bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1679: Single-cell profiling reveals a conserved myogenic hierarchy in pediatric rhabdomyosarcomas amenable to differentiation therapy
Authors: Danielli Sara G. , Porpiglia Ermelinda , De Micheli Andrea J. , Bechtold Ingrid , Marques Joana G. , Kasper Stephanie , Blau Helen M. , Wachtel Marco , Schäfer Beat W. 
Published: June 2022

Abstract
Rhabdomyosarcoma (RMS) is a highly aggressive pediatric soft tissue cancer, associated with the skeletal muscle lineage. Despite undoubted expression of key myogenic regulatory factors, RMS cells are blocked in a proliferative state and do not complete terminal differentiation. The extent to which the skeletal muscle lineage is represented in RMS tumors, as well as the mechanisms leading to developmental arrest, remain elusive. We therefore aimed to identify RMS subpopulations, understand why RMS cells are stalled in their differentiation path, and determine mechanisms to pharmacologically restore myogenic differentiation. Using single-cell RNA sequencing and mass cytometry analysis, we profiled cells from 14 PDX-derived primary cultures and three cell lines of alveolar (aRMS) and embryonal RMS (eRMS) subtypes. We discovered that both RMS subtypes contain different cell subpopulations distributed along the myogenic lineage. aRMS tumors recapitulate a yet unrecognized branched myogenic trajectory, where progenitor cells either commit to differentiation or give rise to actively cycling myoblasts. Following in vitro exposure to chemotherapy, aRMS cells show compositional shifts towards undifferentiated states, consistent with a model where treatment rewires cellular trajectories. To quantify aRMS cellular states, we developed an automated image-based single-cell approach and applied it to identify pro-differentiating agents among a library of &gt;240 FDA-approved drugs. We identified the RAS pathway as an important mediator of myogenic differentiation in several aRMS cultures, demonstrating the potential for differentiation therapy. Current studies are ongoing to validate these results in vivo and to uncover drug combinations that completely overcome the differentiation block. Taken together, this study reveals possible cellular origins for RMS and identifies a potential novel treatment strategy for aRMS that targets cellular differentiation.
Citation Format: Sara G. Danielli, Ermelinda Porpiglia, Andrea J. De Micheli, Ingrid Bechtold, Joana G. Marques, Stephanie Kasper, Helen M. Blau, Marco Wachtel, Beat W. Schäfer. Single-cell profiling reveals a conserved myogenic hierarchy in pediatric rhabdomyosarcomas amenable to differentiation therapy [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 1679.
Abstract 1687: Cyto R1 Platform enriches samples’ viability for single-cell sequencing and downstream assays
Authors: Hyler Alexandra R. , Cole Alicia M. , Barua Ridi , Dzutsev Amiran K. , Schmelz Eva M. 
Published: June 2022

Abstract
Single-cell level investigations such as DNA and RNA sequencing, protein analyses, and phenotypic studies require an input sample with a high rate of viability (&gt;90%). If too many dead cells are present in the input, degraded proteins and ambient DNA or RNA can increase background noise that may lead to missing identification of crucial targets. Since the cost for single-cell sequencing experiments still remains high, it is critical to ensure the input sample is optimized for high viability to ensure cost-effective and reproducible data. Current bead assays or other sample viability enrichment techniques used in preparation for single-cell analyses typically result in a significant sample loss, sometimes sacrificing 80% of the starting sample, and these preparation steps require multiple passes (&gt; 45 minutes time) and costly kits. These beads or kits can be biased and change the cell population, subject cells to unwanted stresses, and diminish sample integrity with the time needed for preparations. Here, we investigate sample cell viability enrichment on the Cyto R1 Platform, a label-free, cell enrichment, sorting, and recovery platform. At the core, the Cyto R1 uses Cyto Chips, microfluidic technologies with electrical fields, to phenotypically enrich and sort various cells based upon cells’ unique physical structures and subcellular features. Thus, the Cyto R1 ensures native cell recovery without any unwanted cell tagging to maximize sample integrity. In this work, a variety of single cell solutions derived from T cell lymphoma tumors, ascites fluid, and organ tissues were enriched for viable cells to obtain a final sample viability over 90%. Additionally, we aimed to achieve a minimum of 50,000 viable cells, a common target for single-cell sequencing, in as rapid a timeframe as possible. In one sample origin tested, murine T cell lymphomas, the average starting viability was 65 ± 6.5%, and the final viability after enrichment on the Cyto R1 Platform was 95.8 ± 1.8%. Similarly, murine ascites cell mixtures were enriched from average viabilities below 55% up to 91.6 ± 4.2%. For all samples tested, &gt;50,000 viable cells were obtained in under 30 minutes. This work demonstrates that the Cyto R1 can effectively and efficiently enrich a variety of starting samples for high viability (&gt;90%) as required for downstream assays and single-cell sequencing.
