bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4972: Anti-tumor activity of Helicon inhibitors of Β-catenin-TCF interaction in patient-derived xenograft models
Authors: Si YaGuang , Choi Minjung , Han Xinwei , White Brian , Wu Ziyang , Visness Erica , Beerepoot Pieter , Jaensch Elizabeth , Ramirez Jessica , Ponthier Charles , Han Xiaogang , Ortet Paula , Du Peicheng , Agarwal Sorabh , Lech Mirek , Fulgham Aaron , Cappucci Sarah , Li Zhi , McGee John , Yu Lihua , Tremblay Martin , Orford Keith , Verdine Gregory , Hurov Jonathan 
Published: April 2023

Abstract
Genetic and epigenetic alterations in the Wnt signaling pathway leading to constitutive activation of the driver oncogene Β-catenin occur in at least 20% of all human cancers. We have developed conformationally hyperstabilized α-helical peptides (Helicons) that bind directly to Β-catenin with picomolar affinity and block its interaction with TCF transcription factors. We describe here the characterization of anti-tumor efficacy, pharmacodynamic biomarkers and mechanism of action using multiple in vivo patient-derived xenograft (PDX) models treated with Helicons. Helicon treatment leads to dose-dependent anti-tumor effects and durable regressions in PDX models from multiple indications with Wnt pathway activating mutations. Anti-tumor responses are seen in the presence of additional driver mutations, including KRAS and PIK3CA. RNA-sequencing and Gene Set Enrichment Analysis confirm Helicon treatment inhibits both Wnt/Β-catenin and MYC-regulated gene sets. Inhibiting Β-catenin-TCF interaction with Helicons represents a first-in-class therapeutic approach for the treatment of cancers resulting from aberrant transcriptional signaling via Β-catenin.
Citation Format: YaGuang Si, Minjung Choi, Xinwei Han, Brian White, Ziyang Wu, Erica Visness, Pieter Beerepoot, Elizabeth Jaensch, Jessica Ramirez, Charles Ponthier, Xiaogang Han, Paula Ortet, Peicheng Du, Sorabh Agarwal, Mirek Lech, Aaron Fulgham, Sarah Cappucci, Zhi Li, John McGee, Lihua Yu, Martin Tremblay, Keith Orford, Gregory Verdine, Jonathan Hurov. Anti-tumor activity of Helicon inhibitors of Β-catenin-TCF interaction in patient-derived xenograft models. [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 4972.
Abstract 4974: Development of novel pyrimido-pyrazolo-quinolone derivative, IND-2 as multi-targeted inhibitor for the treatment of prostate cancer
Authors: Balaji Swapnaa , Neupane Rabin , Karthikeyan Chandrabose , Ramapuram Jayachandra Babu , Tiwari Amit K. 
Published: April 2023

Abstract
Prostate cancer (PC) is the most commonly diagnosed cancer in men. In PC, multiple molecular signaling networks are perturbed, so monotherapies are less effective, creating an urgent need to discover chemotherapeutic agents that target multiple tumor-promoting proteins simultaneously. Drug discovery research is increasingly embracing poly-pharmacology, in which one drug targets multiple oncogenic targets concurrently. We have identified a novel quinoline derivative, IND-2 (4-chloro-2-methylpyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinolone), that has been shown to significantly inhibit the expression of several oncogenic and epigenetic targets in PC cells. It was observed that IND-2 significantly inhibited the proliferation of PC-3 and DU-145 with IC50 values of 3 µM and 3.5 µM, respectively. Furthermore, 5 and 10 µM of IND-2 produced morphological changes in PC-3 cells characteristic of apoptosis. The levels of reactive oxygen species (ROS) increased significantly after IND-2 was added to PC cells. Additionally, 5 and 10 µM of IND-2 reduced mitochondrial membrane potential in PC-3 cells. Furthermore, IND-2 increased the expression of cleaved caspase-3, cleaved caspase-7, and cleaved poly (ADP-ribose) polymerase (PARP). The PC-3 cells incubated with 5 µM of IND-2 showed a significant reduction in expression of B-cell lymphoma 2 (Bcl-2). These data convincingly show that IND-2 inhibits PC cells through apoptosis induction. It is interesting to note that IND-2 (2.5, 5 and 10 µM) also induces mitotic catastrophe in PC-3 cells. Wound healing assay and expression of several EMT (epithelial to mesenchymal) markers indicated significant anti-metastatic activity of IND-2. Target identification studies have demonstrated that IND-2 mimics etoposide (VP-16) and binds more specifically to Topoisomerase IIβ. In our preliminary studies, we found that IND-2 inhibits several oncogenic and epigenetic targets including Topoisomerase II-Hsp90 complex and LSD1/HDAC1 of the transcriptional corepressor CoREST complex. However, these targets need to be validated to understand IND-2's mechanism. Overall, IND-2 may lead to the development of more effective poly-targeted compounds for PC treatment.
