bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5337: Design, synthesis and evaluation of dual-targeted mEGFR and AURK inhibitors as anticancer agents
Authors: Gesinski Dayna , Kurup Sonali 
Published: April 2023

Abstract
Mutant epidermal growth factor receptor (mEGFR) inhibitors constitute the recommended therapy for mEGFR-positive cancers. However, resistance has developed to mEGFR inhibitors due to newer mutations within the enzyme pocket and redundant signaling pathways that bypass mEGFR inhibition. Recent studies have shown that resistance to mEGFR inhibitors could be overcome if given in combination with aurora kinase (AURK) inhibitors. Dual EGFR/AURK kinase inhibitors provide a novel approach to overcome resistance to EGFR inhibitors. In a previous study, Kurup et al. identified 1 as a nanomolar mEGFR inhibitor. Using a structure-based design approach, novel analogs of 1 that incorporated varied sidechains for dual mEGFR and AURK inhibition were designed. The synthesis of the target compounds involved microwave-assisted, copper and palladium catalyzed coupling reactions. This study led to the identification of dual-targeted mEGFR/AURKA and mEGFR/AURKB inhibitors, and compounds with sub-micromolar cellular potencies. The design, synthesis, kinase inhibitory activities and anticancer effects of these novel analogs will be presented. Structure-activity relationships for mEGFR, AURKA and AURKB inhibition will be defined.
Citation Format: Dayna Gesinski, Sonali Kurup. Design, synthesis and evaluation of dual-targeted mEGFR and AURK inhibitors as anticancer agents. [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 5337.
Abstract 5339: 4-Amino-N-phenylbenzamides as dual-targeted mEGFR and AURK inhibitors and anticancer agents
Authors: Rogers Brianne , Rohde Nicholas , Mikitaroff Justin , Matson Joshua , Satawa Samantha , Amissah Felix , Kurup Sonali 
Published: April 2023

Abstract
Small molecule, mutant epidermal growth factor receptor kinase (mEGFR) inhibitors are rendered ineffective in NSCLC due to mutations within the enzyme binding sites and redundant signaling pathways. The mEGFR inhibitors were found to retain their anticancer effects in NSCLC cells if given concurrently with AURK inhibitors. Dual-targeted small molecules designed to inhibit both mEGFR and AURK could demonstrate improved anticancer effects compared to monotargeted mEGFR inhibitors. We conducted molecular modeling studies to determine if there were similarities between the kinase pockets of mEGFR and AURK that could be exploited to develop dual-targeted mEGFR and AURK inhibitors. An overlap was observed for the active and allosteric sites of the kinase pocket for mEGFR and AURK. A series of compounds were synthesized and evaluated against mEGFR, AURKA, and AURKB. We found the kinase inhibitory profile to vary significantly depending on the substitution pattern ranging from selective mEGFR inhibitors to dual mEGFR and AURK inhibitors. The 4-substituted amino-N-phenylbenzamides were identified as dual mEGFR/AURK inhibitors. Dual mEGFR/AURK inhibitors demonstrated varied modes of binding within mEGFR and AURK. The most potent dual mEGFR and AURK inhibitors displayed nanomolar inhibition of mEGFR and AURK, and single-digit micromolar inhibition of non-small cell lung cancer cells. Target compounds were further evaluated in a 96-kinase screening assay and demonstrated selectivity for target kinases. The synthesis, structure-activity relationship (SAR) analysis and anticancer effects will be presented and discussed.
Citation Format: Brianne Rogers, Nicholas Rohde, Justin Mikitaroff, Joshua Matson, Samantha Satawa, Felix Amissah, Sonali Kurup. 4-Amino-N-phenylbenzamides as dual-targeted mEGFR and AURK inhibitors and anticancer agents. [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 5339.
Abstract 5346: Discovery of new targeted protein degraders using DNA-encoded chemistry
Authors: Keefe Anthony D. , Disch Jeremy S. , Duffy Jennifer , Lee Esther C. , Gikunju Diana , Chan Betty , Levin Benjamin D. , Monteiro Michael I. , Talcott Sarah A. , Lau Anthony , Zhou Fei , Kozhushnyan Anton , Westlund Neil E. , Mullins Patrick B. , Yu Yan , von Rechenberg Moritz , Zhang Junyi , Arnautova Yelena , Liu Yanbin , Zhang Ying , McRiner Andrew J. , Kohlmann Anna , Clark Matthew A. , Cuozzo John W. , Huguet Christelle , Arora Shilpi 
Published: April 2023

