bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5872: CDK1-SOX9 axis contributes to chemotherapy resistance in gastric cancer
Authors: Al-Mathkour Marwah M. , Zhu Shoumin , Genoula Melanie , El-Rifai Wael 
Published: March 2024

Abstract
Gastric carcinoma (GC) is the third most prevalent cause of cancer-related mortality worldwide, presenting a formidable challenge with the rise of resistance to chemotherapeutic agents, leading to treatment failures. Cyclin-dependent kinase 1 (CDK1) has garnered attention due to its substantial overexpression in various tumors, including GC, and its association with poor overall survival and relapse-free survival. This study aimed to understand the molecular and functional mechanisms underlying the CDK1-SOX9 axis in GC chemotherapy resistance. Through a comprehensive analysis of data from The Cancer Genome Atlas (TCGA) and our own integrated gene expression study, we found a positive correlation between CDK1 and SOX9 in both human and mouse GC tissues (p&lt;0.001). Additionally, conserved alterations in miRNAs have been identified in the context of gastric carcinogenesis, evident in our local cohort and the TCGA dataset. Our in-depth investigation of premiR-145 has shed light on the existence of several CpG nucleotides. Notably, treatment with a DNMT inhibitor (5-Aza) has triggered the upregulation of miR-145 expression. Furthermore, the ectopic expression of CDK1 has been associated with increased DNMT1 phosphorylation and enhanced enzymatic activity. Conversely, silencing CDK1 reversed this effect, and the inhibition of DNMT1 reduced SOX9 protein expression. Using cisplatin-resistant cell lines revealed a significant increase in CDK1 and SOX9 expression where silencing CDK1 and SOX9 sensitized these cells to chemotherapy. This study provides valuable insights into the intricate mechanisms governing the CDK1-SOX9 axis in GC chemotherapy resistance, providing potential avenues for therapeutic interventions in this challenging malignancy.
Citation Format: Marwah M. Al-Mathkour, Shoumin Zhu, Melanie Genoula, Wael El-Rifai. CDK1-SOX9 axis contributes to chemotherapy resistance in gastric 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 5872.
Abstract 5894: Novel splicing-derived neoantigen in triple negative breast cancer uncovered by SpliceIO™ a robust platform for the discovery and validation of disease-specific immunotherapies
Authors: Williams Nicole , Manzanares Miguel A. , Anderson Kendall , Zunrut Hasan , Gera Sakshi , Habib Nayab , Stanton Shaleigh , Floyd Taylor , Shah Sanjana , Trahan Devon , Akerman Martin , Arun Gayatri 
Published: March 2024

Abstract
Splicing dysregulation is a major hallmark of cancer, affecting tumor progression, metastasis, and therapy resistance. Aberrant alternative splicing (AS) plays a critical role in generating tumor-specific neoantigens targetable through an arsenal of immunotherapeutic modalities. Such neoantigens cannot be discovered using conventional DNA-based tools; they require specialized software for AS analysis using RNA-seq data. SpliceIO is Envisagenics’ AI platform for AS-derived neoantigen discovery. SpliceIO uses a “predictive ensemble” approach to uncover neoantigens that are both stably expressed and located on the extracellular membrane of cancer cells. Using SpliceIO, we have analyzed more than 10,000 RNA-seq samples from 5 patient cohorts covering 5 breast cancer subtypes as well as 2,647 normal RNA-seq samples from GTEx. Our analysis has identified tumor-specific neoantigens present in AS transmembrane proteins specific for Triple Negative Breast Cancer. SpliceIO target candidates were validated experimentally using our well-established pipeline in which isoform specific transcripts are tested in cancer cell lines by PCR and primary tumor tissues by qPCR to confirm RNA expression. Tumor heterogeneity and prevalence is confirmed by RNA in-situ hybridization in Tissue Microarrays. Extracellular localization of the novel epitope is confirmed by clone generation with GFP and c-Myc tagging followed by microscopy, Western blotting, and proteomic analysis. Our top validated target presents high TNBC tumor specificity and heterogeneous distribution, and contains a novel extracellular N-terminal domain. These results strongly support the role of aberrant AS as a major source of tumor-specific neoantigens. Our combined computational and experimental approach promotes novel target discovery, enabling the development of novel immunotherapeutic for TNBC patients who are in critical need of better treatment options.
Citation Format: Nicole Williams, Miguel A. Manzanares, Kendall Anderson, Hasan Zunrut, Sakshi Gera, Nayab Habib, Shaleigh Stanton, Taylor Floyd, Sanjana Shah, Devon Trahan, Martin Akerman, Gayatri Arun. Novel splicing-derived neoantigen in triple negative breast cancer uncovered by SpliceIO™ a robust platform for the discovery and validation of disease-specific immunotherapies [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 5894.
Abstract 5907: Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-317 targeting NaPi2b
Authors: Huang Wentao , Liu Zhifang , Li Yifan , Pan Heng , Qin Xia , Fei Da , Li Runsheng 
Published: March 2024

