bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB281: HIRA suppression is a mechanism of chemotherapy resistance in ovarian cancer
Authors: Yasukawa Maya , Drapela Stanislav , Ilter Didem , Shahzad Mian M. , Gomes Ana P. 
Published: April 2023

Abstract
Ovarian cancer accounts for the fifth most common cause of cancer death among women, despite being relatively rare. This is in large because majority of cases are diagnosed at advanced stage and frequently recur after primary treatment. Despite numerous efforts to develop effective targeted therapies and immunotherapies for ovarian cancer the standard of care remains chemotherapies. We postulate that part of the problem is the paucity of preclinical research and clinical trials focused on dormant persister ovarian cancer cells that remain after chemotherapy treatments. Emerging evidence supports the idea that persister cancer cells undergo a period of dormancy following chemotherapy which enables their survival and drive late recurrence. Thus, there is dire need to understand the pathways that empower the establishment of dormancy following chemotherapies in ovarian cancer. Epigenetic reprogramming is notoriously known to enable cell fate transitions and the establishment of drug resistance. An important layer of epigenetic regulation frequently overlooked in cancer is the regulation of nucleosome composition via histone variants. Importantly, analysis of data from the human protein atlas revealed that histone H3.3 chaperone, Histone Regulator Protein A (HIRA) expression inversely correlated with poor prognosis, suggesting that HIRA suppression might play a role in the development of chemotherapy resistance. Here, we demonstrate that HIRA is a major regulator of cell fate transitions in ovarian cancer cells in response to chemotherapies. Our data indicates that HIRA levels are suppressed in response chemotherapies in cancer cells. Genetic suppression of HIRA in ovarian cancer cells triggered a non-poliferative state characterized by the induction of canonical dormancy markers (p27, an increase in p38 phosphorylation) and cell cycle arrest. Accordingly, HIRA suppression in these cancer cells renders them less sensitive to the standard of care chemotherapy agent paclitaxel. Together, our data demonstrates that HIRA levels play an important role in controlling cell fate decisions in ovarian cancer and regulate chemotherapy sensitivity.
Citation Format: Maya Yasukawa, Stanislav Drapela, Didem Ilter, Mian M. Shahzad, Ana P. Gomes. HIRA suppression is a mechanism of chemotherapy resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB281.
Abstract LB317: Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations
Authors: Ying Haiyan , Xin Wenqun , Deng Haibing , Zhao Yuan , Yu Hongping , Chen Zhui , Xu Yao-chang 
Published: April 2023

Abstract
Introduction: FGFRs play important roles in cancer development and inhibition of FGFR could disrupt tumor cell proliferation and growth. Four selective FGFR inhibitors have been approved (erdafitinib, pemigatinib, infigratinib, and futibatinib) and several others are in clinical development. Unfortunately upon treatment with these first-generation FGFR inhibitors, acquired resistance often develops and is frequently associated with the emergence of secondary FGFR2/3 kinase domain mutations. Therefore, selectively targeting FGFR2/3 as well as their resistant mutations may render a second-generation treatment approach for the refractory/relapsed patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel, next-generation, and highly selective FGFR inhibitor, ABSK121. This novel inhibitor demonstrated robust anti-tumor activity in FGFR-dependent tumor models with strong activities against not only de novo but also acquired resistant mutations.
Method: ABSK121 was evaluated in biochemical and cellular proliferation experiments for its inhibition on wile type FGFR enzymatic activity and FGFR-dependent cancer cell proliferation. Its potency against FGFR mutations was also analyzed in relevant biochemical and cellular experiments. Efficacy studies were conducted in multiple tumor models to confirm its in vivo activities. Preliminary selectivity profile and ADME profiles were also evaluated.
Results: ABSK121 inhibited wild type FGFRs with IC50&lt;10 nM in biochemical assay. ABSK121 also displayed great potency against resistant kinase domain mutations. In cell lines harboring FGFR amplification, fusions, or resistant mutations, ABSK121 demonstrated strong anti-proliferation activity as well as strong inhibition of FGFR downstream signaling activities. In preclinical in vivo studies, oral administration of ABSK121 strongly inhibited the growth of subcutaneous xenograft tumors dependent on wild type or resistant mutant FGFR. Suppression of tumor growth was dose-dependent and well correlated with pharmacodynamic inhibition of FGFR signaling. ABSK121 also showed great kinase selectivity with no CYP or hERG inhibition.
Conclusion: ABSK121, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR inhibitor with great potency against resistant FGFR mutations. Its superior profile supports fast-track preclinical and clinical development.
Citation Format: Haiyan Ying, Wenqun Xin, Haibing Deng, Yuan Zhao, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB317.
Abstract LB326: Combined inhibition of BRD4 and FAK1 as a novel therapeutic strategy for neurofibromatosis type 2 related schwannomas
Authors: Gonzalez Maria Alejandra , Kissil Joseph , Troutman Scott 
Published: April 2023

