bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4106: Curating protein complexes from multiple resources and validate their co-regulations at RNA/protein level in pan-cancer
Authors: Song Yizhe , Zhou Daniel Cui , Li Yize , Wang Liang-Bo , Wendl Michael C. , Getz Gad , Ding Li 
Published: June 2022

Abstract
Protein complexes are sets of proteins that not only physically interact with each other, but also play important roles in progression of diseases like cancer. However, little is known about the co-regulation patterns of complexes and how many of them could be potential therapeutic targets. We collected 16,680 complexes from CORUM, Reactome, Complex Portal, and Havugimana PC. Harmonization of subunits of complexes by UniProt ID removed 4,112 redundant complexes. We further found that 3,018/12,559 complexes have at least one cancer driver gene involved, of which 2,408 complexes were found to have druggable genes, according to CiVic and OncoKB. Co-regulation patterns of 12,559 complexes were annotated utilizing gene expression and protein expression data from 1,101 cases across 10 cancer types (BR, COAD, OV, UCEC, HNSCC, PDAC, LSCC, LUAD, GBM, and ccRCC) from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Pairwise correlations across subunits of each complex at protein and RNA levels were calculated separately. Correlation &gt;0.8 would suggest strong interaction of the subunits of the complex. Protein-only co-regulation complex was declared for protein pairwise correlation &gt;0.8 and RNA pairwise correlation &lt;0.5. RNA-only co-regulation complex was defined vice versa. We found more protein-only co-regulation complexes than RNA-only co-regulation complexes. This validated that RNA expression doesn’t always correlate with protein expression and few complexes were co-regulated at both RNA and protein levels. Our study suggests the value of utilizing proteome data to understand the formation of complex and inner relationships between subunits of complexes.
Citation Format: Yizhe Song, Daniel Cui Zhou, Yize Li, Liang-Bo Wang, Michael C. Wendl, Gad Getz, Li Ding. Curating protein complexes from multiple resources and validate their co-regulations at RNA/protein level in pan-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 4106.
Abstract 4112: Patient derived organoids predict clinical response: A patient in the lab
Authors: Verissimo Carla S. , Smabers Lidwien , Wensink Emerens , Koedoot Esmee , Huismans Maarten , Barón Celia Higuera , Korporaal Ricardo , Teal Emma , Pitsa Katerina-Chara , van Oosten Edwin , Nair Roshni , Valkenburg Liselot , Cirkel Geert , Brousali Anneta , Salij Jorieke , Overmeer René , Braat Manon , Elias Sjoerd , Vries Robert , Kranenburg Onno , Koopman Miriam , Boj Sylvia F. , Roodhart Jeanine 
Published: June 2022

Abstract
Colorectal cancer (CRC) is the third leading cause of cancer and cancer-related death. A large fraction of the CRC patients diagnosed with de novo metastatic disease do not benefit from the standard of care but still experience substantial side effects. Therefore, there is the urgency for a new model to predict clinical response.
Adult epithelial stem cell (ASC) -derived organoids are proving to be a major breakthrough in pre-clinical models. ASC-derived organoids can be developed from healthy as well as diseased tissue, including cancer lesions and therefore are often referred to as patient-derived organoids (PDOs or HUB Organoids࣪). These model is established directly from patient tissue, represent the tissue of origin and faithfully recapitulate patient disease in vitro and can be propagated for drug testing in a matter of weeks. PDOs bridges the gap between the lab and the clinic and effectively bring a “patient in the lab.”
In this study we aimed to validate the predictive value of PDOs in the stratification of metastatic CRC (mCRC) patients for treatment with chemotherapeutic agents. PDOs from mCRC tissues were established following our optimized procedures and drug screening was performed. Clinical response was compared with PDO drug response and the best predicting drug response parameters (growth rate (GR), GRmax, GR50 and area under the curve) were identified. The patient response was evaluated by the percentage of change in size of the target lesions on response scans (% size change), best Response Evaluation Criteria in Solid Tumors (RECIST) response and progression-free survival (PFS). Importantly, we validated the predictive value of organoids towards fluorouracil (5-FU). We are validating these results in a large trial.
Current efforts to further expand our PDO and drug sensitivity biobank will enable the implementation of the personalized HUB Organoid Technology to accurate and fast predict of the treatment response to improve clinical outcome of mCRC patients.
Citation Format: Carla S. Verissimo, Lidwien Smabers, Emerens Wensink, Esmee Koedoot, Maarten Huismans, Celia Higuera Barón, Ricardo Korporaal, Emma Teal, Katerina-Chara Pitsa, Edwin van Oosten, Roshni Nair, Liselot Valkenburg, Geert Cirkel, Anneta Brousali, Jorieke Salij, René Overmeer, Manon Braat, Sjoerd Elias, Robert Vries, Onno Kranenburg, Miriam Koopman, Sylvia F. Boj, Jeanine Roodhart. Patient derived organoids predict clinical response: A patient in the lab [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 4112.
Abstract 4123: Real-world data to identify the genomic association with response to CDK4/6i + Endocrine therapy in ER+ breast cancer patients
Authors: Yu Kun , Chen Tenghui , Korpal Manav , Zhu Ping , Zhang Zhaojie , Yu Lihua , Xiao Yonghong 
Published: June 2022

