bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4127: ANV600 is a potent, Cis-signaling, non-alpha IL-2 agonist which efficiently expands intratumoral stem-like CD8 T cells
Authors: Murer Patrizia , Salazar Ulisse , Egli Nicole , Petersen Laetitia , Neubert Pia , Richter Kirsten , Stocker Christian , Rau Alexander , Katopodis Andreas , Huber Christoph 
Published: April 2023

Abstract
Non-alpha IL-2-based therapeutic modalities with preferential signaling through the IL-2 beta(CD122)/gamma(CD132) receptor are in clinical development and have the potential to substantially increase the therapeutic index of recombinant IL-2 (aldesleukin) for cancer therapy. ANV600 is a novel bispecific compound, which features an anti-IL-2 antibody/IL-2 fusion protein and a proprietary hPD-1 binding moiety for specific delivery of the non-alpha IL-2 to tumor antigen experienced PD-1+ T cells. Compared to the untargeted control, ANV600 has increased potency to induce STAT5 phosphorylation in human PD-1+CD8 T cells in vitro. At the same time, stimulation with ANV600 results in markedly reduced STAT5 phosphorylation on Treg cells compared to aldesleukin. In activated human PBMCs, ANV600 induces PD-1 co-internalization with the CD122-CD132 complex, reducing detectable PD-1 on CD8 and CD4 T-cells. Surface PD-1 levels decrease is not observed on cells incubated with untargeted bispecific compound. In transgenic human PD-1 mice ANV600 treatment leads to marked tumor growth retardation in the B16F10 and MC38 subcutaneous tumor models compared to untargeted compound and vehicle. Immunophenotyping of the tumor infiltrating lymphocytes revealed a dose-dependent increase of intratumoral stem-like PD-1+T cells and cytotoxic GrzB+PD-1+T cells in mice treated with ANV600. ANV600 has potent and selective effects on antigen-experienced CD8 T cells both in human PBMCs and mouse syngeneic tumor models. This agent may be a promising anti-tumor therapeutic against poorly immunogenic tumors and warrants further pharmaceutical development.
Citation Format: Patrizia Murer, Ulisse Salazar, Nicole Egli, Laetitia Petersen, Pia Neubert, Kirsten Richter, Christian Stocker, Alexander Rau, Andreas Katopodis, Christoph Huber. ANV600 is a potent, Cis-signaling, non-alpha IL-2 agonist which efficiently expands intratumoral stem-like CD8 T cells. [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 4127.
Abstract 4144: Characterization of immune cell phenotypes in patient derived malignant pleural effusion treated with thiostrepton
Authors: Messier Terri , Guerra Roxana Del Rio , Naumov George , Cunniff Brian 
Published: April 2023

Abstract
Tumor cells generate elevated levels of reactive oxygen species (ROS) and therefore exhibit increased expression, activity, and reliance on critical ROS scavenging pathways, including the mitochondrial peroxiredoxin 3 (PRX3) system. PRX3 is a critical reactive oxygen species (ROS) scavenging enzyme localized to the mitochondrial matrix. Our group has characterized the mechanism of action of the PRX3 inhibitor and pro-oxidant therapeutic thiostrepton (TS). TS covalently crosslinks the peroxidatic and resolving cysteines of PRX3, leading to increased levels of mitochondrial ROS, resulting in tumor cell death. We have characterized the cellular and chemical composition of malignant pleural effusion (MPE) from patients with advanced cancer and evaluated cellular responses to TS. TS targets PRX3 in both adherent tumor cells and in non-adherent immune cell populations in a dose-dependent manner. We further characterized MPE-infiltrated immune cells and cytokines released following TS-treatment. Together, these data provide the first evidence for the activity of TS in MPE and resulting changes to immune cell profiles. TS is the active pharmaceutical ingredient of RSO-021, a new covalent inhibitor of PRX3 currently being tested in the MITOPE phase 1/2 clinical trial in patients with malignant pleural effusion (MPE) due to advanced solid tumors or malignant mesothelioma (NCT05278975).
Citation Format: Terri Messier, Roxana Del Rio Guerra, George Naumov, Brian Cunniff. Characterization of immune cell phenotypes in patient derived malignant pleural effusion treated with thiostrepton. [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 4144.