Citation Format: Alexandra R. Hyler, Alicia M. Cole, Ridi Barua, Amiran K. Dzutsev, Eva M. Schmelz. Cyto R1 Platform enriches samples’ viability for single-cell sequencing and downstream assays [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 1687.
Abstract 1710: Spatial transcriptomics and multiplexed imaging to explore tumor heterogeneity and immune complexity
Authors: Chen Siqi , Shinkle Andrew , Zhao Yanyan , Mo Chia-Kuei , Houston Andrew , Lal Preet , Herndon John M. , Fields Ryan C. , Gillanders William , Chen Feng , Ding Li 
Published: June 2022

Abstract
Spatial transcriptomics (ST) and CO-Detection by indEXing (CODEX) are becoming the leading transformative approaches for studying spatially resolved tumor heterogeneity and immune complexity. To explore the application of these two cutting-edge technologies and to further investigate the complexities of tumor microenvironment, we applied 10x Visium Gene Expression platform and Akoya CODEX platform on surgical resections from pancreatic ductal adenocarcinoma (PDAC), breast cancer (BRCA), and clear cell renal carcinoma (ccRCC) patients. A total of 30+ protein markers were screened, verified, and conjugated as CODEX antibodies for the 3 types of cancers. Tumor microenvironment was vividly revealed by a set of cancer markers, immune markers, and stroma cells markers on a single ST slide and a single CODEX image. Notably, the distinct immune microenvironment was observed between tumor nests in the neighborhood in terms of cell types, number of cells, and cell distribution patterns. This work highlights the importance of direct visualization for tumor heterogeneity. It also provides a significant insight for understanding tumor complexity and a promising opportunity to benefit personalized medicine.
Citation Format: Siqi Chen, Andrew Shinkle, Yanyan Zhao, Chia-Kuei Mo, Andrew Houston, Preet Lal, John M. Herndon, Ryan C. Fields, William Gillanders, Feng Chen, Li Ding. Spatial transcriptomics and multiplexed imaging to explore tumor heterogeneity and immune complexity [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 1710.
Abstract 1713: Delineation of cell subpopulations and cell cell interactions to determine correlations between drug response and tumor microenvironment in early-stage lung cancer
Authors: Ramos Corinne , Sophie Journe Anne , Gerstenberg Amandine , Pamelard Fabien , Stauber Jonathan 
Published: June 2022

Abstract
Purpose The tumor microenvironment (TME) is an integral player in cancer initiation, tumor progression, response and resistance to anti-cancer therapy. Understanding the complex interactions of tumor immune architecture has therefore become increasingly desirable to guide patient selection. Conventional studies that underestimate the potential value of the spatial architecture of the TME are unable to completely elucidate its complexity. To overcome these limitations, we used quantitative image analysis based on multiplexed immunohistochemistry and deep learning technologies to interrogate complex information from the tumor microenvironment and find predictive insights into treatment response for non-small cell lung cancer (NSCLC).
Method We used tumor tissues samples from resected NSCLC (adenocarcinoma and squamous cell carcinoma) tumors treated with adjuvant pembrolizumab therapy. Patient frozen tissue sections were prepared and stained using a panel of 20 immune or tumor-related antibodies. Different metal tags were assigned to each antibody. The stained cells were then detected and analyzed by the Hyperion™ Imaging System. Further data analysis was performed using proprietary workflow to identify which cells are influencing the treatment response and how they are spatially distributed relative to each other.
