bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

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

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

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

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

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.
Abstract LB271: Synergistic anti-tumor efficacy in olaparib-sensitive and -resistant models via simultaneously inhibition of USP1 and PARP
Authors: Yang Shuqun , Li Zhengtao , Zhou Lei , Zhou Feng , Qin Xiaokang , Xue Liting , Xu Piaopiao , Tang Jianxing , Wang Wendy , Tang Renhong
Published: April 2024

SIM0501 is a potent, orally bioavailable, specific inhibitor for USP1. We have explored its combination with olaparib, an approved PARP inhibitor, in both in vitro cancer cell lines and in vivo tumor models. Specifically, SIM0501 showed synergistic effect with olaparib on cell lines across different cancer types, including breast, ovarian, and prostate cancers. Most of these cell lines contain mutations in the homologous recombinational repair (HRR) pathway, which is likely the reason for their susceptibility to the combined inhibition on USP1 and PARP. In the in vivo efficacy studies, SIM0501 dose-dependently inhibited tumor growth when combined with olaparib, including BRCA1-mutated MDA-MB-436, BRCA-wildtype olaparib-resistant OVCAR3, and olaparib-resistant ovarian PDX models. Further, in the MDA-MB-436 model, delayed addition of olaparib to SIM0501 showed comparable efficacy with simultaneous combination treatment, suggesting the flexibility in add-on dosing strategy. Regarding the biomarker research, dose-dependent increase of Ub-PCNA was demonstrated by western blot (WB) following in vivo efficacy studies. Moreover, we have developed robust IHC detection method for Ub-PCNA, which correlated well with WB results. Since Ub-PCNA is a direct target of USP1, these results will facilitate the clinical assessment of target engagement by SIM0501. In summary, SIM0501 demonstrates strong synergistic anti-tumor growth effect in combination with PARP inhibitors in both in vitro and in vivo pharmacology studies, which supports the clinical testing of SIM0501, in combination with PARP inhibitors in patients harboring HRR mutations.

Citation Format: Shuqun Yang, Zhengtao Li, Lei Zhou, Feng Zhou, Xiaokang Qin, Liting Xue, Piaopiao Xu, Jianxing Tang, Wendy Wang, Renhong Tang. Synergistic anti-tumor efficacy in olaparib-sensitive and -resistant models via simultaneously inhibition of USP1 and PARP [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 LB271.
Abstract LB293: O-GlcNAc transferase drives the proliferative state in adaptive drug tolerance
Authors: Menon Dinoop Ravindran , Hammerlindl Heinz , Gimenez Gregory , Zuegner Elmar , Magens Christoph , Eccles Michael , Fujita Mayumi , Schaider Helmut
Published: April 2024

Drivers of the drug tolerant proliferative persister (DTPP) state have not been well investigated. Histone H3 lysine-4 trimethylation (H3K4me3), an active histone mark, might enable slow cycling drug tolerant persisters (DTP) to regain proliferative capacity. This study aimed to determine H3K4me3 transcriptionally active sites identifying a key regulator of DTPPs in melanoma. Deploying a model of adaptive cancer drug tolerance H3K4me3 ChIP-seq data of DTPPs guided identification of top transcription factor binding motifs. These suggested involvement of O-linked N-acetylglucosamine transferase (OGT), which was confirmed by metabolomics analysis and biochemical assays. OGT impact on DTPPs and adaptive resistance was explored in vitro and in vivo. H3K4me3 remodeling was widespread in CPG island regions and DNA binding motifs associated with O-GlcNAc marked chromatin. Accordingly, we observed an upregulation of OGT, O-GlcNAc and its binding partner TET1 in chronically treated cancer cells. Inhibition of OGT led to loss of H3K4me3 and downregulation of genes contributing to drug resistance. Genetic ablation of OGT prevented acquired drug resistance in vivo. Our findings uncover a fundamental mechanism of adaptive drug resistance that governs cancer cell reprogramming towards acquired drug resistance, a process that can be exploited to improve response duration and patient outcomes.

