bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB044: Selective therapeutic antibodies against oncogenic mutations of the HER2 extracellular region
Authors: Bang Injin , Hattori Takamitsu , Leloup Nadia , Corrado Alexis , Nyamaa Atekana , Koide Akiko , Geles Ken , Buck Elizabeth , Koide Shohei 
Published: April 2024

Abstract
Oncogenic mutations of HER2 have been identified in HER2-low tumors. Such mutations in the extracellular region could serve as tumor-specific antigens that are accessible to antibody therapeutics. Although multiple antibody therapeutics have been successfully developed against cancers that overexpress wild-type HER2, none is specifically applicable to treating tumors driven by HER2 mutants expressed at a low level. Here, we developed antibodies exquisitely selective to HER2 S310F and S310Y, two most common oncogenic mutations in the HER2 extracellular region. Cryo-EM structures of the homodimer of HER2 S310F and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimic the dimerization arm of HER and inhibit HER2 dimerization. These antibodies as T-cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro and in a mouse xenograft model. These results validate HER2 extracellular region mutations as actionable therapeutic targets and offer promising candidates toward clinical development. More generally, they suggest that point mutations in the extracellular region of cell-surface receptors as actionable targets for anti-cancer therapy.
Citation Format: Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide. Selective therapeutic antibodies against oncogenic mutations of the HER2 extracellular region [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB044.
Abstract LB057: Pre-clinical characterization of IBI343, a site-specifically conjugated anti-Claundin18.2 ADC, for treating solid tumors
Authors: Zhou Shuaixiang , Yao Xiong , Guan Jian , Fei Keke , Lu Jia , Wu Weiwei , Liu Yang , Zhu Tianyu , Liao Zhuangguang , Chen Shi , Chen Bingliang , He Kaijie 
Published: April 2024

Abstract
Claudin18.2 is important for the formation and function of tight junctions between cells in epithelial tissues. Normally expressed only in gastric mucosa, Claudin18.2 is overexpressed in multiple types of solid tumors, including gastric, pancreatic, breast and colon cancers. Despite being a well-established tumor-associated antigen, the clinical value and feasibility of targeting Claudin18.2 by various modalities are yet-to-be fully demonstrated. IBI343 is a fully humanized anti-Claudin18.2 monoclonal antibody conjugated to Exatecan via site-specific glycol-conjugation with an average drug-to-antibody ratio (DAR) of 3.6. IBI343 showed robust antigen-specific in vitro cytotoxicity in cancer cell lines with varying levels of Claudin18.2 expression. In addition, due to the cleavable linker design and high hydrophilicity of the payload, IBI343 demonstrated potent bystander killing effects in vitro. The glycan-based conjugation technology leads to enhanced stability of the conjugated linker-payload and the entire ADC molecule, which results in superior pharmacokinetics. IBI343 showed potent in vivo anti-tumor efficacy with complete tumor regressions in multiple xenograft models. Furthermore, it demonstrated strong in vitro and in vivo synergistic effects with various anti-cancer agents, including immune checkpoint blockers and DNA damage repair pathway inhibitors. IBI343 displayed good safety profile in monkey GLP toxicology study (HNSTD = 30 mg/kg). These pre-clinical findings show that IBI343 is a promising anti-cancer agent with large therapeutic window, and support clinical exploration of IBI343 in patients with Claudin18.2-expressing tumors. A companion late-breaking abstract of clinical phase 1 study results (NCT05458219) will also be presented in AACR 2024.
Citation Format: Shuaixiang Zhou, Xiong Yao, Jian Guan, Keke Fei, Jia Lu, Weiwei Wu, Yang Liu, Tianyu Zhu, Zhuangguang Liao, Shi Chen, Bingliang Chen, Kaijie He. Pre-clinical characterization of IBI343, a site-specifically conjugated anti-Claundin18.2 ADC, for treating solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB057.
Abstract LB061: Aurora kinases inhibition enhances neoadjuvant chemotherapy response in triple negative breast cancer
Authors: Xu Jia , Liu Chang , Ning Bohan , Kucukdagli Ali Cem , Chen Yunjia 
Published: April 2024