Results Tumor samples of NSCLC with similar clinical characteristics at the T1N0M0 had different cells types, including CD4+ T cells, CD8+ T cells, CD20+ B cells, CD14+ macrophages, CD56+ natural killer cells, granulocytes, etc. More immunosuppressive cells were found in the sample of patient that did not respond to immunotherapy illustrating that differences in the tumor microenvironment of samples may contribute to different patients’ resistance to immunotherapy. Moreover, unsupervised clustering analysis reveal cell type signatures that are relevant to the prognoses of NSCLC.
Conclusion High-multiplexed proteomics analyses using the Hyperion imaging system help identify and analyze the tumor microenvironment heterogeneity of NSCLC and explain the factors leading to different prognoses for NSCLC patients despite the same TNM stage. Furthermore, additional information for screening drugs for targeted therapy was found, that could greatly improve NSCLC treatments’ individualization.
Citation Format: Corinne Ramos, Journe Anne Sophie, Amandine Gerstenberg, Fabien Pamelard, Jonathan Stauber. Delineation of cell subpopulations and cell cell interactions to determine correlations between drug response and tumor microenvironment in early-stage lung 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 1713.
Abstract 172: Limiting medulloblastoma progression by hindering the Hedgehog signaling pathway with novel atypical protein kinase C inhibitors
Authors: Lajmi Luke , Breedy Sloan , Ratnayake Wishrawana S. , Acevedo-Duncan Mildred 
Published: June 2022

Abstract
Medulloblastoma is the most common pediatric brain tumor, constituting 20% of all childhood brain cancers (Clin. Cancer Res. 2008, 14 (4), 971-976., Oncogenesis 2019, 8 (11), 1-11). It is a highly invasive tumor that originates in the cerebellum and has the ability to metastasize throughout the central nervous system early in its course. The median age of diagnosis is 5 years, with 80% of cases being diagnosed in the first 15 years (Asian J. Neurosurg. 2015, 10 (1), 1-4). Current treatment options include maximal safe resection, chemotherapy and craniospinal radiation (J. Neurosurg. Pediatr. 2019, 24(4), 353-363). Despite such aggressive therapeutic treatments, nearly 30% of afflicted patients succumb to this disease, and survivors cope with the long-term side effects of these treatments that have significant impacts on their quality of life (J. Neurosurg. Pediatr. 2019, 24(4), 353-363). This underscores the need for less invasive and more effective treatment methods to improve overall patient outcomes. We believe that oncogene expression resulting from the Hedgehog (Hh) signaling pathway is responsible for upregulating malignant cancer cell growth, cell survival, and migration. Preliminary dose curve studies, in which D341 and D283 medulloblastoma cell lines were treated with novel atypical protein kinase C (aPKC) inhibitors 2-acetyl-1,3-cyclopentanedione (ACPD) and 3,4-diaminonapthalene-2,7-disulfonic acid (DNDA) (Int. J. Oncol. 2017, 51(5), 1370-1382), have been shown to significantly decrease cell proliferation with increasing inhibitor concentration. Cell line D341 showed 44.2% inhibition when treated with 10 µM of ACPD and 75.2% inhibition when treated with 1 µM of DNDA while cell line D283 showed a 63.2% inhibition at 5 µM of ACPD and 73.6% inhibition at 10 µM. Future studies will be conducted to determine the inhibition mechanism of the Hh pathway in medulloblastoma by probing for different cell cycle and oncoprotein markers using Western blotting, employing the WST-1 assay to evaluate cell viability and cytotoxicity, and implementing migration and invasion assays.
Citation Format: Luke Lajmi, Sloan Breedy, Wishrawana S. Ratnayake, Mildred Acevedo-Duncan. Limiting medulloblastoma progression by hindering the Hedgehog signaling pathway with novel atypical protein kinase C inhibitors [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 172.