Abstract
Background Real-world data (RWD) has been increasingly used for drug development. RWD coupled with genomic data provides an opportunity to identify the association between certain genomic alterations and response to current standard of care (SOC). Such analyses may help identify predictive biomarkers to select patients who will benefit most from SOC, and/or potential therapeutic nodes that can be pharmacologically targeted to overcome resistance to SOC.
Methods We obtained Flatiron CGDB Breast Cancer (as of Q3 2020 release) data set. This data set includes clinical and genomic data from 6,918 breast cancer patients. Time to treatment discontinuation (TTD) was used as real world outcome. We performed two types of genomic-outcome association analysis: 1) Use Cox proportional hazards regression model to identify which baseline mutation (mutation occurred prior to the treatment) could predict the outcome; and 2) use Fisher exact test to identify which mutations are enriched in post-treatment tumors samples, compared to pre-treatment tumor samples.
Result We found TP53 mutation is associated with shorter TTD for Palbociclib + Aromatase inhibitor (AI); Palbociclib + Fulvestrant; and endocrine monotherapy. It is consistent with the reports that TP53 mutation is poor prognostic factor (ref). Interestingly, ESR1 mutation is associated with shorter TTD for Palbociclib + AI and AI monotherapy; but not associated with TTD for Palbociclib + Fulvestrant or Fulvestrant monotherapy. On the other hand, MYC amplification is associated shorter TTD for Palbociclib + Fulvestrant or Fulvestrant monotherapy. We found that genes associated with Palbociclib + Endocrine are by and large same as those associated with endocrine monotherapy; suggesting the association is largely driven by endocrine treatment. Comparison of post-treatment vs. pre-treatment analysis found that ESR1 mutation is enriched in post treatment of AI; but not Fulvestrant.
Conclusion We demonstrated that real-world clinicogenomic data could identify the biologically meaningful genomic biomarkers that are associated with real world response. This study warrants the further investigation of novel genomic biomarkers identified from the analysis.
Citation Format: Kun Yu, Tenghui Chen, Manav Korpal, Ping Zhu, Zhaojie Zhang, Lihua Yu, Yonghong Xiao. Real-world data to identify the genomic association with response to CDK4/6i + Endocrine therapy in ER+ breast cancer patients [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 4123.
Abstract 4144: An AI-based, automated workflow for identification and scoring of invasive tumors in Ki-67 stained breast cancer specimens
Authors: Patel Bhavika , Allen Stephanie , Talwalkar Sameer , Mehra Navi , Thagaard Jeppe , Ramsing Thomas W. , Overgaard Agnete , Caldara Jenifer 
Published: June 2022