Abstract
Neurofibromatosis type 2 (NF2) is a rare disorder that is inherited in an autosomal-dominant manner and is attributed to the loss of heterozygosity (LOH) of the NF2 gene, which encodes for the tumor suppressor protein Merlin. Patients affected by the disease develop vestibular schwannomas (VS), meningiomas, and ependymomas resulting in high morbidity and premature mortality. To date, neurofibromatosis type 2 has no FDA-approved drug-based treatment. Merlin plays a central role in mediating cell contact inhibition (CI) of proliferation. Loss of Merlin leads to abnormal activation of multiple signaling pathways, including those regulated by small G-proteins Ras/Rac/cdc42 and the Hippo-YAP pathway. The Hippo-YAP pathway plays a major role in cell growth and organ size control and at its core is comprised of a kinase cascade that regulates the transcriptional regulator YAP. The function of YAP is crucial for VS development, and there are several mechanisms by which YAP regulates transcription. Some of these functions have been shown to involve the Bromodomain and Extra-Terminal domain (BET) proteins acting as co-factors. We have previously shown that the BET inhibitor JQ1 can selectively reduce the growth of the NF2-null schwannoma and Schwann cells in vitro and tumorigenesis in vivo. Additionally, evidence has shown that Merlin loss can lead to increased cell proliferation that it requires the activity of Focal Adhesion Kinase 1 (FAK1). We have previously demonstrated that FAK1 inhibition via Crizotinib has antiproliferative effects in NF2-null Schwann cells, and is currently in phase II clinical trials in NF2-related VS. In this study, wild-type and NF2-null Schwann cells and schwannoma cell lines were used to determine the impact on cell growth by employing the treatment with the BET inhibitor JQ1 and the FAK1 inhibitor Crizotinib. Our analysis in NF2-null Schwann cells and schwannoma cell lines shows that the combined inhibition exerts an antineoplastic effect at nanomolar concentrations. Moreover, this combination resulted in selective inhibition of NF2-null Schwann cell proliferation when compared to wild-type Schwann cells in vitro, when compared to either drug alone. Our preliminary data suggest that combined targeting of BET and FAK1 may offer a potential therapeutic option for the treatment of NF2-related schwannomas.
Citation Format: Maria Alejandra Gonzalez, Joseph Kissil, Scott Troutman. Combined inhibition of BRD4 and FAK1 as a novel therapeutic strategy for neurofibromatosis type 2 related schwannomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB326.
Abstract LB335: Establishment of the effective dose of the STAT3 inhibitor WP1066 used in combination with STING activation for reprograming the preclinical glioma microenvironment
Authors: Najem Hinda , Tripathi Shashwat , Sooreshjani Moloud , Hurley Lisa , Dussold Corey , Arrieta Victor , Ott Martina , Wei Jun , Curran Michael , Marisetty Anantha , Priebe Waldemar , Platanias Leondias C. , Lesniak Maciej S. , James Charles D. , Horbinski Craig , Ashley David M. , Heimberger Amy B. 
Published: April 2023