Abstract 4151: Anti-CEACAM5 immune stimulant TLR7/8 agonist antibody drug conjugate is a potent myeloid cell activator for the treatment of CEACAM5-expressing tumors
Authors: Decary Stephanie , Blot Lydia , Lahoute Charlotte , Benoist Sandrine , Caron Anne , Graziano Francesca , Trombe Marc , Calvet Loreley , Ferrier Alexandra , Frederic Marc , Sidhu Sukhvinder , Brun Marie-Priscille , Chiron Marielle 
Published: April 2023

Abstract
Toll Like Receptor 7 and 8 (TLR7/8) agonists are a promising approach to treat tumors by harnessing the innate immune system to trigger anti-tumor innate and adaptive immunity. One of the main obstacles to the use of this class of low molecular weight molecules in cancer treatment is the toxicity associated with systemic immune activation after intravenous administration. We developed a novel immune stimulant ADC by conjugating the anti-CEACAM5 (carcinoembryonic antigen related cell adhesion molecule 5) tusamitamab antibody with a resiquimod (R848) TLR7/8 agonist payload. This tumor-targeted compound administered systemically and locally active, is expected to eradicate CEACAM5-positive (+) tumors by recruiting and activating immune cells in tumor microenvironment to promote anti-tumor immune response. Tusamitamab R848 ADC, evaluated in vitro, binds to CEACAM5+ tumor cells via its Fab moiety, and to myeloid cells via its Fc part at nanomolar (nM) concentrations. TLR7/8 pathway activation was evaluated on myeloid THP1 reporter cells. The conjugate elicits a potent and FcyR-dependent activity at low nM concentration. In co-culture of human blood cells and human CEACAM5+ gastric cancer cells, it was shown to induce phagocytosis activity, associated with increased activation/maturation of both monocytes and dendritic cells. Tusamitamab R848 ADC evaluated in vivo in CEACAM5+ pancreatic human tumor model, HPAFII, leads to robust antitumor activity with complete regressions (CR) after single administration at 5 mg/kg. In a pharmacodynamic study using lung tumor patient-derived xenograft mouse model, this ADC triggers murine cytokine inductions, innate immune cell enrollment at tumor site, and tumor necrosis in a dose-dependent manner. Based on preclinical in vitro and in vivo data, the tusamitamab R848 ADC is an innovative ADC approach with the potential to eradicate CEACAM5+ tumors in patients.
Citation Format: Stephanie Decary, Lydia Blot, Charlotte Lahoute, Sandrine Benoist, Anne Caron, Francesca Graziano, Marc Trombe, Loreley Calvet, Alexandra Ferrier, Marc Frederic, Sukhvinder Sidhu, Marie-Priscille Brun, Marielle Chiron. Anti-CEACAM5 immune stimulant TLR7/8 agonist antibody drug conjugate is a potent myeloid cell activator for the treatment of CEACAM5-expressing tumors. [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 4151.
Abstract 423: β-Escin eradicates cancer stem-like population in HER2-positive breast cancer with trastuzumab resistance
Authors: Park Soeun , Park Minsu , Ko Dongmi , Kim Seongjae , Seo Juyeon , Nam Kee Dal , Jung Eunsun , Kang Yong koo , Jang Seojin , Seock So Ra , Kim Yoon-Jae , Kim Ji Young , Seo Jae Hong , Park Jaeyoun 
Published: April 2023

Abstract
Purpose: Trastuzumab resistance is a multifactorial phenomenon arising from the steric effects of p95HER2, activation of HER2 downstream signaling pathways, and the existence of cancer stem cells. We sought to examine the capacity of β-escin, an anti-inflammatory drug, to address trastuzumab resistance in HER2-positive breast cancer cells.
Experimental designs: The effects of β-escin in trastuzumab-sensitive and -resistant cell lines were evaluated for apoptosis, HER2 expression, calpain activation and CSC-like properties. In vivo trastuzumab-resistant xenograft mice model was used to examine tumor growth, angiogenesis and organ toxicity of β-escin.