Citation Format: Swapnaa Balaji, Rabin Neupane, Chandrabose Karthikeyan, Jayachandra Babu Ramapuram, Amit K. Tiwari. Development of novel pyrimido-pyrazolo-quinolone derivative, IND-2 as multi-targeted inhibitor for the treatment of prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4974.
Abstract 4990: Dual inhibitor of ACVR1 and MEK 1/2 E6201 and PI3K/mTOR inhibitor paxalisib synergistically inhibit cell growth in DMG
Authors: Kwon Hyuk Jean , Tindall Abigail , Eberhart Charles , Rubens Jeffrey , Raabe Eric 
Published: April 2023

Abstract
Diffuse midline glioma (DMG) is an aggressive pediatric glioma with no curative treatment options. Mutation in MAPK pathway is common in many DMG tumors, however, has not been largely explored before. E6201 is a dual inhibitor of ACVR1 and MEK 1/2. It is currently in a phase 1 clinical trial for BRAF/MEK mutant melanoma. E6201 achieves higher levels in brain compared to other MEK inhibitors, suggesting it might be a promising therapeutic option for DMG. Previously, E6201 was effective in DMG cell lines with ACVR1 mutation, such as HSJD007. We have evaluated the effect of E6201 in two MAP kinase pathway activated, novel DMG cell lines, DIPG2JA and JHH-DIPG17. DIPG2JA has a KRAS mutation, leading to upregulation of MAPK pathway, and JHH-DIPG17 has two NF1 alterations predicted to disrupt this tumor suppressor, resulting in activation of MAPK pathway. Treatment of DIPG2JA with E6201 identified an IC50 of 44 nM, which is comparable to an IC50 of 71nM in the ACVR1 mutant DMG HSJD007. E6201 suppressed phospho—ERK and induced apoptosis as measured by cPARP western blot in DMG cells. Evaluation of cell viability by CellTiterBlue viability assay demonstrated that E6201 suppressed DMG growth between 0.05uM to 1uM concentrations. (DIPG2JA p=0.0004, JHH-DIPG17 p&lt;0.0001 by t-test compared to control). Compensatory upregulation of mTOR pathway is often associated with downregulation of MAPK pathway, and we hypothesized that E6201 will synergize with a PI3K/mTOR inhibitor to induce DMG cell death. We selected the brain-penetrant PI3K/mTOR inhibitor paxalisib, because this drug is currently being tested in early phase clinical trials for DMG. Through CellTiterBlue cell viability assay, we showed that E6201 synergizes with paxalisib to inhibit cell growth. The ZIP synergy scores were 13.1 for HSJD007 and 12.7 for DIPG2JA according to the SynergyFinder program, suggesting synergistic interaction between E6201 and paxalisib. In vitro experiments for further evaluation of the combination treatment of E6201 and paxalisib are underway and in vivo studies are pending. From our data, E6201 as a single agent is a promising therapeutic option for DMG. With further evaluation of combination of E6201 and paxalisib, we believe that combination therapy will be an even more effective treatment option for DMG.
Citation Format: Hyuk Jean Kwon, Abigail Tindall, Charles Eberhart, Jeffrey Rubens, Eric Raabe. Dual inhibitor of ACVR1 and MEK 1/2 E6201 and PI3K/mTOR inhibitor paxalisib synergistically inhibit cell growth in DMG. [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 4990.
Abstract 5012: Characterizing the functional significance of PDGFRAK385I and PDGFRAK385L extracellular domain mutations in the newly defined myxoid glioneuronal tumor
Authors: Beach Catherine Z. , Somwar Romel , Wood Matthew D. , Davare Monika A. 
