosphate-Ribosylation Factor-6 (ARF6) in endometrial cancer cell lines compared to immortalized EM-E6/E7-TERT endometrial epithelial cells. ARFs belong to the RAS superfamily of small GTPases. ARF family proteins are activated by Guanine nucleotide Exchange Factors (GEFs) and inactivated by GTPase-Activating Proteins (GAPs). When active, they bind effectors, which mediate downstream functions. ARF6 localized on the plasma membrane plays a role in actin cytoskeleton dynamics and endocytic recycling. Dysregulation of expression and/or activity of ARF6 has been associated with enhanced cell migration, invasion, and proliferation in several types of cancer. Knockdown of ARF6 significantly inhibited the invasiveness of the cancer cells. There is a critical need for novel promising anticancer agents with lesser side effects and higher efficacy. Baicalein, extracted from the roots of the Chinese herb Huang Qin (Scutellaria baicalensis), showed a significant anticancer impact on many human cancers. However, the specific molecular mechanisms are still nebulous. Endometrial cancer cell lines were exposed to different concentrations of baicalein for 24 to 120 h. The effect on cell proliferation and invasion was determined utilizing MTS and Boyden chamber assays, respectively. The baicalein induced a dose and time-dependent reduction in cell viability. The invasiveness of cells was attenuated by baicalein. Furthermore, the anticancer effects were mediated by decreased ARF6, Rac1, and PAK1 expression in baicalein-treated cancer cells. In summary, the data reveal that suppression of ARF6 could reduce the invasive potential of endometrial cancer by modulating the major downstream effectors Rac1 and PAK1.
Citation Format: Latoya Mcglorthan, Viqar Syed. Baicalein attenuates endometrial cancer growth by suppressing the ARF6 [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 1864.
Abstract 195: A focused ultrasound blood brain barrier disruption model to test the influence of tight junction genes to treat brain tumors
Authors: Iyer Jayashree , Akkad Adam , Tang Nanyun , Peng Sen , Berens Michael , Zenhausern Frederic , Gu Jian 
Published: June 2022

Abstract
A major hindrance to advances in the care of patients with malignant gliomas is the presence of the blood brain barrier (BBB) and blood-brain tumor barrier (BBTB) that greatly restricts drug access from the plasma to the tumor cells. Bubble-assisted Focused Ultrasound (BAFUS) has proven effective in opening the BBB for treatment of glial tumors in adults and pediatric cases. BAFUS has been previously shown to disrupt noninvasively, selectively, and transiently the BBB in small animals in vivo. However, there is a lack of an in vitro preclinical model suitable for testing the genetic determinants of endothelial cell tight junction integrity and vulnerability to the physical disruption. Our BBB organ-on-chip platform will enable precision medicine of brain cancers through identifying patient-specific parameters by which to open the BBB allowing use of drugs and drug combinations otherwise unsuitable. We intend to sequence these in vitro models to verify that the genotype (alleles/SNPs) of tight junction proteins contribute to BBB structure and integrity. To initiate this effort, we report the development of an ultrasound transparent organ-on-chip model populated by iPSC-derived endothelial cells (iPSC-EC) co-cultured with astrocytes. Western blot, immunocytochemistry, permeability, and transelectrical endothelial resistance (TEER) studies all convey expression of key EC proteins and marked barrier integrity. Further benchmarking of device-ultrasound interactions, successful iPSC differentiation, tight junction formation, and fabrication of nanobubbles and their assistance in ultrasound BBB disruption will be presented. Efforts are underway to analyze nine characteristic BBB tight junction genes from WGS data to determine associations between iPSC-EC genotype and phenotype.
Citation Format: Jayashree Iyer, Adam Akkad, Nanyun Tang, Sen Peng, Michael Berens, Frederic Zenhausern, Jian Gu. A focused ultrasound blood brain barrier disruption model to test the influence of tight junction genes to treat brain 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 195.
Abstract 2035: Imaging mass cytometry identifies structural and cellular composition of the mouse tissue microenvironment
Authors: Raza Qanber , Cohen Michael , Kala Smriti , Lim Liang , Awong Geneve , Quong Andrew , Loh Christina 
Published: June 2022

