bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5961: NRF2-responsive kinases in esophageal squamous cell carcinoma
Authors: Subramaniyan Boopathi , Xiong Zhaohui , Paiboonrungruang Chorlada , Li Yahui , Major M Ben , Chen Xiaoxin 
Published: March 2024

Abstract
Esophageal squamous cell carcinoma (ESCC) ranks as the 7th most frequently diagnosed cancer and the 6th leading cause of cancer-related death worldwide. NRF2 is identified as a therapeutic target for human ESCC, with a mutation rate of approximately 10-22%. Hyperactive NRF2 promotes proliferation, metastasis, and resistance to radiation and chemotherapy in ESCC. Although some evidence suggest NRF2 regulates kinases which contribute to these phenotypes, it remains unclear which kinases are responsive to hyperactive NRF2. Using NRF2 ChIP-seq analysis, we have enrichment of 42 kinases including Akt2 and Pkm and 31 phosphatases including Pten and Dusp16 enriched in the Keap1-/- mouse esophagus in comparison with the wild-type esophagus. We further confirmed the binding of NRF2 to the promoter regions of mouse Akt2 and Pten. mRNA expression profiling revealed enrichement of the PI3K/AKT, RAS, ERK, and GSK3 pathways in the Keap1-/- esophagus as compared to the Nrf2-/-;Keap1-/- esophagus. Immunohistochemical staining showed that pAKT, p-mTOR, pS6, PKM2 were overexpressed in the Keap1-/- esophagus, as well as in the adult NRF2-hyperactive esophagus (Sox2CreER;LSL-Nrf2E79Q/+). Using PhosphoExplorer array and PamChip array to analyze NRF2W24C-KYSE70 cells (in comparison with NRF2null-KYSE70 cells) and Sox2CreER;LSL-Nrf2E79Q/+ mouse esophageal epithelium in comparison with wild-type mouse tissue, we further identified multiple kinases including PI3K as potential NRF2-responsive kinases. These findings suggest a potential role for kinases such as PI3K in NRF2-driven ESCC, and support the idea of targeting both NRF2 and NRF2-responsive kinases as a therapeutic strategy for ESCC.
Citation Format: Boopathi Subramaniyan, Zhaohui Xiong, Chorlada Paiboonrungruang, Yahui Li, M Ben Major, Xiaoxin Chen. NRF2-responsive kinases in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5961.
Abstract 5986: Significance of LIF/LIFR axis in the progression of inflammatory breast cancer
Authors: Romo Bianca , Fuentes Zenaida , Randolph Lois , Santhamma Bindu , Nair Hareesh , Thomas Christoforos , Vadlamudi Ratna , Viswanadhapalli Suryavathi 
Published: March 2024

Abstract
Background: Inflammatory breast cancer (IBC) is a rare form of locally progressed breast cancer. Even though it is uncommon, IBC accounts for 7% of breast cancer deaths. There is a critical need for novel therapeutic targets to develop new therapeutics. IBC is more common in young women. Altered levels of growth factors, and cytokine signaling are suspected to play a role in the progression of IBC. Leukemia inhibitory factor (LIF) is the most pleiotropic member of the interleukin-6 family of cytokines. LIF and its receptor LIFR have been linked to the progression of many cancers including triple negative breast cancer. We recently developed a first-in-class inhibitor targeting LIFR named EC359. However, the role of the LIF/LIFR axis in IBC progression remains unknown. In this study, we examined the significance of LIFR and the effectiveness of LIFR inhibitor EC359 in treating IBC.
Methods: The effect of LIFR inhibitor EC359 on cell survival, colony formation, and apoptosis was evaluated using three well-established IBC model cells (SUM149, SUM190PT, and KPL4). Mechanistic studies were conducted using Western blotting, CRISPR KO, reporter assays, and RT-qPCR. KPL4 cell-based xenografts were used to test the efficacy of EC359 in vivo.
Results: Our results using Western blotting confirmed increased expression of LIF and LIFR in IBC cells compared to normal and ER+ breast cancer cells. Treatment with EC359 significantly decreased IBC cell viability, long term colony formation ability with an IC50 of ~10-20 nM. Similarly, knock out of LIFR significantly reduced the progression of IBC model cells in cell viability and colony formation assays. Further EC359 treatment promoted apoptosis of IBC cells. Mechanistic studies confirmed that EC359 treatment substantially reduced LIF/LIFR downstream signaling including STAT3, AKT, and mTOR signaling. We also tested the utility of EC359 in treating IBC in vivo using KPL4 xenografts. EC359 (5mg/kg/day) is highly efficacious in reducing IBC xenograft tumor growth in vivo. IHC analyses of tumors confirmed decreased cell proliferation as measured by Ki67 staining.
Conclusion: Collectively, these studies demonstrated the therapeutic benefit of using EC359 to target the LIF/LIFR axis and opened the door for the development of new treatment approaches.
Citation Format: Bianca Romo, Zenaida Fuentes, Lois Randolph, Bindu Santhamma, Hareesh Nair, Christoforos Thomas, Ratna Vadlamudi, Suryavathi Viswanadhapalli. Significance of LIF/LIFR axis in the progression of inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5986.
Abstract 6004: HOXC8 epigenetically controls caspse-1 expression and pyroptosis in lung cancer cells
Authors: Sun Lei , Padia Ravi , Calbay Ozlem , Chi Cheng , Akter Mahmuda , Jin Lingtao , Huang Shuang 
Published: March 2024