Abstract
Understanding the rate of tumor cell growth in breast cancer specimens may be indicative of disease aggressiveness, a tumor characteristic which can be used to make an informed treatment decision. The nuclear protein Ki-67 is increased in cells as they prepare to divide or proliferate and is therefore widely used as a proliferation marker for tumor progression. This degree of tumor cell proliferation, or the proliferative index, is commonly detailed in pathology reports shared with the patient care team. In this study, we utilized the Ki-67 [K2] immunohistochemistry (IHC) assay to stain 10 breast cancer specimens. Stained slides were imaged using the AT2 scanner (Leica Biosystems, Buffalo Grove, IL) and analyzed using the Visiopharm Image Analysis platform. Previous efforts to assess Ki-67 positivity utilizing image analysis have relied on the use of a secondary stain or manual effort by the pathologist to exclude non-invasive tumor regions. These antiquated methods are costly to the lab as they require additional materials or valuable pathologist time. Our novel image analysis approach utilizes artificial intelligence (AI) to automatically denote non-invasive verses invasive tumor regions, which can then be used to quantify the Ki-67 proliferative index. This valuable tool will allow for greater accuracy, cost-savings, and time efficiency when analyzing breast cancer samples compared to traditional methods.
Citation Format: Bhavika Patel, Stephanie Allen, Sameer Talwalkar, Navi Mehra, Jeppe Thagaard, Thomas W. Ramsing, Agnete Overgaard, Jenifer Caldara. An AI-based, automated workflow for identification and scoring of invasive tumors in Ki-67 stained breast cancer specimens [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 4144.
Abstract 4148: Non-redundant upregulation of CD112R (PVRIG) and PD-1 on cytotoxic T-lymphocytes located in T-cell-nests of colorectal cancer
Authors: Lennartz Maximilian , Yang Cheng , Mandelkow Tim , Bady Elena , Simon Ronald , Hube-Magg Claudia , Sauter Guido , Blessin Niclas C. 
Published: June 2022

Abstract
Focal T-lymphocyte aggregates occur commonly in colorectal cancer, but their biological significance is unknown. To study focal aggregates of T-lymphocytes, a deep learning-based framework for automated identification of T-cell accumulations (T-cell-nests) was developed using CD8, PD-1, CD112R, and Ki67 multiplex fluorescence immunohistochemistry. To evaluate the clinical significance of these parameters, a cohort of 523 colorectal cancers with clinical-follow up data was analyzed. The spatial analysis of locally enriched CD8+ T-cell densities and cell-to-cell contacts identified T-cell-nests in the tumor microenvironment of colorectal cancer. CD112R and PD-1 expression on CD8+ T-cells located in T-cell-nests was found elevated as compared to CD8+ T-cells in all other tumor compartments (p&lt;0.001 each). Although the highest mean CD112R expression on CD8+ T-cells was observed at the invasive margin, the PD-1 expression on CD8+ T-cells was elevated in the center of the tumor (p&lt;0.001 each). Across all tissue compartments, proliferating CD8+ T-cells showed higher relative CD112R and PD-1 expression compared to non-proliferating CD8+ T-cells (p&lt;0.001 each). Integration of all available spatial and immune checkpoint expression parameters (AUC: 0.65) revealed a superior predictive performance for overall survival compared to the commonly used CD8+ TILs density (AUC 0.57, p&lt;0.001). Cytotoxic T-cells with elevated CD112R and PD-1 expression levels are orchestrated in T-cells-nests of colorectal cancer, predict favorable patient’s outcome and the spatial non-redundancy underlies fundamental differences of both inhibitory immune checkpoints that provide a rationale for dual anti-CD112R/PD-1 immune checkpoint therapy.
Citation Format: Maximilian Lennartz, Cheng Yang, Tim Mandelkow, Elena Bady, Ronald Simon, Claudia Hube-Magg, Guido Sauter, Niclas C. Blessin. Non-redundant upregulation of CD112R (PVRIG) and PD-1 on cytotoxic T-lymphocytes located in T-cell-nests of colorectal 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 4148.
Abstract 415: The characterization of in vitro models demonstrating a significant delay of acquired resistance to ulixertinib (ERK1/2)
Authors: Knoerzer Deborah , Reddy Anupama , Sorrell David , Emery Caroline M. 
Published: June 2022