Abstract 1738: DNA-launched nanoparticle vaccines induce cytolytic T cell responses for in vivo tumor control
Authors: Liaw Kevin , Xu Ziyang , Chokkalingam Neethu , Kulp Daniel , Weiner David 
Published: June 2022

Abstract
Nanotechnology-based approaches have achieved promising results for the development of novel immunotherapeutic cancer vaccines through the decoration of antigens on nanoparticle scaffolds for multivalent display. However, their translation have been limited due to challenges with purification, scalability, and robust induction of cytolytic T cell responses critical to anti-tumor activity. We designed a nanovaccine construct by fusing the HPV E7 immunodominant epitope onto lumazine synthase scaffold. We demonstrate that through electroporation-facilitated DNA delivery encoding the antigen-scaffold construct, this nanovaccine is expressed and self-assembles in vivo into 60-mer nanoparticles. Compared to CpG-adjuvanted peptide and monomeric DNA vaccination, this DNA-launched nanovaccine induced greater CD8+ cellular responses against the E7 epitope and target tumor cells. In both flank and lung models of TC-1 HPV-associated cancers, the nanovaccine achieved significant tumor regression and prolonged survival compared to CpG-adjuvanted peptide. Anti-tumor immunity was retained upon rechallenge &gt;150 days after initial challenge, supporting the induction of long-term immune memory. In addition, we demonstrate that this DNA-launched nanovaccine platform can be used to form hybrid nanoparticles displaying multiple antigens simultaneously. These hybrid nanoparticles exhibit synergistic efficacy, with improved tumor control over administration of separate single-antigen nanovaccines. These promising results, along with facile characterization, scalability, and stability, support that DNA-launched nanovaccines can induce potent anti-tumor cellular immunity and are ideally positioned for further translational development for clinical evaluation.
Citation Format: Kevin Liaw, Ziyang Xu, Neethu Chokkalingam, Daniel Kulp, David Weiner. DNA-launched nanoparticle vaccines induce cytolytic T cell responses for in vivo tumor control [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 1738.
Abstract 1760: The antibody-drug conjugate GENA-111 conjugated to auristatin F shows therapeutic potency in BCAM positive epithelial cancer
Authors: Yu Hyunkyung , Bellocq Nathalie , Ha Youngeun , Kim Hyunuk , Kim Yunyeon , Jeon Bu-Nam , Marx Léo , Pantin Mathilde , Yoo Hyunjin , Byun Seungmin , Chung Joo-Yeon , Cha Mi Young , Garrouste Patrick , Lévy Frédéric 
Published: June 2022

Abstract
Antibody-drug conjugates (ADCs) are considered as promising cancer treatment modalities that combine the selectivity of antibodies and the cytotoxic properties of payloads using chemical linkers. However, despite their success, ADCs still suffer from drawbacks, e.g., systemic toxicity, which limit their potential clinical applications. The systemic toxicity of an ADC is mainly related to the stability of its linker, and to the selectivity of its antibody towards the targeted antigen expressed on cancer cells. Lu/BCAM (Lutheran/basal cell adhesion molecule) is a member of the immunoglobulin superfamily and is a receptor for laminin, a protein that facilitates cell adhesion, migration, and invasion. A growing number of studies show that BCAM plays an essential role in tumor progression and is overexpressed on epithelial cancers e.g., skin cancer. Here we describe GENA-111, a human monoclonal anti-BCAM IgG4 (S228P) antibody that binds to human BCAM with high affinity, and that is significantly internalized by BCAM-positive tumor cells. We also describe the GENA-111-auristatin F ADC, wherein the GENA-111 antibody has been armed with an auristatin F derivative using a new linker technology and a stabilized thiol maleimide conjugation. This new linker technology comprises a cleavable peptidic sequence that facilitates multidrug attachment and the production of ADCs with tailored drug-to-antibody ratios (DARs). Cytotoxic drugs are rapidly and selectively released from the linker by the carboxypeptidase activity of Cathepsin B. In vitro cytotoxicity examination showed the potent cytotoxic effects of this GENA-111-auristatin F ADC on BCAM-expressing tumor cells, with a positive correlation between cytotoxicity and BCAM expression. Moreover, this ADC was also shown to significantly reduce the growth of tumor cells, including A431, T47D, and Huh7. The GENA-111-auristatin F ADC was evaluated in a xenograft mouse model established by subcutaneous injection of A431 cells, a BCAM positive human skin cancer cell line. The results of this study will be presented and discussed. Taken together, our data suggest that an ADC targeting BCAM e.g., GENA-111-auristatin F, might be a promising treatment strategy for BCAM positive epithelial cancer patients.