Citation Format: Dinoop Ravindran Menon, Heinz Hammerlindl, Gregory Gimenez, Elmar Zuegner, Christoph Magens, Michael Eccles, Mayumi Fujita, Helmut Schaider. O-GlcNAc transferase drives the proliferative state in adaptive drug tolerance [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 LB293.
Abstract LB300: RNA splicing variants of the novel long non-coding RNA, CyKILR, exhibit distinct possess divergent biological functions in lung cancer
Authors: Xie Xiujie , Macknight Patrick H. , Lu Amy L. , Chalfant Charles E.
Published: April 2024

The cyclin-dependent kinase inhibitor 2A (CDKN2A) gene encodes the tumor suppressors, p16(INK4A) and p14(ARF), and is found inactivated or deleted in non-small cell lung cancer at a high percentage. In this study, a novel, uncharacterized long non-coding RNA (lncRNA) (ENSG00000267053) located on chromosome 19p13.12 was found overexpressed in non-small cell lung cancer (NSCLC) cells with a wild-type and active CDKN2A gene. The expression of this Cyclin-Dependent Kinase Inhibitor 2A-regulated lncRNA (CyKILR) was also associated with the expression of the tumor suppressor, Liver kinase B1 (LKB1), a product of the STK11 gene. Characterization of CyKILR identified distinct RNA splicing variants classified into two groups based on their exon 3 inclusion/exclusion status, CyKILRa (exon 3 included) and CyKILRb (exon 3 excluded). The CDKN2A and STK11 gene products not only regulated the expression of CyKILR mRNA in non-transformed cells, but also the interplay between these genes synergistically regulated inclusion of exon 3 into the mature CyKILR RNA as shown by dramatic loss of exon 3 inclusion when mRNAs from both tumor suppressor genes were downregulated by siRNA. Functionally, CyKILRa predominantly localized to the nucleus, and targeted downregulation of the CyKILRa using antisense RNA oligonucleotides (ASOs) significantly enhanced cellular proliferation, migration, and clonogenic survival in mechanistic studies. In contrast, CyKILRb predominantly localized to the cytoplasm, and downregulation of CyKILRb using siRNA significantly reduced cell proliferation, migration, and clonogenic survival. Additionally, downregulation of CyKILRb, in stark contrast to CyKILRa, reduced tumor growth in vivo. Interrogation of cell signaling pathways by transcriptomics analyses demonstrated that CyKILRa suppressed key mitogenic pathways further demonstrating the tumor suppressive role of this CyKILR variant. On the other hand, CyKILRb induced key survival pathways further corroborating the oncogenic nature of this variant. Taken together, our findings shed light on the complexity of lncRNA expression and the alternative RNA splicing of lncRNAs as well as their roles in cell signaling and tumorigenesis.

Citation Format: Xiujie Xie, Patrick H. Macknight, Amy L. Lu, Charles E. Chalfant. RNA splicing variants of the novel long non-coding RNA, CyKILR, exhibit distinct possess divergent biological functions in lung 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 LB300.
Abstract LB307: The role of tumor microenvironment derived growth factors in pediatric brain tumors
Authors: Cruz Andrea , Johnson Brenden , Gatesman Taylor , Halbert Mathew , Taori Suchet , Hu Baoli , Kohanbash Gary , Pollack Ian F. , Agnihotri Sameer
Published: April 2024

Introduction: Children with H3K27-altered diffuse midline gliomas (DMG-H3K27a), have a 5-year survival rate of only 2% following diagnosis. While in-depth genomic characterization has been performed in DMG-H3K27a, very few druggable targets have been identified. A common feature of DMG-H3K27a is infiltration of microglia, macrophages, other myeloid cells, collectively referred to as GAMs. Cellular crosstalk between non-tumor and tumor cells in the tumor microenvironment (TME) can both promote and or inhibit tumor growth, thus representing an opportunity in the pursuit of novel therapeutics. We have recently determined that DMG-H3K27a tumor cells stimulate microglial secretion of pro-tumor growth factors.

Hypothesis: Microglial-derived growth factors activate receptor tyrosine kinases (RTKs) via paracrine signaling in DMG-H3K27a.

Methods: We used scRNA-seq and RNA-seq datasets and, in parallel, in vitro studies, such as co-culture studies, ELISA assays, western blotting, and growth assays to test our hypothesis. In addition, we are developing a mouse-human chimeric neutralizing antibodies of our top targets for in vivo studies.

Preliminary Results: Microglial cells secrete growth factors into the TME, which promotes DMG-H3K27a cell proliferation and growth. Targeting growth factors with neutralizing antibodies attenuates glioma cell proliferation in co-culture studies.

Conclusion: This research uncovers an important signaling network between GAMs and DMG-H3K27a that can be therapeutically targeted.