Abstract
Ulixertinib (BVD-523) is a first-in-class small molecule inhibitor of ERK1/2 currently being investigated in several oncology clinical trials, both as a single agent and in combination with other anti-cancer therapeutics. Clinical acquired resistance has been described by others for numerous efficacious small molecule agents. Relevant to the MAPK pathway, emergence of resistance to BRAF and MEK inhibitors limits their clinical efficacy.
In vitro models of ulixertinib resistance were generated in an endeavor to characterize and predict potential clinical mechanisms of resistance and guide rational combination therapies. The BRAF-V600E mutant melanoma cell line, A375, was cultured in progressively increasing concentrations of ulixertinib or other MAPK pathway inhibitors (dabrafenib and/or trametinib). Drug-resistant A375 clones were readily obtained following growth in high concentrations of dabrafenib or trametinib. In contrast, developing resistance to ulixertinib proved challenging. Eventually, ulixertinib resistant clones emerged and demonstrated varying degrees of cross-resistance to other MAPK pathway inhibitors and displayed bell-shaped dose-response curves indicative of drug addiction for optimal proliferation. To elucidate potential mechanisms of resistance, Reverse Phase Protein Array profiling of 306 proteins was performed on parental A375 and ulixertinib-resistant clones following treatment with ulixertinib at varying concentrations and treatment times. Principal component analysis revealed clustering of resistant clones by ulixertinib treatment conditions (concentrations and duration). Differences between parental A375 and ulixertinib resistant clones were revealed, including components of MAPK, HER2, and autophagy markers.
This work begins to tease out potential mechanisms of resistance to ulixertinib and guide potential combination partners that could circumvent acquired resistance.
Citation Format: Deborah Knoerzer, Anupama Reddy, David Sorrell, Caroline M. Emery. The characterization of in vitro models demonstrating a significant delay of acquired resistance to ulixertinib (ERK1/2) [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 415.
Abstract 4153: First-in-class inhibitors of ERAP1 alter the HLA-I-restricted cancer immunopeptidome leading to the generation of novel peptides presented for immune recognition
Authors: Paes Wayne , Leishman Andrew , Anderton Kate , Liao Hanqing , Woodhouse Isaac , Parker Robert , Nicastri Annalisa , Joyce Peter , Ternette Nicola 
Published: June 2022

Abstract
The antigen processing machinery of a cell shapes the repertoire of peptides presented for immune recognition on the cell surface. Human leukocyte antigen class I (HLA-I) molecules present peptides that are recognised by both CD8+ T cells and NK cells, and these complexes play a vital role in the recognition and eradication of malignant cells. During direct presentation, the endoplasmic reticulum aminopeptidase 1 (ERAP1) enzyme processes a subset of HLA-I ligand precursors which are translocated into the endoplasmic reticulum (ER) following intracellular proteasomal degradation. Here, we show that inhibition of ERAP1 with highly potent and selective small molecule inhibitors drives significant qualitative and quantitative changes in the HLA-I-restricted immunopeptidome, resulting in the generation of altered and novel peptides from tumour-associated antigens that are then presented on HLA-I molecules. A major consequence of inhibiting the processing of precursor ligands by ERAP1 within the ER of cancer cells was not only the generation of unique peptides which were not detectable under baseline conditions, but a shift in the peptide length distribution towards longer HLA-I-restricted peptides. Importantly, we demonstrate that the degree of bias towards longer HLA-I-bound ligands uniquely presented following ERAP1 inhibition was governed by both ERAP1 and HLA-I haplotypes. Such dramatic changes in the peptide repertoire presented for immune recognition have the potential to enhance anti-tumoural immunogenicity through T cell recognition of a novel cancer immunopeptidome, and, in addition to global shifts in the peptide length distributions, unique peptides presented for immune recognition during ERAP1 inhibition may be used as biomarkers for monitoring activity of this novel therapeutic approach in the clinic.
Citation Format: Wayne Paes, Andrew Leishman, Kate Anderton, Hanqing Liao, Isaac Woodhouse, Robert Parker, Annalisa Nicastri, Peter Joyce, Nicola Ternette. First-in-class inhibitors of ERAP1 alter the HLA-I-restricted cancer immunopeptidome leading to the generation of novel peptides presented for immune recognition [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 4153.
Abstract 416: A novel non-covalent and rapidly reversible proteasome inhibitor for multiple myeloma and various solid cancers
Authors: Ahn Won-Gyun , Jeon Yeejin , Yang Yeong-In , Kim Jaeseung , Lee Seung-Joo , Koch Uwe , Zischinsky Gunther , Choidas Axel , Pasha Ayesha , Klebl Bert , Huber Robert , Hamacher Michael , Nam Kiyean 
Published: June 2022