Abstract
Purpose: Trials of immunotherapy in diffuse glioma patients have been mostly unsuccessful. We therefore sought to determine the combined effects of the signal transducer and activator of transcription 3 (STAT3) inhibitor WP1066 and the STING agonist IACS-8803 in a preclinical model of glioma.
Experimental Design: C57BL/6 mice (n=9-10/group) with orthotopically engrafted GL261 cells were treated orally with WP1066, a blood-brain-barrier penetrant inhibitor of STAT3, in combination with the STING agonist IACS-8803 administered directly into the tumor. Analysis of treatment effects included immunoblots, ubiquitination, multiplex immunohistochemistry, and NanoString immune phenotyping of glioma-infiltrating immune cells.
Results: The STING agonist 8803 at 2.5µg/mouse, in combination with WP1066 dosed at 30mg/kg with a 12-hour delay, increased animal subject median survival (MS) to 58 days, in contrast to monotherapy (WP1066=25 days, 8803=29 days) or control (25 days) (p=0.002 of combo relative to all other groups). Dose escalation of WP1066 to 60 mg/kg, administered simultaneously with 8803, completely abrogated the therapeutic combinatorial effect. Five ubiquitin-binding domains were predicted on STING using the UbPred program; concentrations of 5µM or higher of WP1066 induced polyubiquitination of phosphorylated STING. Immune profiling during the therapeutic window demonstrated a multi-pathway induction of anti-tumor immunity.
Conclusions: Co-administration of a reduced effective dose of WP1066 is necessary with STING agonist 8803 to effectively enhance the anti-glioma immune reactivity in the tumor microenvironment.
Citation Format: Hinda Najem, Shashwat Tripathi, Moloud Sooreshjani, Lisa Hurley, Corey Dussold, Victor Arrieta, Martina Ott, Jun Wei, Michael Curran, Anantha Marisetty, Waldemar Priebe, Leondias C. Platanias, Maciej S. Lesniak, Charles D. James, Craig Horbinski, David M. Ashley, Amy B. Heimberger. Establishment of the effective dose of the STAT3 inhibitor WP1066 used in combination with STING activation for reprograming the preclinical glioma microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB335.
Abstract LB341: Single-cell CRISPR screens in primary human T cells identify regulators of Th2 cell skewing
Authors: Loregger Anke , Irnstorfer Johanna , Untermoser Nicole , Vinko Nikola , Krejci Adam , Schmidt Henrik , Bürckstümmer Tilmann 
Published: April 2023

Abstract
CRISPR screens have become the primary discovery engine in modern biology. However, many screening workflows are still performed in cancer cell lines and coupled to simplistic read-outs such as cellular fitness. At Myllia Biotechnology, we combine CRISPR screening with single-cell RNA sequencing, leveraging two transformative technologies to enable genetic screening for complex phenotypes. We utilize the CRISPR screening workflow to map the impact of thousands of genetic perturbations on the global transcriptome at single-cell resolution. Our powerful approach has broad applications in identifying novel drug targets or elucidating unknown mechanisms of actions of drugs.
Primary human T cells are currently of great interest in the scientific community. They are not only key players in autoimmunity and other inflammatory diseases, but also represent attractive targets for immunotherapy of cancer. To enable the discovery of novel targets, we built a workflow that utilizes CD4+ T cells from peripheral blood and allows functional genomic screens in these cells. Upon activation, naïve CD4+ T cells proliferate and differentiate into specific T helper cell subsets, such as Th1, Th2, or Th17 cells. Here, we present data of an experiment in which we screened for regulators of T helper cell differentiation and skewed cells towards the Th2 subset. We aimed to identify genes whose knockout boosts or attenuates the ability of primary naïve CD4+ T cells to become Th2 cells. Th2 cells support the humoral immune response, and their dysfunction has been linked to inflammatory diseases, including asthma.
In our screen, the different T cell subsets could be captured using curated transcriptomic signatures. Importantly, several gene KOs introduced in a pooled fashion using CRISPR/Cas9 accumulated in distinct subpopulations, suggesting that these genes regulate the differentiation of naïve T cells into the various T helper cell subsets.
Overall, our pooled screening approach in primary human T cells allows for novel insights in the plasticity of T cells and identifies genes that could serve as drug targets in autoimmunity, inflammation and immuno-oncology.
Citation Format: Anke Loregger, Johanna Irnstorfer, Nicole Untermoser, Nikola Vinko, Adam Krejci, Henrik Schmidt, Tilmann Bürckstümmer. Single-cell CRISPR screens in primary human T cells identify regulators of Th2 cell skewing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB341.
Abstract LB344: Complement-mediated signaling during cross-presentation of tumor antigen augments T cell responses
Authors: Bird Caryn L. , Pacholczyk Gabriela A. , Johnson Theodore S. 
Published: April 2023