Abstract
Homeobox C8 (HOXC8) is a transcription factor preferentially overexpressed in a large percentage of lung adenocarcinoma (LUAD). To investigate the function of HOXC8 in LUAD, we showed that knockdown of HOXC8 led to massive LUAD cell death in a mechanism of pyroptosis because both YVAD, a caspase-1 (CASP1) inhibitor, and disulfiram, which prevents gasdemin D (GSDMD) pore formation, blocked cell death caused by HOXC8 depletion. Intriguingly, ASC and NLRP3, components of canonic inflammasome, were not involved in pyroptosis occurring in HOXC8-depleted cells. Instead, we found that silencing HOXC8 led to a marked increase in CASP1 abundance. As forced expression of CASP1 is sufficient to induce CASP1 activation and pyroptosis, we reason that HOXC8 deters pyroptosis by suppressing the level of CASP1. Moreover, we revealed that knockdown of HOXC8 augmented CASP1 transcription involving in HDAC1/2. In fact, HOXC8 and HDAC1 were in the same immunocomplex and the presence of HOXC8 is required for the recruitment of HDAC1 to CASP1 promoter. Since HOXC8 also binds CASP1 promoter, we conclude that HOXC8 negatively regulates CASP1 expression by drafting HDAC1/2 to CASP1. This study suggests that HOXC8 participates LUAD development by controlling CASP1 expression and pyroptosis.
Citation Format: Lei Sun, Ravi Padia, Ozlem Calbay, Cheng Chi, Mahmuda Akter, Lingtao Jin, Shuang Huang. HOXC8 epigenetically controls caspse-1 expression and pyroptosis in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6004.
Abstract 6010: BRCA2 reversion alleles confer PARPi resistance via homology-directed repair, not fork protection
Authors: Jensen Ryan , Moore Gemma , Lahiri Sudipta 
Published: March 2024