Abstract
Triple-Negative Breast Cancer (TNBC) is a type of breast cancer without expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). TNBC accounts for around 15-20% of all breast cancers, and it remains the most challenging subtype to treat because of its aggressive phenotype and limited treatment strategies. Since TNBC does not respond to endocrine and HER2-targeted therapy, chemotherapy and anti-PD-L1 immunotherapy remain the major treatment strategies so far. However, not all TNBC patients respond to chemotherapy, suggesting that TNBC is a complicated disease. Identifying biomarkers to further predict and subdivide TNBC patients with distinct chemotherapy responses and outcomes is very important. To profile the protein expression and phosphorylation alterations, comprehensive proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant chemotherapy for TNBC. From a Reverse Phase Protein Array (RPPA) on TNBC cell lines MDA-MB-468 cells and MDA-MB-231 cells treated with Docetaxel, Paclitaxel, Epirubicin, and Doxorubicin, we found only a short list of protein changes after chemotherapy. Among them, the most significant changes in protein are phosphor-AURKA/B/C, AURKA, AURKB, and PLK1, which fall into the mitotic kinase group and are confirmed by western blot analysis. In addition, no significant change in the mRNA level was found after chemotherapy treatment, suggesting a post-transcription level molecular mechanism regulates the upregulation of AURKA and AURKB protein. In fact, the protein level of AURKB decreased more significantly with Cycloheximide (CHX) treatment alone compared with the co-treatment of CHX and Paclitaxel, indicating Paclitaxel extended the lifetime of Aurora Kinases protein and increased the protein stability. Moreover, AURKB or AURKA overexpression in TNBC cells renders them resistant to Paclitaxel treatment and attenuates the apoptosis effect triggered by chemotherapy treatment, suggesting Aurora Kinases could mediate the chemo-resistance in TNBC. To overcome the resistance to chemotherapy, we treated resistant TNBC cells with the combination of Aurora kinase inhibitors and anthracycline/taxane chemotherapy and found that Aurora kinase inhibition significantly enhanced the chemotherapy effect. In summary, we found that Aurora Kinases upregulation by treatment with Taxanes-type and Anthracyclines-type chemotherapy could render chemotherapy resistance to TNBC cells.
Citation Format: Jia Xu, Chang Liu, Bohan Ning, Ali Cem Kucukdagli, Yunjia Chen. Aurora kinases inhibition enhances neoadjuvant chemotherapy response in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB061.
Abstract LB099: Identifying actionable genomic alterations in non-small cell lung cancer through the analysis of extracellular vesicles in plasma
Authors: He Hongzhang , Milosevic Jadranka , Zheng Siyang 
Published: April 2024

Abstract
Lung cancer is the second most common cancer worldwide, accounting for 2.2 million new cases and 1.8 million deaths in 2020. Personalized targeted therapy based on actionable molecular markers has completely transformed the therapeutic landscape in NSCLC, which has improved considerably the overall survival. However, ~50% of NSCLC patients with tissue biopsy inaccessible or inadequate, limiting biomarker testing and access to targeted therapies. The availability of a wide range of highly effective targeted therapy options for NSCLC justifies the significance of developing non-invasive and cost-effective detection assays for guiding targeted therapy selection in NSCLC.Extracellular vesicles (EVs) are lipid-bilayer-enclosed vesicles of sub-micrometer size that are secreted by virtually all cell types. They contain hundreds of different proteins, thousands of intact RNA species, and double-stranded DNA (dsDNA) fragments that sample the entire human genome. Recent findings further corroborate the potential role of EVs in early cancer screening, cancer diagnosis, treatment selection and monitoring. In this study, we used lipid nanoprobe (LNP) for EV isolation from plasma and droplet digital PCR assay for detecting actionable genomic alternation to aid targeted therapy selection in NSCLC. Specifically, we extracted EV associated DNA/RNA from plasma first, and then we used the individual ddPCR assays for detecting KRAS mutations, EGFR mutations, and ALK fusions from isolated EVs associated nucleic acids, respectively. We identified KRAS mutations G12C/G12S/G13C/G12A/Q61H, EGFR L858R mutation and exon 19 deletion, and ALK-EML4 gene fusion variant 3 from 12 NSCLC patients that matched the mutation status obtained from patient tissue specimens. Only in 1 out 13 patients, EV mutation status did not match the mutation status from the tissue specimen. This data indicated that clinical actionable gene mutations are present in EVs associated nucleic acids isolated from plasma samples of NSCLC patients. We anticipate that this novel non-invasive EVs-based actionable genomic alterations detection test would efficiently assist physicians/oncologists in selecting optimal targeted therapies for cancer treatment, as recommended by National Comprehensive Cancer Network (NCCN) guidelines for NSCLC.
Citation Format: Hongzhang He, Jadranka Milosevic, Siyang Zheng. Identifying actionable genomic alterations in non-small cell lung cancer through the analysis of extracellular vesicles in plasma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB099.
Abstract LB114: STING licensing of type I dendritic cells potentiates antitumor immunity
Authors: Wang Jian , Li Suxin , Wang Maggie , Wang Xu , Chen Shuqing , Sun Zhichen , Ren Xiubao , Huang Gang , Sumer Baran D. , Yan Nan , Fu Yang-Xin , Gao Jinming 
Published: April 2024