Published: April 2023

Abstract
In 2021, the World Health Organization (WHO) approved new diagnostic guidelines that stratify central nervous system (CNS) tumors based on molecular, transcriptomic, and epigenetic analysis instead of relying solely on phenotypic characterization and added twenty-two new CNS tumor entities based on these guidelines. Our focus is on one of these newly defined entities—myxoid glioneuronal tumors—a slow growing, mucinous glial tumor defined by a pathognomonic dinucleotide substitution in the extracellular domain of PDGFRA p.K385I/L. PDGFRA p.K385I/L remains a variant of unknown significance, however, constitutive activation of PDGFRA is well established as a pharmacologically actionable, oncogenic driver present in a variety of tumor types. Here we report the functional characterization of PDGFRAK385I and PDGFRAK385L by assessing transforming potential using Ba/F3 cells and immortalized human astrocytes. Our results demonstrate that both p.K385I and K385L substitutions are oncogenic, driving cytokine-independent Ba/F3 cell growth and anchorage-independent colony formation. Western blot analysis of downstream cellular signaling pathways in the absence of PDGF-ligand further confirm the activating nature of these mutations, showing robust phosphorylation of PDGFRA and constitutive phosphorylation of downstream signaling effectors ERK1/2, SHP2, and STAT3. To assess whether PDGFRAK385I and PDGFRAK385L are pharmacologically actionable, we tested multiple tyrosine kinase inhibitors with known activity against PDGFRA aberrant cancers using our mutant-transformed PDGFRA Ba/F3 cells. We found that the PDGFRAK385I and PDGFRAK385L mutants were sensitive to inhibitors axitinib, AZD-3229, and avapritinib at therapeutically relevant concentrations. Further, these mutants showed resistance to imatinib, nilotinib, and crenolanib underscoring the importance of pharmacogenomic investigation. No appreciable difference in sensitivity or resistance profiles was observed between the two mutants. In summary, our findings indicate that these previously uncharacterized p.K385I/L extracellular domain mutations in PDGFRA are oncogenic and represent a pharmacologically actionable target that could be harnessed to increase therapeutic options in the setting of myxoid glioneuronal tumors.
Citation Format: Catherine Z. Beach, Romel Somwar, Matthew D. Wood, Monika A. Davare. Characterizing the functional significance of PDGFRAK385I and PDGFRAK385L extracellular domain mutations in the newly defined myxoid glioneuronal tumor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5012.
Abstract 5027: Targeting ARAF p.S214C mutation with sorafenib in non-small cell lung cancer
Authors: Lee Carol , Chan Sze Man , Yeung Sai Fung , Tsui Stephen Kwok-Wing 
Published: April 2023

Abstract
Sorafenib is an FDA-approved multi-kinase inhibitor for the treatment of several cancer types, but is still under investigation for non-small cell lung cancer (NSCLC). Although sorafenib has not shown significant survival benefit in clinical trials for NSCLC patients, one study identified a patient with advanced lung adenocarcinoma harboring ARAF p.S214C mutation as an exceptional sorafenib responder. As NSCLC lacks clinically validated predictive biomarkers for drug responses, we aim to evaluate the potential of ARAF p.S214C mutation as a biomarker for sorafenib sensitivity and its mechanism of action. Constructs with ARAF p.S214C mutation, ARAF-wild type (WT) and EGFR-vector control were ectopically expressed in a lung adenocarcinoma cell line, H2023, by retroviral transduction. Western blot confirmed stable overexpression of ARAF proteins over time. MTT assay showed that sorafenib inhibited growth of cells expressing ARAF p.S214C more pronouncedly than cells expressing ARAF-WT or vector control. In addition, spheroids formed by cells expressing ARAF p.S214C were more sensitive to sorafenib inhibition, indicating sorafenib sensitivity of ARAF p.S214C in NSCLC in vitro. To evaluate whether such sorafenib sensitivity is dependent on the kinase activity of ARAF, phospho-MEK and MAPK levels in mutant cells will be determined. As ARAF belongs to the Raf protein family which also includes BRAF and RAF1, knockdown studies and co-immunoprecipitation will be performed to determine whether BRAF and RAF1 are essential for ARAF p.S214C activity. The in vivo sorafenib sensitivity of ARAF p.S214C will be validated in tumor xenografts established from cells expressing the above constructs upon sorafenib treatment. Tumor volume will be assessed and expression of the tumor marker cytokeratin will be evaluated by immunohistochemistry. This study may reveal ARAF p.S214C as a potential biomarker for sorafenib sensitivity and a new target for precision medicine in NSCLC.