Results: β-escin induced mitochondrial-mediated apoptosis accompanied by reactive oxygen species (ROS) production and increased active p18Bax fragmentation, leading to caspase-3/-7 activation. β-escin downregulated p95HER2, HER2 and HER3 as well as their phosphorylation. β-escin-induced HER2 degradation appears to be mediated by calpain activation. We observed that treatment with β-escin induced cleavage of HER2 and p95HER2 (at 75, 50 and 42 kDa fragments) in HER2 overexpressing MDA-MB-231 cells. Attenuation of CSC-related features by β-escin challenge was accompanied by marked reductions in CD44high/CD24low stem-like cells and aldehyde dehydrogenase 1 (ALDH1) activity as well as hindrance of mammosphere formation. β-escin administration also significantly retarded tumor growth and angiogenesis in a trastuzumab-resistant JIMT-1 xenograft model via downregulation of CSC-associated markers and intracellular domain HER2. Importantly, β-escin selectively inhibited malignant cells and was less toxic to normal mammary cells, and no toxic effects were found in liver and kidney function in animals.
Conclusion: Herein, for the first time, we report the potent efficacy of β-escin, a drug repurposing candidate with an exceptional safety profile in addressing trastuzumab-resistant HER2-positive breast cancer.
Citation Format: Soeun Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Eunsun Jung, Yong koo Kang, Seojin Jang, So Ra Seock, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo, Jaeyoun Park. β-Escin eradicates cancer stem-like population in HER2-positive breast cancer with trastuzumab resistance [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 423.
Abstract 4261: Genomic landscape of 2128 thyroid cancers from the aacr genie database: Implications for targeted therapies
Authors: Nelson Blessie Elizabeth , Gouda Mohammed , Roszik Jason , Hu Mimi L. , Cabanillas Maria , Subbiah Vivek 
Published: April 2023

Abstract
Background: Understanding molecular biology of thyroid cancer has revolutionized diagnosis, tumor classifications and identifying effective precision oncology therapies.
Methods: Using AACR GENIE database v.12, we cataloged genetic and co-occurring alterations in all thyroid cancers.
Results: We identified 2128 cases from 153,834 samples where tumor sub-histologies included Papillary Thyroid Cancer (PTC: 55%; 1162), Poorly Differentiated Thyroid Cancer (PDTC: 12%; 262); Medullary Thyroid Cancer (MTC: 12%; 244), Anaplastic Thyroid Cancer (ATC: 10%; 220); Follicular Thyroid Cancer (FTC: 5%; 111); Hurthle Cell Thyroid Cancer (HCTC: 5%; 95); and others (1; 34). Median age at sequencing was 59 years. Gender distribution was higher in female (54%; n=1104) compared to male (46%; n=933). Ethnicities included 73.2% (n=1,493) White, 8.9% (n=178) Asian, and others.Most frequent genomic mutational alterations overall were BRAF (40.8%; 868) [96% (n=845) V600E, 0.6% (n=5) G469A, 0.6% (n=5) V600_K601delinsE, 0.2% (n=2) K601E, 0.2% (n=2) A404Cfs*9, and 2.7% (n=24) others]; TERT (35%; 624); NRAS (11.6%; 247); TP53 (11.6%; 247) and RET (9.3%; 197) genes. There was variability in genomic alterations between sub-histologies (Table 1).
There was statistically significant co-occurrence between BRAF and TERT, TERT and TP53, TERT and NRAS alterations (p&lt;0.001). Mutually exclusive alterations were BRAF and NRAS, BRAF and RET, TERT and RET, NRAS and RET, TP53 and RET, and BRAF and TP53 (p&lt;0.001).Copy number alterations (CNA) were observed in 497 samples and were most frequent in CDKN2A, NKX2-1, CDKN2B, NF2, and CRKL genes (16.5%, 16%, 15.5%, 13.1%, and 13%). 362 oncogenic fusions were noted predominantly in CCDC6-RET, RET-NCOA4, ETV6-NTRK3, BRAF-Intragenic (20%, 7.2%, 3%, 1.6%).
Conclusion: Genomic profiling identified full breadth of BRAF, RET and NRAS alterations and co-occurring oncogenic driver alterations. This approach may refine use of targeted therapy in thyroid cancer.