Citation Format: Hyunkyung Yu, Nathalie Bellocq, Youngeun Ha, Hyunuk Kim, Yunyeon Kim, Bu-Nam Jeon, Léo Marx, Mathilde Pantin, Hyunjin Yoo, Seungmin Byun, Joo-Yeon Chung, Mi Young Cha, Patrick Garrouste, Frédéric Lévy. The antibody-drug conjugate GENA-111 conjugated to auristatin F shows therapeutic potency in BCAM positive epithelial 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 1760.
Abstract 1764: Development of an alphalex™-auristatin low pH targeting conjugate for the treatment of solid tumors
Authors: Gayle Sophia , Aiello Robert , Bechtold Jane , Bourassa Patricia , Csengery Johanna , Hagen Connor , Howard Katia , Jones Kelli , Lopresti-Morrow Lori , Maguire Robert , Paradis Timothy , Pasqualini Theresa , Tweed Joseph , Tylaska Laurie , Zhang Qing , Paralkar Vishwas 
Published: June 2022

Abstract
Auristatins such as monomethyl auristatin E (MMAE) are a class of high potency microtubule targeting compounds that have an extremely narrow therapeutic window. Targeting potent auristatins to the tumor is the only feasible method of unlocking the clinical potential of such toxic molecules. While there are currently four marketed antibody-drug conjugates (ADCs) featuring auristatins, these ADCs face the same fundamental issues - tumor restriction by target antigen and the potential for off target release of payload.
Alphalex࣪ is a tumor targeting technology consisting of a unique variant of a family of pH-Low Insertion Peptides (pHLIP®) that target acidic cell surfaces (references 1-2), a cleavable small molecule linker, and an anti-cancer agent warhead. Alphalex࣪ thereby allows for antigen independent targeting of the tumor and enables intracellular delivery of the warhead by leveraging the low pH microenvironment of the tumor, a universal feature common to all tumors due to the Warburg effect.
Here we report the preclinical efficacy, safety, and antigen-independent tumor-targeting properties of alphalex࣪ conjugated to MMAE. We demonstrate the ability of alphalex࣪-MMAE to display potent in vitro and in vivo efficacy in colorectal, non-small cell lung, and prostate carcinoma cell lines. We further show that alphalex࣪-MMAE efficiently and safely delivers efficacious levels of MMAE selectively to tumor and demonstrates extreme plasma stability, with 0.02% warhead release over 24h in the rat. Based on the excellent preclinical safety and efficacy profile of alphalex࣪-MMAE, Cybrexa will move forward with the goal of initiating IND-enabling studies in 2022.
References:
1. Wyatt LC, Lewis JS, Andreev OA, Reshetnyak YK, Engelman DM. Applications of pHLIP Technology for Cancer Imaging and Therapy. Trends Biotechnol. 2017 Jul;35(7):653-664.
2. Wyatt LC, Moshnikova A, Crawford T, Engelman DM, Andreev OA, Reshetnyak YK. Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors. Proc Natl Acad Sci USA. 2018 Mar 20;115(12):E2811-E2818.
Citation Format: Sophia Gayle, Robert Aiello, Jane Bechtold, Patricia Bourassa, Johanna Csengery, Connor Hagen, Katia Howard, Kelli Jones, Lori Lopresti-Morrow, Robert Maguire, Timothy Paradis, Theresa Pasqualini, Joseph Tweed, Laurie Tylaska, Qing Zhang, Vishwas Paralkar. Development of an alphalex™-auristatin low pH targeting conjugate for the treatment of solid 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 1764.