Abstract
The existing proteasome inhibitors, such as bortezomib and ixazomib, are effective in multiple myeloma, but have little activity against solid tumors. These are covalent boronic acid-based compounds and are associated with undesired side effects, mainly hematologic toxicity and peripheral neuropathy. A variety of improved covalent proteasome inhibitors have been developed, but lack of oral availability and low distribution in tumors make them ineffective in solid tumors. In addition, they still have a narrow therapeutic window due to unexpected adverse effects such as cardiac and pulmonary toxicity. We report a non-covalent and rapidly reversible proteasome inhibitor as a potential anti-cancer agent against solid tumors as well as multiple myeloma. These novel inhibitors, called QL compounds, are non-covalent chymotrypsin-like selective proteasome inhibitors that can be taken orally. They effectively inhibited tumor growth in multiple myeloma xenograft model without hematologic toxicity through improved PK properties, especially partition of compound between plasma and RBC. Moreover, this improved PK properties of the QL compounds allowed for sufficient distribution outside the blood compartment and induced tumor growth inhibition in some types of solid cancer xenograft models that were sensitive to proteasome inhibition. These results indicate that non-covalent and rapidly reversible proteasome inhibitors are an ideal strategy for multiple myeloma and potential agents for solid tumors.
Citation Format: Won-Gyun Ahn, Yeejin Jeon, Yeong-In Yang, Jaeseung Kim, Seung-Joo Lee, Uwe Koch, Gunther Zischinsky, Axel Choidas, Ayesha Pasha, Bert Klebl, Robert Huber, Michael Hamacher, Kiyean Nam. A novel non-covalent and rapidly reversible proteasome inhibitor for multiple myeloma and various solid cancers [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 416.
Abstract 4161: An in vivo screen to identify short peptide mimotopes with enhanced anti-tumor immunogenicity
Authors: He Xuedan 
Published: June 2022

Abstract
Tumor-associated self-antigens are cancer vaccines targets but suffer from limited immunogenicity. There have been examples of mutated, short self-peptides inducing epitope-specific CD8+ T cells more efficiently than the wild-type epitope, but current approaches cannot yet reliably generate such enhanced mimotopes (“e-mimotopes”). Here, we present a generalized strategy to develop e-mimotopes, using the tyrosinase-related protein 2 peptide Trp2180-188, a major histocompatibility complex (MHC)-I epitope, as a test case. Using a vaccine adjuvant that induces peptide particle formation and strong cellular responses with nanogram antigen doses, a two-step method systematically identified e-mimotope candidates with murine immunization. First, position-scanning peptide micro libraries were generated in which each position of the wild-type epitope sequence was randomized. Randomization of only one specific residue of the Trp2 epitope increased anti-tumor immunogenicity. Second, all 20 amino acids were individually substituted and tested at that position, enabling the identification of two e-mimotopes with single amino acid mutations. Despite similar MHC-I affinity compared to the wild-type epitope, e-mimotope immunization elicited improved Trp2-specific cytotoxic T cell phenotypes and improved T cell receptor affinity for both the e-mimotopes and the native epitope, resulting in better outcomes in multiple prophylactic and therapeutic tumor models. The screening method was also applied to other targets with different murine MHC-I restriction elements, including the gp70 AH1 epitope, to identify additional e-mimotopes with enhanced potency.
Citation Format: Xuedan He. An in vivo screen to identify short peptide mimotopes with enhanced anti-tumor immunogenicity [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 4161.