Abstract
BRCA2 reversion alleles have been identified in relapsed, treatment resistant cancer patients. The reversions restore the open reading frame of the BRCA2 protein often resulting in significant sequence deletions with unknown functional consequences. No reports to date have introduced patient reversion mutations into a BRCA2 null cell model to analyze which BRCA2 functions are re-established and whether all or a subset of activities are required for PARPi resistance. Our study utilized BRCA2 reversion alleles identified through sequencing of circulating tumor DNA (ctDNA) from PARPi resistant ovarian cancer patients. We rigorously evaluated whether altered BRCA2 reversion proteins restore homology-directed repair (HDR), fork protection, or gap suppression to determine the specific activities required for PARPi resistance. We found that reverted BRCA2 proteins are functional for HDR by assessing survival response to PARPi, analyzing RAD51 foci at DSBs, DR-GFP reporter assays, RAD51 binding, and CRISPR/Cas9 gene targeting assays. Surprisingly, using the DNA fibercombing approach to assess replication fork dynamics, we identify two separation-of-function mutants, T1974 and C1654_M1890, which are deficient in fork protection, yet confer PARPi resistance. The mutations are located within the BRC 5-8 domain of BRCA2 proposed to play an important role in RAD51 nucleoprotein filament stability. Biochemical analyses of the purified proteins using single molecule FRET (smFRET) indicate reduced filament stability potentially explaining the deficit in fork protection. In conclusion, these separation-of-function BRCA2 mutations provide new mechanistic insight into the underlying biology of BRCA2 and reveal the specific functions needed to overcome PARPi-mediated cell death.
Citation Format: Ryan Jensen, Gemma Moore, Sudipta Lahiri. BRCA2 reversion alleles confer PARPi resistance via homology-directed repair, not fork protection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6010.
Abstract 6025: Discovery of novel macrocyclic peptide radioligands for tumor therapy by mRNA display
Authors: Jaekel Anika , Sherry Kathryn , Desai Prachi , Fox David , Guo-Qing Tang , Sturzbecher-Hoehne Manuel , Mewis Dennis , Noridomi Kaori , Rayman Liam , Ye Ping 
Published: March 2024

Abstract
Radioligand therapeutics (RLT) aim to selectively deliver radioisotopes to cancer tissues to eradicate tumor cells while limiting the damage to surrounding tissues. They are composed of a tumor-targeting ligand and a radioactive payload. The therapeutic potential of RLT strongly depends on their biostability and residence time in tumor and healthy tissue after injection. Macrocyclic peptides are effective tumor-targeting ligands because their size and molecular characteristics confer optimal pharmacologic properties that can be fine-tuned during the development process. mRNA display is a powerful platform for macrocyclic peptide drug discovery that identifies high affinity peptide ligands through in vitro selection. Here, we describe the selection and initial characterization of macrocyclic peptides discovered by mRNA display that bind to the extracellular domain of a tumor target. Enrichment of the library for peptides that bound to the recombinant target protein was observed after four rounds of selection with no further enrichment in round five. The library of round 5 was sequenced by Illumina sequencing and the top 1,000 sequences (highest counts) were used to perform cluster analysis. We tested the top sequences of 43 different clusters in in vitro translation binding assays to validate the selection output and identify sequences for hit confirmation. Most of the sequences tested showed clear binding to the target protein and only a few peptides showed binding to a closely related protein from the same protein family. No non-specific binding of the discovered peptides to an irrelevant protein was observed showing the high specificity of the generated library. From this confirmatory selection data, we chose a subset of peptides for chemical synthesis. Binding affinity measurements were determined by surface plasmon resonance (SPR) and cellular binding of selected candidates to target-positive and -negative tumor cells was analyzed by flow cytometry. From this hit confirmation data, in vitro internalization and in vitro anti-tumor efficacy of radiolabeled peptide candidates for RLT are assessed. Our data highlights the potential of mRNA display platforms for fast and efficient discovery of highly specific macrocyclic peptides with optimal binding properties suitable for RLT.
Citation Format: Anika Jaekel, Kathryn Sherry, Prachi Desai, David Fox, Tang Guo-Qing, Manuel Sturzbecher-Hoehne, Dennis Mewis, Kaori Noridomi, Liam Rayman, Ping Ye. Discovery of novel macrocyclic peptide radioligands for tumor therapy by mRNA display [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6025.
Abstract 6052: Systematic identification of novel targeted protein degradation mechanisms using SITESEEKER® technology
Authors: Dillon Christian 
Published: March 2024