Abstract
Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplars exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant that rapidly generated bispecific nanomolar degraders of ERα, with PROTACs inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.
Citation Format: Anthony D. Keefe, Jeremy S. Disch, Jennifer Duffy, Esther C. Lee, Diana Gikunju, Betty Chan, Benjamin D. Levin, Michael I. Monteiro, Sarah A. Talcott, Anthony Lau, Fei Zhou, Anton Kozhushnyan, Neil E. Westlund, Patrick B. Mullins, Yan Yu, Moritz von Rechenberg, Junyi Zhang, Yelena Arnautova, Yanbin Liu, Ying Zhang, Andrew J. McRiner, Anna Kohlmann, Matthew A. Clark, John W. Cuozzo, Christelle Huguet, Shilpi Arora. Discovery of new targeted protein degraders using DNA-encoded chemistry. [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 5346.
Abstract 5373: Autoencoder-based multimodal prediction of survival for non-small cell lung cancer
Authors: Ellen Jacob G. , Jacob Etai , Nikolaou Nikos , Markuzon Natasha 
Published: April 2023

Abstract
Most non-small cell lung cancer (NSCLC) prognosis prediction approaches use one data type and do not take advantage of the large amount of multimodal data available. To evaluate and explore the benefits of multimodal data integration, we present a combined feature selection and denoising autoencoder pipeline for NSCLC survival prediction and survival subtype identification using microRNA (miRNA), mRNA, DNA methylation, long non-coding RNA (lncRNA) and clinical data. Survival performance for both lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) patients was compared across modality combinations, data integration time and training data types. Multimodal data combinations outperformed single data modalities, with the early integration of all data modalities achieving concordance indexes (C-indexes) of 0.67 (±.04) and 0.63 (±.02) for LUAD and LUSC, respectively versus corresponding C-index of 0.64 (±.02) and 0.59 (±.03) for the best single cell modality (clinical). Notably, combining just lncRNA and clinical data facilitated effective survival discrimination, with C-indexes of 0.69 (±.03) for LUAD and 0.62 (±.03) for LUSC. Overall, higher performance was achieved by using a single denoising autoencoder for all biological data (early integration) and by training on both LUSC and LUAD patient data together. Two survival subtypes (log rank test p-value=1e-9) were identified, with 991 differentially expressed transcripts in the poorer survival group. Our analysis shows the value of multimodal data integration for predicting NSCLC progression, with especially good performance using the combination of lncRNA and clinical data. Early integration of biological data, with an initial linear feature selection technique and a denoising autoencoder for dimensionality reduction, showed effective survival performance and survival subtype identification. Further research is underway to expand analysis to different cancer types and data modalities and extract more biological interpretability from autoencoder models.
Citation Format: Jacob G. Ellen, Etai Jacob, Nikos Nikolaou, Natasha Markuzon. Autoencoder-based multimodal prediction of survival for non-small cell 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 5373.
Abstract 5420: Deep learning-based mapping of tertiary lymphoid structure scores from H&E images of renal cell carcinoma trained by spatial transcriptomics data
Authors: Cook Seungho , Shin Haenara , Seo Mi-Kyoung , Lee Dae Seung , Choi Hongyoon 
Published: April 2023