Abstract
Introduction: NaPi2b is a multi-transmembrane type II sodium-dependent phosphate transporters that regulates phosphate homeostasis in normal physiological condition [1]. It is highly expressed in ovarian cancer (OC), non-small-cell lung cancer (NSCLC), and papillary thyroid cancer, with limited expression in normal tissue, making it a promising target for antibody-drug conjugates (ADCs) [2,3]. LM-317 is a novel NaPi2b targeted humanized monoclonal antibody LM-117 conjugated to the next-generation topoisomerase I inhibitor LDX2 via a cleavable linker, with antibody-drug ratio of 8. Here, we present the preclinical in vivo and in vitro results of LM-317.
Results: LM-317 is highly specific cross-reactive with rhesus monkeys, cynomolgus monkeys, mouse, and rat NaPi2b. Concentration-dependent cell binding and internalization effects of LM-317 were observed in human NaPi2b-expressing cells, and OC and NSCLC cells expressing NaPi2b, with EC-50 of 0.92 - 9.7 nM and 1.51 - 4.76 nM, respectively. The cytotoxicity effect of LM-317 in NaPi2b -positive tumor cells was superior to LM-117-DXD, with IC-50 of 0.002 - 0.52nM. The in vivo studies showed that 1 mg/kg of LM-317 almost completely eradicated tumors in the OVCAR-3 xenograft mice model of OC, and similar antitumor activity was observed in the NCI-H175-xenograft mice model of NSCLC at the dose of 3 mg/kg. Single dose of 6 mg/kg of LM-317 showed sustained tumor eradication in the NSCLC xenograft -mouse model. LM-317 also exhibited potent tumor regression in the PDX model of OC and NSCLC. The tumor growth inhibition (TGI) value was 80%-100% in OC and NSCLC PDX models with different expression degree of NaPi2b after treatment with LM-317. The antitumor activity of LM-317 in cell line- and PDX models of OC and NSLCL was comparable to those of LM-117-DXD.
Conclusion: The novel ADC LM-317 targeting NaPi2b showed robust antitumor activity in vitro, and in the OC and NSCLC cell line derived models and PDX models. LM-317 could potentially provide therapeutic benefit to treat NaPi2b-positive tumors including OC and NSCLC in the future.
Reference: 1.S. Banerjee et al. Cancer Treatment Reviews 112 (2023) 1024892.Finstad CL, Lloyd KO, Federici MG, et al. Clin. Cancer Res. 1997;3(8):1433-14423.Zhang et al. Tumor Biology July 2017: 1-7.
Citation Format: Wentao Huang, Zhifang Liu, Yifan Li, Heng Pan, Xia Qin, Da Fei, Runsheng Li. Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-317 targeting NaPi2b [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 5907.
Abstract 5910: Developing a novel humanized anti-FABP4 antibody for breast cancer treatment
Authors: Hao Jiaqing , Yorek Matthew , yu Jian , Avellino Anthony , Li Bing 
Published: March 2024