Table 1. Histology Most frequent Alterations % n PTC BRAF 62.3% 724 TERT 32.7% 332 PDTC TERT 49% 117 NRAS 28.2% 74 MTC RET 71.3% 174 HRAS 7.8% 19 ATC TP53 58.2% 128 TERT 56.7% 106 FTC TERT 41% 27 NRAS 26.1% 29 HCTC TERT 41% 34 TP53 17.9% 17
Citation Format: Blessie Elizabeth Nelson, Mohammed Gouda, Jason Roszik, Mimi L. Hu, Maria Cabanillas, Vivek Subbiah. Genomic landscape of 2128 thyroid cancers from the aacr genie database: Implications for targeted therapies. [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 4261.
Abstract 4276: Recovering false negatives in CRISPR fitness screens with JLOE
Authors: Dede Merve , Hart Traver 
Published: April 2023

Abstract
It is widely accepted that pooled library CRISPR-Cas9 knockout screens offer greater sensitivity and specificity than prior technologies in detecting essential genes whose disruption leads to fitness defects, a critical step in identifying candidate cancer targets. However, the assumption that CRISPR screens are saturating has been largely untested and it is still poorly understood whether possible systematic biases in CRISPR screens affect our understanding of human cell-intrinsic gene essentiality. In the absence of a ground truth, the actual true positive, false positive and false negative rates of a typical genome-wide CRISPR-Cas9 knockout screen are still unknown.
Through integrated analysis of screen data in hundreds of cancer cell lines generated by the Cancer Dependency Map, we examine some of the biases characteristic of genome-wide CRISPR-Cas9 knockout screening. With our computational modeling approaches, we estimate the true positive rate, false positive rate and show that a typical CRISPR screen has a ~20% false negative rate, in addition to library-specific false negatives. Furthermore, replicability of essential gene hits falls sharply as gene expression decreases, while cancer subtype-specific genes within a tissue show distinct profiles compared to false negatives. With our cumulative analyses across tissues, we identified an improved new set of core essential genes, which, like the previous set, can be used as a metric for the quality control of genome-wide CRISPR-Cas9 knockout screens. Our results also suggest only a small number of lineage-specific essential genes, with the overwhelming majority of genes showing overlap between related tissues and are enriched for transcription factors that define pathways of tissue differentiation. To recover false negatives in these genome- wide CRISPR knockout screens, we introduce a method called Joint Log Odds of Essentiality (JLOE), which extends fundamental concepts from our Bayesian framework of BAGEL algorithm to improve analysis across multiple cell line screens. JLOE uses information derived from previous screens to update the probability of essentiality of each screen based on prior observations. We show that JLOE selectively rescues the false negatives without an increased false discovery rate and improves screen concordance with the Sanger dataset, reducing the number of background-specific essential genes. Overall, our methods offer a significantly improved analysis of genome-wide CRISPR-Cas9 knockout screens, detecting and correcting for the previously unidentified false negatives and enhancing our identification of cancer-specific vulnerabilities as therapeutic targets.
Citation Format: Merve Dede, Traver Hart. Recovering false negatives in CRISPR fitness screens with JLOE. [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 4276.