Citation Format: Carol Lee, Sze Man Chan, Sai Fung Yeung, Stephen Kwok-Wing Tsui. Targeting ARAF p.S214C mutation with sorafenib in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5027.
Abstract 5028: The regulation of inflammatory signaling in cancer via A20 phosphorylation
Authors: Palacios Tania Lopez , Chan Tsz-Yin , Egbert Christina , Truman Jacob , Ashworth Spencer , Vaughan Alec , Andersen Joshua L. 
Published: April 2023

Abstract
A20 is an anti-inflammatory protein with a dual ubiquitin-editing activity. Through its N-terminal ovarian tumor (OTU) domain, A20 negatively regulates NF-ĸB by removing the K63-linked ubiquitin chains on RIP1 that act as platforms for NF-ĸB activation downstream of tumor necrosis factor alpha (TNFα). On the other hand, A20 also catalyzes the addition of K48-linked ubiquitin chains on RIP1 via its C-terminal zinc finger domain 4 (ZnF4) to promote its proteasomal degradation. Through both mechanisms, A20 is a means of negative feedback on TNFα-induced NF-ĸB activity. Importantly, inactivation of A20 is frequently found in B-cell lymphomas, where loss-of-function A20 truncations promote cell proliferation and upregulation of NF-ĸB signaling. Among the post-translational modifications (PTMs) reported in A20, there are several phosphorylation events in its C-terminus, including within the ZnF4 domain. Besides its known E3 ubiquitin ligase activity, previous reports show that the C-terminal region of A20 is important for ubiquitin binding, having preference for K63-linked poly-ubiquitin. However, a little is known about the effects of phosphorylation at this region on A20 activity as well as its consequences in downstream signaling. Our current work suggests that phosphorylation in the C-terminus of A20 inhibits its E3 ubiquitin ligase activity and disrupts its interaction with ubiquitin, which may also affect its deubiquitinase activity by preventing its recruitment to ubiquitinated proteins in the TNFα receptor (TNFR) complex. We also propose that the C-terminal region is important for the formation of the A20 ubiquitin-editing complex, necessary to downregulate NF-ĸB-activated inflammatory signals. Based on these observations, we hypothesize that not only gene-inactivating mutations, but also post-translational mechanisms, such as phosphorylation, inhibit A20 to promote cancer development. Our research is now focused on understanding the upstream signaling that regulates A20 phosphorylation.
Citation Format: Tania Lopez Palacios, Tsz-Yin Chan, Christina Egbert, Jacob Truman, Spencer Ashworth, Alec Vaughan, Joshua L. Andersen. The regulation of inflammatory signaling in cancer via A20 phosphorylation. [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 5028.
Abstract 5053: A critical role for copper in enhanced radioirdide uptake in thyroid cancer cells
Authors: Brookes Katie , Zha Ling , Kim Jana , Kannappans Vinodh , Wang Weiguang , Sunassee Kavitha , Blower Philip J. , Smith Vicki E. , Read Martin L. , McCabe Christopher J. 
Published: April 2023

Abstract
New drug approaches are urgently required to improve radioiodide (RAI) uptake for efficient ablation of thyroid cancer cells in RAI-refractory disease. Employing high-throughput screening of FDA-approved compounds we recently identified drugs capable of robust induction of sodium iodide symporter (NIS) activity to promote RAI uptake1. In particular, a leading drug candidate - the well-established anti-alcoholism drug disulfiram (DSF) - had not been previously implicated in regulating NIS. Here, we demonstrate that the ability of DSF to increase RAI-uptake in thyroid TPC-1 (3.1-fold; p&lt;0.01) and 8505C (4.9-fold; p&lt;0.001) cells can be significantly potentiated by combination with Cu2+ to 5.1-fold and 18.9-fold increases respectively. Despite promising data, DSF is known to have poor bioavailability in vivo due to its rapid metabolism to diethyldithiocarbamate (DDC) within the stomach and circulation with subsequent methylation in the liver. Whilst methylated-DDC did not have any effect on NIS function, DDC chelated to divalent copper ions [Cu(DDC)2] was highly effective at increasing RAI uptake (up to 8-fold; P&lt;0.001) in multiple thyroid cell types and induced significant NIS protein expression (up to 36.2-fold; 250nM; P&lt;0.001). Importantly, Cu(DDC)2 retained the ability to enhance NIS function in thyroid cells ablated for expression of either VCP or its co-factor NPL4, indicating its effect on NIS was via VCP-independent pathways. Instead, a transcriptional effect of Cu(DDC)2 was revealed by significant induction of NIS mRNA levels in TPC-1 (8.5-fold; P&lt;0.001) and 8505C (104.8-fold; P&lt;0.001) cells. In wild-type Balb/c mice the intraperitoneal administration of albumin nano-encapsulated Cu(DDC)2 significantly induced thyroidal uptake of technetium-99m (99mTc) after 30 min (~40% increase; n=11 per group; 3 mg/kg dose; P&lt;0.001). Thus, our study demonstrates a promising drug strategy utilizing copper to significantly enhance NIS function with clinical potential to improve treatment effectiveness in RAI-refractory thyroid cancer patients.