Abstract
Circulating levels of adipocyte fatty acid binding protein (A-FABP, also known as FABP4) are linked with metabolic dysregulation. Our previous study demonstrated that high serum levels of FABP4 increased the risk of breast cancer, indicating that circulating FABP4 could be a potential therapeutic target for this disease. In this study, we generated mouse monoclonal antibodies (mAb) against FABP4 by immunizing C57BL/6 mice with recombinant human FABP4. After screening over 1300 hybridoma clones, we identified an FABP4 neutralizing mAb, named 12G2, which inhibited breast cancer growth in various mouse models. To facilitate clinical application, we engineered chimeric and humanized variants of the 12G2 mAb. Notably, the humanized variant, 12G2-variant 9 (12G2-vt9), effectively inhibited mammary tumor growth and progression by reducing the activity of FABP4/ALDH1 in different breast cancer mouse models. Our findings suggest that 12G2-Vt9 is a promising neutralizing mAb targeting FABP4-mediated cancer stemness through ALDH1 signaling, offering potential as a targeted therapeutic antibody for the clinical treatment of breast cancer.
Citation Format: Jiaqing Hao, Matthew Yorek, Jian yu, Anthony Avellino, Bing Li. Developing a novel humanized anti-FABP4 antibody for breast cancer treatment [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 5910.
Abstract 5914: Non-muscle myosin IIA as a promising therapeutic target in breast cancer
Authors: Feroz Wasim , Mishra Rosalin , Kilroy Mary Kate , Garrett Joan T. 
Published: March 2024

Abstract
We aimed to determine the role of non-muscle myosin IIA (NMIIA) in breast cancer using various cancer cell lines including estrogen receptor (ER)+, HER2+ and triple negative breast cancers (TNBC). Myosin heavy chain 9 (MYH9) gene encodes for the heavy chain of the hexameric protein NMIIA. We have recently identified that NMIIA serves as a binding partner for HER3 following the inhibition of the HER family member compared to the vehicle control treatment, as observed in HER3 immunoprecipitates. We checked the basal protein and mRNA levels of NMIIA in different breast cancer cell lines and found higher levels of NMIIA in both HER2+ and TNBC cell lines compared to ER+ cell lines. These data correlate with clinical data of primary breast cancer patients with high MYH9 being less likely in ER+ breast cancer patients and more likely in the PAM50 subtypes basal and HER2 enriched breast cancer patients. By employing a pool of four siRNA targeting MYH9, our data indicated a reduction in proliferation of HER2+ and TNBC cell lines when compared to the control siRNA. We have previously found that loss of MYH9 sensitizes to the HER family inhibitor neratinib treatment as assessed by cell proliferation, colony formation on matrigel, cell migration and invasion. We aimed to determine if pharmacological inhibition of the NMIIA pathway would sensitize to neratinib. RhoA-associated kinase (ROCK) serves as a master regulator of NMIIA activity as it directly phosphorylates the regulatory light chain (RLC) of NMIIA. Pharmacological inhibition of ROCK-NMIIA pathway using the ROCK inhibitor GSK269962A alone or in combination with neratinib reduced the cell proliferation in HER2+ cell lines BT474 and MDA-MB-453 as indicated by MTT and cell proliferation assay. It is well known that HER2-targeted therapies cause the upregulation of HER3. Given our identification of NMIIA as one of the interacting partners of HER3, our focus will be on investigating the NMIIA-HER3 signaling axis to elucidate its contribution to an adaptive response to HER2 inhibition and potential treatment resistance. Furthermore, we will explore strategies to target NMIIA in breast cancer.
Citation Format: Wasim Feroz, Rosalin Mishra, Mary Kate Kilroy, Joan T. Garrett. Non-muscle myosin IIA as a promising therapeutic target in 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 5914.
Abstract 5928: Structure-activity relationships for the pan-quadruplex experimental drug QN-302 and two analogs probed with comparative transcriptome profiling and molecular modeling
Authors: Ahmed Ahmed A. , Haider Shozeb , Arshad Tariq , Neidle Stephen 
Published: March 2024