Citation Format: Andrea Cruz, Brenden Johnson, Taylor Gatesman, Mathew Halbert, Suchet Taori, Baoli Hu, Gary Kohanbash, Ian F. Pollack, Sameer Agnihotri. The role of tumor microenvironment derived growth factors in pediatric brain 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 LB307.
Abstract LB347: PLA2G2D/PGD2-PTGDR signaling deficiency restricts the melanoma progression and lung metastasis
Authors: Dhakal Hima , Zheng Jian
Published: April 2024

Normal 0 false false false EN-US KO X-NONE/* Style Definitions */table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0in; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-font-kerning:1.0pt; mso-ligatures:standardcontextual;} Melanoma is a serious form of skin cancer with an approximate incidence more than 160,000 cases and 41,000 melanoma-associated death per annual globally. Malignant Melanoma is more dangerous because of its rapid spread and metastasis if it were not treated at an early stage. The high mortality of malignant melanoma incites an urgent need to refine the current treatments. Phospholipase A2 group IID (PLA2G2D) is an inducible enzyme expressed in myeloid cells, positively associated with immune infiltration through producing anti-inflammatory prostaglandin D2 (PGD2). The aging-related increase of PLA2G2D and PTGDR, a PGD2 receptor, makes them attractive targets for treating aged-related diseases, such as chronic inflammation and cancer diseases. In this study, by using Pla2g2d-/- and Ptgdr-/- mice, we found that PLA2G2D or PTGDR deficiency effectively restricted the in-situ growth and lung metastasis of subcutaneously implanted melanoma B16F10. These benefits are associated with the early enrichment of γδ-T cells in the tumor mass. The activation and accumulation of γδ-T cells can be induced in B16F10-bearing WT mice by the adoptive transfer of Pla2g2d-/- or Ptgdr-/- DCs. Pro-inflammatory characteristics of Pla2g2d-/- or Ptgdr-/- DCs, especially the production of IL-1b, contribute to γδ-T cells recruitment. These tumor-restraining effects were further confirmed in DC-specific PTGDR deficient (zDCcrePtgdrfloxp ) mice. Taken together with the prominent expression of PLA2G2D and PTGDR in human lung cancer tissue, this study demonstrates the potential of PLA2G2D-PGD2/PTGDR signaling-targeted therapy in treating melanoma and lung metastasis.

Citation Format: Hima Dhakal, Jian Zheng. PLA2G2D/PGD2-PTGDR signaling deficiency restricts the melanoma progression and lung metastasis [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 LB347.
Abstract LB374: The microbial landscape of colorectal cancer across 11 countries
Authors: Abbasi Ammal , Alexandrov Ludmil
Published: April 2024

Colorectal cancer (CRC) is the second most frequent cause of cancer-related deaths globally. CRC is influenced by the colorectal microbiome, which plays a pivotal role in inflammation, DNA damage, and production of cancer-promoting metabolites. Most prior CRC microbial studies have identified multiple microbes enriched in tumor samples, but these examinations have generally focused on CRC from a specific country and have not accounted for CRC patient’s tumor site, sex, diet, or geographical location. Further, the interconnection between somatic alterations and microbiome composition has not been comprehensively explored. Here, we examine the microbiome profiles of 963 whole-genome sequenced CRC and their matched-normal blood from 11 different countries with highly varying age-standardized incidence rate (ASR) for colorectal cancer. Matched normal blood samples exhibited a strong intra- and inter-microbial heterogeneity across the 11 countries. In contrast, while CRC tumors exhibited a higher microbial diversity when compared to their matched-normal samples, the top 10 most abundant CRC taxa were strikingly similar across all countries, suggesting a global convergence of the CRC microbiome composition. Moreover, a positive correlation was observed between the colorectal cancer ASR across 11 countries and the CRC microbial diversity (rho=0.91, p-value: 0.0002), suggesting that countries with high incidence rates also have high microbial diversities. After accounting for age, shipment batch, sex, and country-specific effects on the microbiome composition, we observed a core set of five microbial species enriched in CRC across all countries, which included Bacteroides fragilis,Phocaeicola Vulgatus, Faecalibacterium Prausnitzii, Fusobacterium Nucleatum, and Escherichia Coli. A strong correlation (rho=0.84, p-value: 0.0013) was observed between Bacteroides fragilis and a novel mutational signature characterized by A/T[C>G]T and T[T>G]N substitutions. No association was observed between polyketide synthase gene complex (pks)+ microbe and the presence of the pks-derived colibactin mutational signatures. Furthermore, additional associations were observed between the microbiome and other mutational signatures and driver genes. Overall, this study delivers a global atlas of the microbial landscapes of CRC genomes across 11 countries and their links with genetic changes and epidemiological risk factors.