Abstract
Production of complement C3a and C5a locally at the immune synapse by activated dendritic cells (DCs) enhances T cell responses in multiple experimental models. Complement signaling through cognate C3a receptor (C3aR) and C5a receptor (C5aR) modulate effector T cell stability, proliferation and differentiation. We have previously shown that complement C3 plays a mechanistic role in driving synergistic anti-tumor effects of blocking indoleamine 2,3-dioxygenase (IDO) during radiation and chemotherapy in a murine brain tumor model that expresses the gp10025-33 peptide antigen. We hypothesize that, when anti-tumor responses are allowed to happen, complement C3 production by local DCs acts as a costimulation factor, operating through C3aR and C5aR on the T cell surface to allow optimal T cell activation and proliferation. To study the role of complement C3 as a costimulation factor during T cell responses against a nominal tumor antigen (gp10025-33 peptide, expressed by B16F10 melanoma), we used T cells from syngeneic pmel-1 mice (TCR transgenic with CD8 T cells that recognize the cross-presented gp10025-33 peptide) co-cultured with gp10025-33 peptide and dendritic cells from either wild-type (WT) or C3-defiecient (C3-KO) mice. In addition, we used in vitro culture conditions where gp10025-33 tumor peptide was in stringent limited supply to model homeostatic conditions of the tumor microenvironment. We found that, when stimulated by DCs from C3-KO mice, pmel-1 CD8 T cells had decreased activation marker expression, proliferation, and cytokine effector function relative to stimulation by DCs from WT mice. Next, we bred pmel-1 mice onto a syngeneic background deficient in receptors for both C3a and C5a complement factors (C3aR-KO/C5aR-KO double knock-out mice). We used CD8 T cells from the resulting mouse strain (pmel-1/C3aR-KO/C5aR-KO) co-cultured with WT DCs to study the role of complement signaling in T cells during responses to tumor antigen. Using the same stringent antigen conditions, CD8 T cells from the pmel-1/C3aR-KO/C5aR-KO mice had decreased activation marker expression and proliferation, and differences in cytokine function compared to CD8 T cells from the pmel-1 mice. These findings suggest that lack of local complement production by the DCs in the tumor microenvironment may inhibit anti-tumor immune responses, and that complement signaling through C3aR and C5aR on T cells may play an important role during such anti-tumor responses.
Citation Format: Caryn L. Bird, Gabriela A. Pacholczyk, Theodore S. Johnson. Complement-mediated signaling during cross-presentation of tumor antigen augments T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB344.
Abstract LB352: KRAS inhibition enhances immunogenicity of KRASG12C colorectal cancer
Authors: Tian Jun , de la Cruz Ferran Fece , Burke Kelly , Oka Tomonori , Curtis Jacquelyn M. , Sindurakar Princy , Wong Edmond , Demehri Shadmehr , Sharpe Arlene , Corcoran Ryan 
Published: April 2023