Abstract
The tetrasubstituted naphthalene diimide compound QN-302 binds to G-quadruplex DNA structures. It inhibits the transcription of cancer-related genes in pancreatic ductal adenocarcinoma (PDAC) cells, shows high potency in PDAC cells in vitro and in PDAC animal models. It is currently in Phase 1 clinical evaluation as an anticancer drug for advanced, metastatic solid tumors. A study of structure-activity relationships of QN-302 and two related analogs (CM03 and SOP1247) is reported here. These have been probed using comparisons of transcriptional profiles from whole-genome RNA-seq analyses, together with qualitative molecular modelling. Compounds CM03 and SOP1247 differ by the presence of a methoxy substituent in the former: these two have closely similar transcriptional profiles, whereas that of QN-302, although showing effects in the same cancer-related pathways, highlights the down regulation of distinct genes, for example in the hedgehog pathway. The distinct pattern of genes affected by QN-302 is hypothesized to contribute to its superior potency compared to CM03 and SOP1247. Its superior ability to stabilize quadruplex structures has been attributed to its benzyl-pyrrolidine substituent fitting into and filling most of the space in a quadruplex groove compared to the hydrogen atom in CM03 or the methoxy group in SOP1247.
Citation Format: Ahmed A. Ahmed, Shozeb Haider, Tariq Arshad, Stephen Neidle. Structure-activity relationships for the pan-quadruplex experimental drug QN-302 and two analogs probed with comparative transcriptome profiling and molecular modeling [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 5928.
Abstract 5947: Discovery of ACE-47228211, a highly potent and selective SOS1 inhibitor
Authors: Wang Junmei , Li Wenqian , Kumar Sanjeev , Pan Weitao , Wen Zhiming , Yin Tinggui , Zhao Genshi , Yu Kuo-Long 
Published: March 2024

Abstract
Dysregulation of receptor tyrosine kinase (RTKs) and KRAS signaling is the most frequent causes of cancer development and progression. SOS1 is one of the major guanine nucleotide exchange factors (GEFs) that facilitates the conversion of the inactive GDP-bound KRAS “off” state to the activated GTP-bound KRAS “on” state. SOS1 is therefore required for dysregulated RTKs, and wildtype and mutant KRAS proteins to drive cancer cells. In addition, SOS1 plays a crucial role in modulating the reactivation of the RAS/MAPK signaling upon the treatment of RAS/MEK/ERK inhibitors. Thus, blocking SOS1 and KRAS protein-protein interactions could be an effective strategy for targeting KRAS-MAPK driven cancers. Here, we report the discovery of a highly potent and orally bioavailable small molecule SOS1 inhibitor, ACE-47228211. This molecule has a unique novel scaffold. It exhibits an IC50 of 8.5 nM in the SOS1-KrasG12D (GDP) exchange assay and 5.0 nM in cellular ERK phosphorylation assay in H1957 cells. ACE-47228211 at 3 mg/kg (BID) demonstrated significant tumor growth inhibition in MiaPaca-2 KRAS G12C tumor model than MRTX0920 at 50 mg/kg (BID). When combined with Sotorasib (5 mg/kg QD), a Kras G12C inhibitor, ACE-47228211 at 3 mg/kg exhibited synergistic effect similar to MRTX0920 at 50 mg/kg. Further, ACE-47228211 demonstrated synergistic effects with EGFR and FGFR2 inhibitors in RTK mutant tumor models. ACE-47228211 has excellent ADME and physical properties with low risks of hERG, CYP inhibition and drug-drug interactions. The evaluation of ACE-47228211 in a safety panel of 87 targets and a kinase panel of &gt;500 targets shows that this molecule has favorable selectivity and safety profiles. The molecule is currently in IND enabling stage of development.
Citation Format: Junmei Wang, Wenqian Li, Sanjeev Kumar, Weitao Pan, Zhiming Wen, Tinggui Yin, Genshi Zhao, Kuo-Long Yu. Discovery of ACE-47228211, a highly potent and selective SOS1 inhibitor [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 5947.
Abstract 6026: A novel lutetium-177 radioligand therapy targeting FAP has potent antitumor activity in xenograft cancer model
Authors: Lindeman Spencer , Higgins Jack 
Published: March 2024