1Read ML, Brookes K, Thornton CEM, Fletcher A, Nieto HR, Alshahrani M, Khan R, Borges de Souza P, Zha L, Webster JRM, Alderwick LJ, Campbell MJ, Boelaert K, Smith VE, McCabe CJ (2022) Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter. Cell Chem Biol. 29(3):502-516.e7.
Citation Format: Katie Brookes, Ling Zha, Jana Kim, Vinodh Kannappans, Weiguang Wang, Kavitha Sunassee, Philip J. Blower, Vicki E. Smith, Martin L. Read, Christopher J. McCabe. A critical role for copper in enhanced radioirdide uptake in thyroid cancer 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 5053.
Abstract 5199: B7-H3 & PD-L1 double-humanized BALB/c mouse: a novel animal model for preclinical studies of human B7-H3 antibodies or bispecific antibodies
Authors: Guo Shiying , Song Lingyu , Qin Xin , Xu Jianming , Sun Hongyan , Ju Cunxiang , Wang Hongyu , Chen Santi Suryani , Li Zhiying , Moore Mark Wade , Zhao Jing , Gao Xiang 
Published: April 2023

Abstract
Immune checkpoint molecule B7-H3, also known as CD276, is a member of the B7-CD28 family of immunomodulatory proteins. It is a type I membrane protein with sequence similarities to the extracellular domain of programmed death-ligand 1 (PD-L1).
B7-H3 is highly expressed in most human cancers, but has limited distribution in normal tissues, remaining elusive of its receptor. Due to its promising safety as a dominant tumor target, various strategies have been developed to modulate the effect of B7-H3 via monoclonal antibodies, bispecific antibodies, ADC, or CAR-T. To study the effect of these therapies in an immunocompetent mouse model, we established a double humanized B7-H3 and PD-L1 mouse model on BALB/c background (BALB/c-hB7-H3/hPD-L1). In this model, the extracellular domain of murine fragments was replaced by the human counterparts while the trans-membrane and cytoplasmic domain were kept intact. When engrafted with CT26 colon cancer cells, which stably overexpress human B7-H3 and PD-L1 while endogenous murine counterparts were knocked out, the tumor growth was inhibited certain degree by anti-B7-H3 antibody (8H9 Biosimilar, 20mpk, TGI=18.56%) treatment while inhibited significantly after the monotherapy of anti-PD-L1 (Tecentriq, 3 mpk, TGI=55.89%, p&lt;0.001). The same dosage combination of anti-B7-H3 and anti-PD-L1 had a significant inhibition on tumor growth (TGI=76.85%, p&lt;0.001), and had a synergistic effect (CDI&lt;0.7) compared with the monotherapy. Analysis of tumor-infiltrating lymphocytes (TILs) at the end of the efficacy study showed that the proportion of CD45+ immune cells was significantly increased in all of the treated groups. The NK cells were significantly increased and the Treg cells were significantly decreased especially in the combined treatment group.
Based on the above, the B7-H3 and PD-L1 double humanized mouse model is suitable for the pre-clinical evaluation of mono or combined immune checkpoint blockade with anti-human B7-H3 and PD-L1 therapy.
Citation Format: Shiying Guo, Lingyu Song, Xin Qin, Jianming Xu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. B7-H3 & PD-L1 double-humanized BALB/c mouse: a novel animal model for preclinical studies of human B7-H3 antibodies or bispecific antibodies. [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 5199.