Abstract
Purpose Tertiary lymphoid structures are organized aggregates of immune cells present in the tumor microenvironment (TME) in which novel targets as well as beneficial biomarkers for immunotherapy in cancer were found. Here, we have developed and validated a deep learning model by integrating H&E images of renal cell carcinoma and spatial transcriptomics data to infer spatial mapping of tertiary lymphoid structure scores in TME only using hematoxylin and eosin (H&E) images.
Methods A total of 20 H&E images combined with spatial transcriptomics data of renal cell carcinoma were used to develop a model. Tertiary lymphoid structure scores can be acquired for each spot in spatial transcriptomics by geometric mean of the specific gene expression relevant to B cell, T cell, immunoglobulin, fibroblast, complement, and others. A convolutional neural network using H&E image patches as inputs was developed to predict the tertiary lymphoid structure scores from H&E-stained tissue image patches of renal cell carcinoma acquired by different patients. For the external validation, the model estimated the tertiary lymphoid structure scores from H&E-stained tissue image patches of renal cell carcinoma of The Cancer Genome Atlas (TCGA-RCC).
Results The tertiary lymphoid structure scores inferred by the model using H&E image patches were significantly correlated with those derived by spatial transcriptomics data as an internal validation (r = 0.68, p &lt; 1e-10). The mean value of the deep learning-based tertiary lymphoid structure scores estimated by the TCGA-RCC tissue images was significantly correlated with the tertiary lymphoid structure scores, T cell enrichment scores and immune cell enrichment scores estimated by bulk RNA-seq data from the corresponding TCGA data.
Conclusions A deep learning model to infer spatial tertiary lymphoid structure in the tumor microenvironment using H&E images was developed. As the tertiary lymphoid structure is a key to predict responsiveness of immune checkpoint inhibitors, mapping the score only using H&E images could be clinically translated into image-based biomarkers. This approach can provide objective and flexible deep learning-based models for characterizing tumor microenvironment related to spatial immune distribution.
Citation Format: Seungho Cook, Haenara Shin, Mi-Kyoung Seo, Dae Seung Lee, Hongyoon Choi. Deep learning-based mapping of tertiary lymphoid structure scores from H&E images of renal cell carcinoma trained by spatial transcriptomics data. [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 5420.
Abstract 544: Dissecting the functional impairment of wild-type Tp53 in human glioblastoma
Authors: García-Montaño Leopoldo A. , Muñoz Yamhilette Licón , Martinez Frank , Gallegos Kandee , Kang Huining , Piccirillo Sara G. 
Published: April 2023

Abstract
Glioblastoma (GBM) is the most common malignant brain tumor in adults and is characterized by heterogeneous nature, invasive potential, and poor treatment response. Work from The Cancer Genome Atlas (TCGA) has identified the tumor suppressor gene TP53 as one of the GBM drivers. However, in contrast to several cancers, only ~ 35% of GBM cases carry mutations in the TP53 gene. Furthermore, recent work from our lab showed that TP53 mutations emerge as ‘late’ events during GBM growth. This led us to hypothesize that wild-type (wt) Tp53 function is impaired in GBM. To test our hypothesis, we used clinical and molecular data of 591 GBM patients from TCGA and compared survival, age, gender, race, TP53 levels, and MGMT methylation status between wt and mutant patients. We also compiled a list of key players regulating Tp53 activity and used expression data to (i) compare the correlation of TP53 levels with the expression of each player and (ii) identify differentially expressed genes between our two groups. Our preliminary data suggest that wt TP53 patients live less in comparison to mutant patients and that both groups respond similarly to treatment, suggesting impairment of wt Tp53 function. We did not observe differences in age, sex, race, TP53 levels, or MGMT methylation status between the two groups. However, correlation analysis revealed that, among Tp53 activators, MAPK8 shows a strong negative correlation with TP53 expression in the wt group, raising the possibility that Tp53 function may be impaired. Furthermore, gene expression analysis of key Tp53 players showed that approximately 21% are differentially expressed between wt and mutant patients. Altogether, our results suggest that Tp53 function is impaired in wt patients and provide insights into the possible players affecting its activity. Our future work will focus on validating these results using GBM patient-derived cells and mouse models.
Citation Format: Leopoldo A. García-Montaño, Yamhilette Licón Muñoz, Frank Martinez, Kandee Gallegos, Huining Kang, Sara G. Piccirillo. Dissecting the functional impairment of wild-type Tp53 in human glioblastoma [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 544.
Abstract 5492: Determining effects of the CD206 positive M2 macrophage depleting engineered exosome in combination with anti PD1 therapy in breast tumor
Authors: Parvin Mahrima , Rashid Mohammad H. , Alptekin Ahmet , Arbab Ali S. 
Published: April 2023