Abstract
Fibroblast Activation Protein (FAP) is an attractive target for cancer therapy due to its overexpression in most solid tumors, predominantly localized on cancer associated fibroblasts. Unfortunately, trials with first generation FAP-targeted radioligand therapies (RLTs) have produced only modest clinical responses, indicating the need for improvements. We developed a library of over 40 fully synthetic, novel FAP-targeted RLTs comprising a FAP inhibitor with a stable linker to an albumin binding domain and a DOTA-lutetium-177 payload. Screening this library for binding, biodistribution and pharmacology properties identified a 177Lu-FAP RLT lead molecule. The novel 177Lu-FAP RLT demonstrates high selectivity and binds to FAP with a sub-nanomolar binding affinity. Biodistribution of the 177Lu-FAP RLT was evaluated in mice bearing U87MG tumors, demonstrating delivery and retention of a high tumor absorbed dose. In vivo efficacy of the 177Lu-FAP RLT at 150 µCi or 500 µCi was evaluated in mice bearing U87MG tumors. The 177Lu-FAP RLT elicits potent and dose-dependent antitumor activity with &gt;80% reduction in tumor volume of 8/10 mice following a single 500 µCi dose. The treatment was well-tolerated, with no significant weight loss or deaths. The outstanding antitumor activity and high selectivity for FAP support further evaluation of this investigational RLT in patients with solid tumors.
Citation Format: Spencer Lindeman, Jack Higgins. A novel lutetium-177 radioligand therapy targeting FAP has potent antitumor activity in xenograft cancer model [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 6026.
Abstract 6049: Cell-based PROTAC screening for cancer drug discovery
Authors: Wan Yong , Ma Haiqing , Wu Jianghong 
Published: March 2024

Abstract
Proteolysis-Targeting Chimeras (PROTACs) have emerged as a promising strategy for selectively degrading specific target proteins, thereby offering a novel approach to precision cancer therapy. Among the most notable oncogenes, KRAS with the G12C mutation is responsible for 45%-50% of KRAS mutations in non-small cell lung carcinomas. Additionally, BRD4, a well-studied member of the Bromo- and Extra-Terminal (BET) protein family, is implicated in various hematological and solid tumors. The implementation of cell-based screening for PROTACs targeting either KRAS(G12C) or BRD4 represents a highly valuable platform for advancing cancer drug discovery. We utilized the NanoBRETTM Ternary Complex Assay, NanoBiTTM Assay, and Western Blot assay to evaluate the efficacy of PROTACs. The NanoBRETTM Ternary Complex Assay revealed that KRAS G12C degrader-1 and LC-2 effectively degrade KRAS(G12C), while dBET6 and MZ-1 demonstrated the ability to degrade BRD4. Notably, the NanoBiTTM assay showed that LC-2 dose-dependently degrades KRAS(G12C) in HEK293 cells co-transfected with KRAS(G12C)-LgBiT and KRAS(G12C)-SmBiT. Moreover, BET6 exhibited a dose-dependent degradation of endogenous BRD4 in HepG2 cells, and LC-2 demonstrated the degradation of endogenous KRAS(G12C) in MiaPaCa2 cells. In summary, the development of a robust cell-based assay platform for high-throughput screening of PROTACs marks a substantial advancement in cancer drug discovery. This approach not only enables the identification of promising PROTACs but also holds the potential for more effective and targeted interventions in the ongoing battle against cancer.
Citation Format: Yong Wan, Haiqing Ma, Jianghong Wu. Cell-based PROTAC screening for cancer drug discovery [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 6049.