Abstract
RAS mutations are the most common oncogenic mutations, present in &gt;20% of human cancers. KRAS, the predominantly mutated isoform of RAS, is mutated in 40% of colorectal cancer (CRC), leading to constitutive activation of the MAPK (RAS/RAF) pathway and other downstream effectors. Due to the difficulty of targeting RAS, the first KRASG12C selective inhibitor has only been developed recently and approved by the FDA for non-small cell lung cancer. However, the inhibitor demonstrated much lower response rates in CRC (&lt;20%) than other cancer types. Thus, developing effective therapies for KRAS mutant (KRASm) CRC still remains challenging. Oncogenic KRAS signaling has been shown to have immunosuppressive effects on tumor microenvironment, thus we hypothesized that KRAS inhibitor can indirectly enhance antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. Indeed, using a syngeneic KRASG12C CRC mouse model with knockout of APC, TP53, SMAD4 and expressing KRASG12C, we observed significant increase in the percentage of CD3+CD8+ T cells as well as changes in myeloid populations in tumors treated with KRASG12C inhibitor compared with vehicle control. Combination of KRASG12C/PD-1 inhibition produced a more substantial and sustained reduction in tumor growth compared with KRAS or PD-1 inhibition alone. KRASG12C CRC mouse model represents a proper tool to study tumor cell-intrinsic mechanism of cooperativity between KRAS inhibition and immune response, since KRASG12C inhibitor targets KRASm tumor cells only without having direct effects on stromal and immune cells. Interestingly, we found tumor-intrinsic immune programs induction by KRAS/MAPK inhibition in KRASG12C CRC mouse models and patient-derived organoid models. We also found that KRASG12C inhibition upregulates T-cell recruiting chemokines CXCL9 and CXCL10 via IRF1 in KRASm tumor cells, which might be one of the potential mechanisms underlying enhanced infiltration of CD3+CD8+ T cells. These data suggest a link between KRAS inhibition and anti-tumor immunity, thus provide insights into novel combination strategies for KRASG12C colorectal cancers.
Citation Format: Jun Tian, Ferran Fece de la Cruz, Kelly Burke, Tomonori Oka, Jacquelyn M. Curtis, Princy Sindurakar, Edmond Wong, Shadmehr Demehri, Arlene Sharpe, Ryan Corcoran. KRAS inhibition enhances immunogenicity of KRASG12C colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB352.
Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer
Authors: Hinshaw Dominique C. , Benavides Gloria A. , Metge Brandon J. , Swain Courtney A. , Kammerud Sarah C. , Alsheikh Heba A. , Elhamamsy Amr , Chen Dongquan , Darley-Usmar Victor , Rathmell Jeffrey C. , Welner Robert S. , Samant Rajeev S. , Shevde Lalita A. 
Published: April 2023

AbstractThe tumor immune microenvironment dynamically evolves to support tumor growth and progression. Immunosuppressive regulatory T cells (Treg) promote tumor growth and metastatic seeding in patients with breast cancer. Deregulation of plasticity between Treg and Th17 cells creates an immune regulatory framework that enables tumor progression. Here, we discovered a functional role for Hedgehog (Hh) signaling in promoting Treg differentiation and immunosuppressive activity, and when Hh activity was inhibited, Tregs adopted a Th17-like phenotype complemented by an enhanced inflammatory profile. Mechanistically, Hh signaling promoted O-GlcNAc modifications of critical Treg and Th17 transcription factors, Foxp3 and STAT3, respectively, that orchestrated this transition. Blocking Hh reprogramed Tregs metabolically, dampened their immunosuppressive activity, and supported their transdifferentiation into inflammatory Th17 cells that enhanced the recruitment of cytotoxic CD8+ T cells into tumors. Our results demonstrate a previously unknown role for Hh signaling in the regulation of Treg differentiation and activity and the switch between Tregs and Th17 cells in the tumor microenvironment.
Transcendence: A Defensible and Fruitful Concept for Religious Studies
Authors: DeJonge Michael P. 
Published: April 2023

Abstract
Scholars of religion who make use of the concept of transcendence are likely to encounter objections that this concept is too vague, too metaphysical, and too theological for use in Religious Studies. This article develops a differential-phenomenological concept of transcendence that is not susceptible to these charges and that, thanks to its complex logical structure, is potentially fruitful for use in Religious Studies.
Contributions of LOSC Jurisprudence to Reaching and Justifying a Negotiated Outcome – and Contributions of Negotiated Settlements to the Law of the Sea
Authors: Fife Rolf Einar 
Published: April 2023

Abstract
Releasing the full potential of the United Nations Convention on the Law of the Sea (LOSC) also requires concluding agreements – and an understanding of the dynamics behind reaching agreement. Legal reasoning in negotiations is not divorced from judicial reasoning. Justification by drawing upon the latter may be required in the fundamental process of overcoming disagreement. Jurisprudence may provide arguments of acceptability for negotiating States. Moreover, negotiations should not merely be dismissed as ‘bargaining under the shadow of the Convention’. Rather, they may be part of a broader interaction with contributions of the judiciary and indicate future paths for the Convention’s implementation. Furthermore, this may give rise to reflections on the roles of heuristics for negotiators and for policy- and decision-makers. This suggests revisiting the notion of legal policies of States – including how States should define unresolved issues and decide on the best timing and means for their effective resolution.