Abstract
Introduction: Triple negative breast cancer (TNBC) subtype of breast cancer, which lacks molecular markers such as HER2 and estrogen/progesterone receptors, has limited treatment options. Exosomes are nano-sized (30-150 nm) spherical vesicles, derived from the endosomal system for intercellular communications, can be engineered to express targeting peptides to target specifically CD206 positive M2 macrophage. Investigators have used either synthetic nanoparticles or fusion protein to deliver Fc-IgG2b to initiate Antibody dependent cellular cytotoxicity (ADCC) but reports are showing a lack of ADCC following tagging with gold nanoparticles. To overcome this, in our lab, we developed engineered exosomes in non-tumorous cells, HEK293, to carry therapeutic Fc-mIgG2b to enhance ADCC and to carry peptide to deplete CD206+ M2 macrophages. We investigated the effectiveness of engineered therapeutic exosomes to target and deplete immunosuppressive CD206+ M2 macrophages in TNBC in combination with anti PD-1.
Methods: In this study, we developed syngeneic metastatic TBNC model (luciferase + 4T1 cells in Balb/c) by implantation of 50K 4T1-luci cells in fat pad. On day 1 of tumor implantation, animals were treated with vehicle, engineered exosomes, anti-PD1 plus engineered exosomes, 2 dose/week for 3 weeks. They were euthanized 1 day after the last dose of treatment. Single-cell suspension was made from the primary TME, lung, and spleen. Using flow cytometry surfaces markers were investigated to determine different T-cell and myeloid cell populations.
Results: We observed very surprising results following three weeks of therapies. Although the number of cytotoxic T-cells was significantly higher in the primary and metastatic TME in exosome-treated animals, there was also an increased number of proliferative T reg cells. The number of CD8+ cells was decreased following concurrent therapy with an anti-PD1 antibody. Most interestingly, lung tissue macrophages (CD11c) showed significantly increased PD-L1 expression following exosomes and anti PD1 with engineered exosomes therapies.
Conclusion: This study demonstrates that treatment with engineered therapeutic exosome targeting M2 macrophages with anti PD-1 could be utilized effectively. This study will also make a greater impact in exosome engineering based targeted therapy and will open new arena to target and deplete pathogenic cell in different tumors using engineered exosome.
Citation Format: Mahrima Parvin, Mohammad H. Rashid, Ahmet Alptekin, Ali S. Arbab. Determining effects of the CD206 positive M2 macrophage depleting engineered exosome in combination with anti PD1 therapy in breast tumor. [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 5492.
Abstract 5579: Single cell characterization of circulating plasma cells and BCMA levels in patients with multiple myeloma
Authors: Setayesh Sonia Maryam , Shishido Stephanie , Ndacayisaba Libere , Naghdloo Amin , Mason Jeremy , Tessone Dean , Kaleta Carli , Orlowski Robert Z. , Manasanch Elisabet E. , Hicks James , Kuhn Peter 
Published: April 2023