Abstract
The rise of Targeted Protein Degradation (TPD) is rapidly changing perceptions about therapeutic target druggability and is rewriting many preconceived notions on drug design. However, the majority of monovalent molecular glue and heterobifunctional degraders in clinical and preclinical development rely predominantly on the recruitment of a single E3 ligase, Cereblon. Arising resistance, toxicities and restricted Protein-of-Interest scope may limit clinical potential, highlighting the need to uncover novel TPD mechanisms. To expand the potential of this modality, we have developed SITESEEKER®, a screening technology operating at substantially greater magnitude of complexity than extant target discovery platforms. SITESEEKER® utilizes computationally-derived encoded mini-protein fragments with huge shape diversity to systematically identify novel degrader mechanisms and define functionally-active binding sites on targets. SITSEEKER® allows for the discovery of targets that may be missed through traditional gene editing or knockdown approaches and can additionally provide valuable mechanistic insights that help to inform, unlock and truncate the path from target ID to drug discovery. We describe the identification of a cache of degrader motifs which showcase the breadth of proteome space yet to be explored within TPD. Moreover, we identify peptide motifs capable of driving degradation in a selective manner with potential to be translated into tissue- or cancer-selective degraders. The functional dependencies of prioritized degraders have been mapped to their cognate E3 ligase using combinatorial screening, giving rise to a number of E3 ligases with potential to be hijacked for TPD. PhoreMost is progressing a pipeline of monovalent and heterobifunctional oncology degrader programs arising from its platform. We demonstrate the effective hijacking of selected E3 ligases, identified by SITESEEKER®, through the discovery of high affinity small molecule binders and subsequent discovery of efficient heterobifunctional degraders against selected Proteins-of-Interest.
Citation Format: Christian Dillon. Systematic identification of novel targeted protein degradation mechanisms using SITESEEKER® technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6052.
Abstract 6103: The association of genetic polymorphisms in DNA repair genes XRCC1 and 3 with cervical cancer risk among Bangladeshi females
Authors: Rahman Md Mustafizur , Das Laboni , Rahman Sadia , Hossain Amir , Sultana Razia 
Published: March 2024

Abstract
Introduction and Objective: Worldwide, cervical cancer ranks the second most common cancer in women. Sequence variations in DNA repair genes X-ray repair cross complementing (XRCC) 1 and 3 genes can lead to can result cellular function aberration leading to cancers. Single nucleotide polymorphisms (SNPs) in XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) genes have been shown to cause individual variation in their DNA repair capacity. The aim of this study was to investigate the association of XRCC1 Arg399Gln and XRCC3 Thr241Met SNPs with susceptibility to cervical cancer among Bangladeshi populations.
Methods: In the current case-control study 124 cervical cancer patients and 148 age matched healthy controls were recruited. Genomic DNAs were isolated from peripheral blood collected from the participants and genotyped for candidate SNPs using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
Results: For XRCC1, heterozygous Arg/Gln and combined heterozygous plus variant homozygous Gln/Gln genotypes showed 1.78-fold (95% CI 1.0037 to 2.8771, p=0.0484) and 1.8627-fold (95% CI 1.1470 to 3.0250, p = 0.0119) increased risk of cervical cancer, respectively, when compared with normal homozygous Arg/Arg genotype. The variant Gln allele was positively associated with cervical cancer by 1.68-fold increase (95% CI 1.1732 to 2.3980, p = 0.0046). Similarly, for XRCC3, Thr/Met heterozygous and combined Thr/Met + Met/Met genotypes were found to be associated with 1.6993-fold (95% CI 1.0398 to 3.0166, p=0.0354) and 1.8312-fold (95% CI 1.0890 to 3.0791, p = 0.0225) higher risk, respectively, when compared with normal homozygous Thr/Thr genotypes. The variant Met allele showed significant association with 1.71-fold increased risk.
Conclusion: XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) SNPs may be positively associated with increased cervical cancer risk in Bangladeshi females.
Citation Format: Md Mustafizur Rahman, Laboni Das, Sadia Rahman, Amir Hossain, Razia Sultana. The association of genetic polymorphisms in DNA repair genes XRCC1 and 3 with cervical cancer risk among Bangladeshi females [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6103.
Abstract 6190: Patterns of EGFR and HER3 co-expression in solid tumors
Authors: Wood Matthew , Morrison Cody , Khalili Jahan Salar , Zhu Yi 
Published: March 2024