Abstract 43: Application of MiniPDX® in clinical indication identification and anti-tumor drug development
Authors: Long Yuan , Xie Bin , Chen Hongkui , Zhao Shizhu , Li Le , Xi Song , Wen Danyi 
Published: April 2023

Abstract
MiniPDX® represents a novel in vivo drug sensitivity test with fast turnaround (7-10 days), using either fresh patient tumor samples or tissues from established PDX models. We systematically evaluated and compared the response rates of MiniPDX® assays and PDX assays pair-wise in 26 PDX models across 3 types of cancers to 12 clinically relevant regimens for chemical and targeting drugs. The results showed a high correlation between drug responses of the two assays, with sensitivity and specificity of 80% and 93%, respectively. More studies of different tumor types showed that MiniPDX drug sensitivity test results were consistent with clinical responses in most patients, which indicated that MiniPDX® models have great potential in guiding personalized cancer therapy. LIDE has completed over 3,000 MiniPDX® tests for clinical precision medicine, covering more than 50 indications. MiniPDX® was used to rank clinically approved drugs or drug regimens to guide the selection of the best individualized treatment strategy. At the same time, screening other compounds facilitates selection of the best drug candidates for further R&D. Importantly, performing MiniPDX® Mouse Trial using fresh tumor samples generated from clinic is beneficial for determination of potential clinical indications. Only thousands of fresh cells leftover from MiniPDX® preparation are sufficient to get genomic and transcription data by OncoVee™ K-cell technology. The combination of MiniPDX® assay and omics data would be very useful for determination of potential bio-markers in order to distinguish responders and non-responders in population with certain indication(s) and leveraged for patient stratification and selection criteria in clinical trial design. Currently, we are developing a new version of MiniPDX® assay for immunotherapy (IO-FIVE, Immuno-Oncology Fast In Vivo Efficacy test) by using fresh patient cancer cells with autologous immune cells to maximally mimic human tumor microenvironment before seeding in immune-deficient mice. Total cell viability and cell phenotyping are tracked before and after drug treatment to evaluate its in vivo efficacy within two weeks. More than 60 samples have been tested and the IO-FIVE functional assay can effectively distinguish the non-responder from responders for immunotherapeutic drugs. Several Investigator Initiated Trials (II-T) are on-going to further validate the correlation of IO-FIVE result to clinic endpoint.
Citation Format: Yuan Long, Bin Xie, Hongkui Chen, Shizhu Zhao, Le Li, Song Xi, Danyi Wen. Application of MiniPDX® in clinical indication identification and anti-tumor drug development [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 43.
Abstract 4353: Utilizing scRNA sequencing to understand biomarkers of response and resistance to Sacitizumab Govetican in localized TNBC
Authors: Peiris Nicole , Cristea Simona , Zhang Mengran , Koh Siang , Coates James , Smidt Ilze , Bossuyt Veerle , Spring Laura , Bardia Aditya , Ellisen Leif 
Published: April 2023

Abstract
Triple-Negative Breast Cancer (TNBC) is an aggressive breast cancer subset, which lacks expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2. This subset of breast cancer disproportionately affects Black and African American women and improving TNBC treatment options is vital to reducing breast cancer mortality. The novel antibody-drug conjugate, Sacitizumab Govetican (SG), which targets TROP2 at the cell surface, has shown promising clinical results from the NeoSTAR trial (NCT04230109), a phase II study evaluating neoadjuvant SG therapy in a localized TNBC setting. As part of the NeoSTAR clinical trial, we have collected and processed pre- and post- SG treatment patient samples, with the aim of understanding response to this monotherapy. Herein, we identify biomarkers of response and resistance to SG monotherapy through the use of single cell RNA sequencing of matched pre- and post-treatment patient biopsies combined with exome sequencing these patient samples. Pre-treatment core needle biopsy samples, and if applicable, post-treatment residual disease biopsies were dissociated into single cell suspensions and subjected to single cell RNA sequencing. Additionally, fixed patient tissue samples were processed accordingly for exome sequencing analyses. Overall, we analyzed over 144,000 cells from 37 total scRNA seq libraries with an average of 3800 cells per biopsy sample, demonstrating the feasibility of this method. From these analyses, we observed several cell-type differences between patients who achieved a pathological complete response (pCR) and patients who had residual disease (RD). Specifically, our data shows that tumor infiltrating lymphocytes are a potential prognostic biomarker of response to SG. Furthermore, we detected alterations in among stromal and immune cell subsets, among non-responders, indicating that these cell types maybe indicative of SG resistance. Taken together, we outline biomarkers of response to SG treatment for an improved understanding of resistance mechanisms in the neoadjuvant setting to improve TNBC outcomes among patients.
Citation Format: Nicole Peiris, Simona Cristea, Mengran Zhang, Siang Koh, James Coates, Ilze Smidt, Veerle Bossuyt, Laura Spring, Aditya Bardia, Leif Ellisen. Utilizing scRNA sequencing to understand biomarkers of response and resistance to Sacitizumab Govetican in localized TNBC. [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 4353.