Abstract
Multiple myeloma (MM), a disease caused by the clonal proliferation of plasma cells (PCs), is the second leading hematologic malignancy in the world, with a global incidence rate increase of 126% and mortality rate increasing by 94% in the past decade. Recently, B cell maturation antigen (BCMA) has emerged as a promising biomarker and therapeutic target for MM due to its selective high expression on malignant PCs, improving the treatment landscape. However, the current diagnostic workup relies on bone marrow aspirates (BMA) which are highly invasive and do not allow for the detection of BCMA levels on circulating PCs, severely limiting the options for repeatable assessments and treatment-monitoring. In our study, we report the utility of a blood-based liquid biopsy, using enrichment-free high definition single cell assay (HDSCA) for the detection, quantification, and morphological characterization of circulating PCs and other BCMA+ cells. We applied a previously validated 4-color immunofluorescence assay using DAPI, CD138, BCMA, and CD45 to examine matched peripheral blood and BMAs from 68 patients across the MM disease spectrum (11 monoclonal gammopathy of undetermined significance [MGUS], 21 smoldering MM [SMM], 18 newly diagnosed MM, and 18 relapsed refractory MM [RRMM]) and peripheral blood from 23 normal donors as controls. Our analysis revealed diverse subtypes of circulating CD138(+/-), BCMA(+/-), and CD45(+/-) cells across the patients, representing both normal and abnormal PCs. We detected significantly higher circulating CD138+ BCMA(+/-) cells in MM precursor conditions (MGUS, SMM), compared to the normal donors. Additionally, we were able to detect BCMA+ oncosomes (identified by the lack of a nuclear structure) in the circulation of patients from both precursor and overt disease conditions. Our findings establish the utility of HDSCA blood-based liquid biopsy for early disease detection and anti-BCMA therapy response monitoring in MM and other B-cell malignancies expressing BCMA.
Citation Format: Sonia Maryam Setayesh, Stephanie Shishido, Libere Ndacayisaba, Amin Naghdloo, Jeremy Mason, Dean Tessone, Carli Kaleta, Robert Z. Orlowski, Elisabet E. Manasanch, James Hicks, Peter Kuhn. Single cell characterization of circulating plasma cells and BCMA levels in patients with multiple myeloma. [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 5579.
Abstract 558: EGFR inhibition in lung adenocarcinoma upregulates cell surface expression of the placental antigen ALPP and enhances efficacy of ALPP-ADC therapy
Authors: Chen Yihui , Hong Monica , Xu Hanwen , Vykoukal Jody , Park Soyoung , Cai Yining , León-Letelier Ricardo A. , Hsiao Fu Chung , Dennison jennifer B. , Ostrin Edwin J. , Fahrmann Johannes F. , Katayama Hiroyuki , Hanash Samir M. 
Published: April 2023

Abstract
Expression levels of placental alkaline phosphatase (ALPP) and ALPP-like 2 (ALPPL2) are relatively low in most cancer types, limiting potential benefits from ALPP or ALPPL2 targeting therapies. Enhancing their expression would be an attractive approach for targeted therapy. We have undertaken analysis of ALPP and ALPPL2 protein expression in whole cell extracts (WCE) and the surfaceome of 158 cancer cell lines and found ALPP, and to a less extent ALPPL2, to be expressed on the surface at relatively low levels across multiple cancer types. We explored various means to enhance ALPP expression in lung adenocarcinoma (LUAD) and found that induction of cancer cell quiescence via nutrient deprivation, or treatment with EGFR inhibitors, greatly enhanced ALPP surface expression. Mechanistic studies revealed that enhancement of surface ALPP expression in LUAD cells following gefitinib treatment was mediated through repression of MEK/ERK signaling and activation of the transcription factor FoxO3a, which was identified as an upstream transcriptional regulator of ALPP. Using xenograft models of LUAD, we further demonstrated that gefitinib treatment upregulates surface expression of ALPP in LUAD cells but not in normal tissues. Combination therapy with gefitinib and an ALPP antibody conjugated with Monomethylauristatin F resulted in enhanced tumor suppression compared with gefitinib alone. Our findings support a novel combination treatment modality that boosts the efficacy of ALPP-ADC directed therapy.
Citation Format: Yihui Chen, Monica Hong, Hanwen Xu, Jody Vykoukal, Soyoung Park, Yining Cai, Ricardo A. León-Letelier, Fu Chung Hsiao, jennifer B. Dennison, Edwin J. Ostrin, Johannes F. Fahrmann, Hiroyuki Katayama, Samir M. Hanash. EGFR inhibition in lung adenocarcinoma upregulates cell surface expression of the placental antigen ALPP and enhances efficacy of ALPP-ADC therapy [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 558.