Abstract
EGFR and HER3 are members of the ERBB receptor family and transmit growth and survival signals to cancer cells upon ligand binding. While both receptors are well established targets for cancer therapy, greater understanding of the relationship of their expression patterns in human cancer is needed to establish the scope of therapeutic potential. To evaluate the co-expression pattern of EGFR and HER3, cancer FFPE tissue microarrays from several cancer types were evaluated by immunofluorescence imaging and digital pathology, including cell-by-cell marker intensity and spatial analyses within the tumor and stromal compartments. Tissue cores were assigned H-scores, and individual cells were binned into 0, 1+, 2+, 3+ scoring based on established digital pathology methods using QuPath software. Spatial cytometry was used to further evaluate single-cell expression intensity. Analysis was conducted widely on multiple normal human tissues as well as cases of NSCLC adenocarcinoma n=86, NSCLC squamous cell carcinoma n=84, SCLC n=43, TNBC n=45, Biliary tract cancers n=80, Nasopharyngeal carcinomas n=60. Overall, the results of this analysis show the intermediate to high prevalence of EGFR and HER3 co-expression within each indication, as well as the frequency of EGFR and HER3 expressing cells. Furthermore, EGFR and HER3 heterodimers were confirmed by proximity ligation assay in certain index cases. Notably, of several observations, we observe NSCLC cases show a profound absence of EGFR- HER3+ tumor cells. Additionally, we observe that co-expression of EGFR and HER3 in normal human tissues is rare and of low signal intensity.
Citation Format: Matthew Wood, Cody Morrison, Jahan Salar Khalili, Yi Zhu. Patterns of EGFR and HER3 co-expression in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6190.
Abstract 62: Intra-tumor persistence of activated anti-mesothelin hYP218 CAR T cells is associated with increased efficacy in gastric and colorectal cancers
Authors: Mir Sameer A. , Venugopalan Abhilash , Zhang Jingli , Khanal Mana Kamana , Stathopoulou Chaido , Sengupta Manjistha , Jiang Qun , Hassan Raffit 
Published: March 2024

Abstract
Purpose: Patients with gastric and colorectal cancers that have progressed after standard therapies have poor prognosis. Given the high expression of mesothelin in these tumor types, we examined the potential utility of the anti-mesothelin hYP218 CAR T cells to treat these cancers.
Experimental Design: Cell surface mesothelin expression in a panel of gastric and colorectal cancer cell-lines was analyzed using flow cytometry. In vitro efficacy of hYP218 CAR T cells against these cell lines was evaluated using cytotoxicity and cytokine release assays. In vivo efficacy of hYP218 CAR T cells was studied using gastric (HGC27) and colorectal (SW48) tumor xenografts in NSG mice. NSG mice were injected with 1 × 106 cancer cells and the tumors were allowed to grow until they reached a volume of 80-100mm³, after which the mice were treated with either 5 × 106 hYP218 CAR T cells, 5 × 106 untransduced T cells, or saline and monitored over time. Persistence of CAR T cells in the tumor was evaluated over time and expression of activation and exhaustion markers were studied.
Results: hYP218 CAR T cells demonstrated strong cytotoxic activity against mesothelin positive gastric and colorectal cancer cell lines and exhibited increased pro-inflammatory cytokine production. In both the HGC27 and SW48 tumor models hYP218 CAR T cells demonstrated significant reduction in tumor volume and overall survival compared to mice treated with untransduced T cells or saline. CAR T cells isolated from tumors of both the xenograft models, at day 40 after treatment, displayed higher expression levels of activation markers CD39 and CD69 when compared to the infused product. Furthermore, a concomitant elevation in the levels of effector cytokines, TNF-α and IFN-γ, was detected in the blood of treated mice demonstrating the functional capacity of the CAR T cells to not only persist but also to maintain an activated state.
Conclusions: hYP218 CAR T cells show anti-tumor efficacy against gastric and colorectal tumor xenografts due to increased accumulation of activated CAR T cells in the tumor and warrants further investigation for treatment of patients with these cancers.
Citation Format: Sameer A. Mir, Abhilash Venugopalan, Jingli Zhang, Mana Kamana Khanal, Chaido Stathopoulou, Manjistha Sengupta, Qun Jiang, Raffit Hassan. Intra-tumor persistence of activated anti-mesothelin hYP218 CAR T cells is associated with increased efficacy in gastric and colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 62.