Abstract
Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a “shock-and-lock” dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells (Tmem173− / − ) is important for antitumor efficacy. Specific depletion of cDC1 (Batf3− / − ) or STING deficiency in cDC1 (XCR1creSTINGfl/fl ) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wildtype cDC1 in Batf3− / − mice restored antitumor efficacy while transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wildtype but not Batf3− / − mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival while also showing increased expressions after neoadjuvant pembrolizumab therapy in non-small cell lung cancer patients. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis.
Citation Format: Jian Wang, Suxin Li, Maggie Wang, Xu Wang, Shuqing Chen, Zhichen Sun, Xiubao Ren, Gang Huang, Baran D. Sumer, Nan Yan, Yang-Xin Fu, Jinming Gao. STING licensing of type I dendritic cells potentiates antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB114.
Abstract LB144: The short-term associations of air pollutants with inflammation and oxidative stress markers in the Korean population
Authors: Lee Kyoungho , Kim Ji Hyun 
Published: April 2024

Abstract
Inflammation and oxidative stress responses induced by air pollutants are major biological mechanisms that can lead to multiple chronic diseases. We investigated the association between short-term exposure to ambient air pollutants and circulating levels of inflammatory cytokines, as well as a urinary marker of oxidative DNA damage in Korean adults (n=2,199) from the Korea Genome and Epidemiology Study. Circulating levels of inflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, and TNF-α, as well as urinary levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), were selected as biomarkers of interest. We estimated a range of air pollutants, such as particulate matter (PM, PM10 and PM2.5) and nitrogen dioxide (NO2), utilizing a chemical transport model. The exposure duration was defined based on 1- to 7-day averages. To explore the association between air pollution and biomarkers, we utilized multivariable linear models adjusting for major covariates, including demographic, lifestyle, relative humidity, and temperature. PM10 was linked to increased levels of IL-1β, IL-10, TNF-α, and 8-OHdG, and PM2.5 was associated with elevated levels of IL-1β, IL-10, IL-8, TNF-α, and 8-OHdG. With each 10 μg/m3 increase in the weekly average of PM, the largest magnitude of percent changes were observed for IL-1β levels (PM10: 2.7%, 95% CI 0.6 to 4.8; PM2.5: 6.4%, 95% CI 2.4 to 10.5). NO2 showed statistically non-significant associations with any of the biomarkers. As a result, short-term exposure to ambient PM may trigger oxidative damage and pro-and anti-inflammatory responses.
Citation Format: Kyoungho Lee, Ji Hyun Kim. The short-term associations of air pollutants with inflammation and oxidative stress markers in the Korean population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB144.
Abstract LB185: High resolution telomere measurements in human cancer and aging using long-read nanopore sequencing
Authors: Sanchez Santiago , Gu Jessica , Golla Anudeep , Shomali William , Martin Annika , Hockemeyer Dirk , Savage Sharon , Artandi Steven 
Published: April 2024

Abstract
Telomere length is an important biomarker of cellular replicative potential and aging, but existing measurement methods are limited in resolution and accuracy. During human carcinogenesis, telomeres shorten profoundly in the earliest stages that precede tumor invasion. Telomere shortening can either halt cancer progression by inducing senescence and cell death or can promote cancer development by destabilizing chromosomes and generating chromosomal rearrangements. Stabilization of telomeres, typically by the upregulation of telomerase, is required for progression of nearly all human cancers. Here, we deploy digital telomere measurement by nanopore sequencing to understand how distributions of human telomere length change during aging and following carcinogenesis. We measure telomere attrition and de novo elongation with unprecedented resolution in genetically defined populations of human stem cells, in cells from the peripheral blood of healthy individuals and patients with genetic defects in telomere maintenance, cancer patients, and cancer cell lines. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres in white blood cells. In patients with inherited defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. Next, we investigated the telomere lengths of a cohort of twenty colorectal tumors with patient-matched healthy colonic epithelia and found that two-thirds of colorectal tumors have telomere length distributions significantly shorter than the surrounding normal tissue. Finally, we explore the utility of telomere length distributions in cancer cell lines as clinically actionable disease biomarkers. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.
Citation Format: Santiago Sanchez, Jessica Gu, Anudeep Golla, William Shomali, Annika Martin, Dirk Hockemeyer, Sharon Savage, Steven Artandi. High resolution telomere measurements in human cancer and aging using long-read nanopore sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB185.
Abstract LB203: CRISPR anchor screens to identify co-vulnerabilities and drug combinations in DepMap
Authors: Serra-Vinardell Jenny , Posner Zoe , Cameron Alison , Chen Yuqi , Karisani Negin , De Kegel Barbara , Dempster Joshua M. , Aguirre Andrew J. , Vazquez Francisca 
Published: April 2024