Abstract
Imaging Mass Cytometry™ (IMC™) is a vital tool to deeply characterize the complexity and diversity of any tissue without disrupting spatial context. The Hyperion™ Imaging System utilizes IMC, based on CyTOF® technology, to simultaneously assess up to 40 individual structural and functional markers in tissues, providing unprecedented insight into the organization and function of tissue microenvironment. We have previously demonstrated the application of IMC in combination with Maxpar® panel kits to highlight cellular composition of human tissues. Here, we showcase the recently released Maxpar OnDemand Antibodies for IMC application on mouse tissue. We introduced 11 additional biomarkers to our existing mouse antibody catalog, providing the basis for the use of high-multiplex imaging in preclinical investigations. To demonstrate the IMC workflow on mouse tissue, we analyzed a normal mouse tissue microarray using IMC spatial proteomic analysis. Tissues were stained with a 20-marker panel designed to highlight tissue architecture and major immune lineage markers combined with our IMC Cell Segmentation Kit*. The IMC Cell Segmentation Kit facilitates identification of cellular borders using plasma membrane markers that lead to improved nucleus and plasma membrane demarcation. We generated a detailed spatial map of the heterogeneous tissue architecture and successfully identified immune, epithelial, and stromal cell populations in various mouse tissues. Additionally, we classified the activation state of immune cell populations, adhesion state of epithelial cells, and molecular composition of the extracellular matrix.Overall, this work demonstrates the capability of IMC to identify subcellular localization of cellular and structural markers in the mouse tissue microenvironment. Information gained from IMC studies will enable in-depth high-throughput phenotypic characterization of the tissue microenvironment in various mouse models of development and disease, and thus accelerate preclinical discoveries.
*The IMC Cell Segmentation Kit is part of the Innovative Solutions menu of custom-made reagents and workflows developed and tested by Fluidigm scientists to give faster access to new cutting-edge solutions for high-multiplex single-cell analysis. Innovative Solutions are not part of the Maxpar catalog.
For Research Use Only. Not for use in diagnostic procedures.
Citation Format: Qanber Raza, Michael Cohen, Smriti Kala, Liang Lim, Geneve Awong, Andrew Quong, Christina Loh. Imaging mass cytometry identifies structural and cellular composition of the mouse tissue microenvironment [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 2035.
Abstract 2044: The target antigen determines the mechanism of acquired resistance to T cell based therapies
Authors: Martínez-Sabadell Alex , Morancho Beatriz , Rius Irene , Escorihuela Marta , Luque Antonio , Chicote Irene , Palmer Hector García , Bacac Marina , Arribas Joaquin , Lahuerta Enrique Javier Arenas 
Published: June 2022

Abstract
Introduction: Immunotherapy has revolutionized the way many cancers are treated. Despite its success, cancer patients eventually progress due to the emergence of resistance. In this scenario, the selection of the tumor antigen is important and can be decisive in the success of the clinical response, particularly when resistance emerge. T cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the T cell receptor and to a tumor-specific or a tumor-associated antigen. It is assumed that, as all TCBs have the same mechanism of action, mechanisms of resistance are independent of the tumor antigen.
Objective: This study was designed to identify the mechanisms that trigger the resistance against HER2 and CEACAM5 T cell bispecific antibodies. We assessed TCB sensitivity using in vitro and in vivo assays combining human cell lines or patient-derived models with human lymphocytes.
Material and Methods: Using gastric CEA+/HER2+ MKN45 cells as a model and TCBs directed against CEA or HER2, here we show for the first time that the mechanism of resistance to a T cell-based therapy is dependent on the tumor antigen.
Results: Acquired resistant models to a high-affinity CEA-targeted TCB exhibit a reduction of CEA antigen levels due to epigenetic transcriptional silencing, which is reversible upon 5-AZA treatment. In contrast, a HER2-TCB resistant model maintains HER2 levels as HER2 downregulation led to an impairment of proliferation. Furthermore, using this latter model, we identified that disruption of interferon- gamma signaling confers resistance to killing by active T lymphocytes.
Conclusions: Our results unveil different mechanisms of acquired resistance to TCBs depending on the selected antigen, which will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances.
Citation Format: Alex Martínez-Sabadell, Beatriz Morancho, Irene Rius, Marta Escorihuela, Antonio Luque, Irene Chicote, Hector García Palmer, Marina Bacac, Joaquin Arribas, Enrique Javier Arenas Lahuerta. The target antigen determines the mechanism of acquired resistance to T cell based therapies [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 2044.
Abstract 2056: PI3Kgamma inhibition reduces inflammation and promotes survival in cancer and SARS-CoV-2
Authors: Varner Judith A. , Ghebremedhin Anghesom 
Published: June 2022

Abstract
Solid tumors are characterized by extensive immune suppressive inflammation, vascular leak, fibrosis and organ damage. Similarly, SARS-CoV-2 infections induce aberrant pulmonary and systemic inflammation, vascular leak, coagulation, fibrosis and fatal organ damage. We previously demonstrated that macrophages in solid tumors strongly expressed phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinately controls granulocyte and monocyte trafficking to tumors as well as wound-healing-type macrophage transcription in cancer and fibrosis. We also observed that macrophages in COVID-19 lungs strongly expressed PI3Kγ. To identify therapeutic strategies to suppress COVID-19-associated inflammation, we characterized lung tissue of COVID-19 patients using multiplex immunohistochemistry and tissue transcriptomics. Lungs of deceased patients exhibited substantial infiltration by neutrophils and wound-healing macrophages, fibrosis and alveolar type II cell depletion. In animal models of lung inflammation, bacterial infections, viral infection and SARS-CoV-2 infection, PI3Kγ deletion or inhibition with the cancer therapeutic IPI-549 (eganelisib) suppressed pulmonary and systemic inflammation, reduced lung damage, and promoted survival. These studies demonstrate the essential role of PI3Kγ in inflammatory diseases as well as cancer and support the use of PI3Kγ inhibitors such as eganelisib to suppress inflammation and promote survival in pulmonary infections like SARS-CoV-2 and cancer.
Citation Format: Judith A. Varner, Anghesom Ghebremedhin. PI3Kgamma inhibition reduces inflammation and promotes survival in cancer and SARS-CoV-2 [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 2056.