Abstract
The Cancer Dependency Map (DepMap) aims to systematically map the landscape of cancer vulnerabilities by profiling a wide range of cancer cell lines that collectively represent the heterogeneity of human cancer. An increasing number of targets and biomarkers emerging from this effort are in drug development or clinical trials. However, it is clear that drug resistance is a significant challenge and that drug combinations will be required. CRISPR anchor screens involve introducing an "anchor" which can be either a drug or genetic perturbation, alongside the sgRNA library. This approach provides a way to investigate resistance mechanisms, potential drug combinations, or co-vulnerabilities. As a proof of concept, here we describe CRISPR anchor screens with MRTX1133 as the anchor, which is a potent and selective KRASG12D inhibitor currently in clinical trials.
We performed genome-scale loss-of-function CRISPR-Cas12a screens in the presence of MRTX1133 in pancreatic and lung cancer cell lines that harbor the KRASG12D. The goal of these screens was to identify cancer dependencies that are either present or enhanced in the presence of MRTX1133. We find multiple such MRTX1133-induced dependencies that are either common across all cell lines screened or unique to one or a few. This shows that the response to MRTX1133 can vary depending on the context, highlighting the importance of finding biomarkers to predict the response. Identifying the biomarkers of these context-specific dependencies would provide strategies to select patient populations that would respond to the drug combinations. This study not only provides valuable insights into enhancing the efficacy of KRAS-targeted therapies but also serves as a pioneering effort in incorporating innovative CRISPR screen modalities into the DepMap.
Citation Format: Jenny Serra-Vinardell, Zoe Posner, Alison Cameron, Yuqi Chen, Negin Karisani, Barbara De Kegel, Joshua M. Dempster, Andrew J. Aguirre, Francisca Vazquez. CRISPR anchor screens to identify co-vulnerabilities and drug combinations in DepMap [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB203.
Abstract LB220: Farnesyltransferase inhibitors show synergistic anticancer effects in combination with novel KRAS G12C inhibitors
Authors: Timar Jozsef , Baranyi Marcell , Molnar Eszter , Randelovic Ivan , Cserepes Mihaly , Tovari Jozsef , Hegedus Balazs 
Published: April 2024

Abstract
Background. Farnesyltransferase inhibitors (FTI) failed as monotherapies for various cancer types until the discovery of their potency in HRAS mutant human head and neck and bladder cancers. On the other hand, RAS mutant cancers have been a great challenge for cancer research until the discoveries and approvals of several KRAS-G12C allele specific inhibitors. However, G12C inhibitors were effective mainly in lung cancer and de novo and acquired resistance prompted the development of various combinational modalities including immunotherapy as well as SOS- and SHP2-inhibitors. Based on in-silico analysis of drug sensitivities of KRAS mutant cancer cell lines treated with various drugs including FTIs, we have explored the possibility of the combination of FTIs with KRAS inhibitors.Methods. Clinically approved farnesyl-transferase inhibitors (tipifarnib and lonafarnib) were combined with, novel KRAS G12C inhibitors (sotorasib and adagrasib) using human lung-, pancreatic and colorectal- adenocarcinoma cells in vitro and in vivo. Antitumoral effects were evaluated for cell proliferation, apoptosis and migratory activity. Mechanisms of action were investigated by immunoblot analyzes of various farnesylated proteins, RAS activation and signaling, videomicroscopy and also by histopathology of xenograft tumors.
Results. Synergistic anticancer effects were observed upon the combination of FTIs with G12C inhibitors in KRAS G12C mutant human cancer cell lines in vitro. We found that the combination interfered with the compensatory re-activation of HRAS, farnesylation of RHEB in the PI3K/mTOR pathway and lamin. Furthermore, we observed enhanced efficacy of sotorasib upon combination with tipifarnib in the xenograft models of lung adenocarcinoma affecting mitotic- and apoptotic rates and inducing necrosis.Discussion. Our findings suggest the potential clinical applicability of the combination of KRAS-G12C inhibitors and farnesyl-transferase inhibitors. Furthermore, our preliminary data suggest that the synergistic effect of FTIs on KRAS-G12C inhibitors can be projected to G12D inhibitors as well.
Citation Format: Jozsef Timar, Marcell Baranyi, Eszter Molnar, Ivan Randelovic, Mihaly Cserepes, Jozsef Tovari, Balazs Hegedus. Farnesyltransferase inhibitors show synergistic anticancer effects in combination with novel KRAS G12C inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB220.