Citation Format: Ammal Abbasi, Ludmil Alexandrov. The microbial landscape of colorectal cancer across 11 countries [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 LB374.
Abstract LB434: Rapid and reproducible expansion of rare tumor cells: The R3CE platform for personalized medicine
Authors: Kuo Wen-Hung , Huang Yen-Jang , Chen Jia-Yang , Wu Yi-Chun , Chen Chia-Chun , Pegram Mark D. , Chang Ying-Chih
Published: April 2024

We have developed a novel single-cell derived 3D organoid culture platform, Rapid, Reproducible, Rare Cell 3D Expansion (R3CE), capable of generating 3D organoids from solid tumors and normal tissues obtained via surgical tissues and needle biopsies within one week. This method demonstrates over 90% success in banking for at least two passages with over 106 cells across various cancer types, including breast cancer, colorectal cancer, hepatoma cancer, and ovarian cancer. The organoids maintain high fidelity to original tissues, as evidenced by H&E staining, WES, and protein marker analysis across generations. Notably, the R3CE platform can also cultivate circulating tumor cells (CTCs) from peripheral blood. The drug sensitivity profiles of RCE-cultured CTCs closely mirrored clinical outcomes in breast cancer patients. For a patient with stage IV HER2-positive breast cancer, our real-time assay results led to an adjustment in treatment from lapatinib/5-FU to lapatinib/Trastuzumab emtansine (TDM-1), which resulted in substantial clinical improvement. To our knowledge, the R3CE platform is the first 3D organoid system that does not require aggregation or 3D scaffold such as matrigel system. These advancements position the R3CE platform as a promising tool for personalized medicine, offering a rapid and accurate method for drug screening and therapeutic response prediction to guide clinical decision-making in cancer treatment.

Citation Format: Wen-Hung Kuo, Yen-Jang Huang, Jia-Yang Chen, Yi-Chun Wu, Chia-Chun Chen, Mark D. Pegram, Ying-Chih Chang. Rapid and reproducible expansion of rare tumor cells: The R3CE platform for personalized medicine [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 LB434.
Abstract LB447: Drug delivery and efficacy testing using vascularized tumor-on-a-chip
Authors: Kim Da-Hyun
Published: April 2024

The inhibition of tumor angiogenesis is considered a promising strategy to impede cancer progression, as the vasculature associated with tumors plays a crucial role in supplying blood and facilitating metastasis. Therefore, the in vitro replication of vascularized tumors is essential for comprehending cancer pathology and discerning the mechanisms governing tumor cell proliferation, metastasis, and response to pharmaceutical interventions. In this study, we fabricated vascularized tumor-on-a-chip to recapitulate the pathological features of solid tumors. We first developed hybrid spheroids consisting of tumor and endothelial cells, resulting in self-assembled intratumoral vessels. This approach enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed of only cancer cells. RNA sequencing analysis revealed that the tumor-EC hybrid spheroids exhibited expression profiles associated with aggressive behaviors, such as cancer progression, invasion and metastasis. The blood vessels sprouting around the hybrid spheroids on the chip displayed the distinctive characteristics of leaky tumor vessels. We further validated the suppressive effects of axitinib on tumor growth and angiogenesis, depending on exposure dose and time. Notably, we successfully induced both lymphangiogenesis and angiogenesis around the tumor hybrid spheroids by promoting interstitial flow. In summary, our findings demonstrated that vascularized tumor-on-a-chip reproduces various characteristics of vascularized tumors. Consequently, our model stands as a valuable platform for investigating interactions between within tumor microenvironments and exploring therapeutic strategies in cancer.

Citation Format: Da-Hyun Kim. Drug delivery and efficacy testing using vascularized tumor-on-a-chip [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 LB447.
Abstract NG06: Tracing the developmental origins of group 3 medulloblastoma
Authors: Saulnier Olivier
Published: April 2024

Citation Format: Olivier Saulnier. Tracing the developmental origins of group 3 medulloblastoma [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 NG06.
Abstract PL03-02: From microniches to single cells: Understanding the impact of intratumoral microbes on spatial and cellular heterogeneity in cancer
Authors: Bullman Susan
Published: April 2024

The tumor microenvironment (TME) is a dynamic network that includes a variety of non-malignant cells such as endothelial cells, fibroblasts, and immune cells, which play a crucial role in tumor behavior. Advances in molecular analysis have recently identified the presence of intratumoral microbiota in several solid cancer types. However, the specific ways these microorganisms interact with human cells within the TME and contribute to disease progression are not yet fully understood. Our recent research provides new insights into how bacterial components of the intratumoral microbiota contribute to tumor heterogeneity, particularly in head and neck and colorectal cancers. To investigate these interactions, we have adapted and applied emerging technologies in spatial transcriptomics, spatial proteomics, and single-cell sequencing (INVADEseq). Our spatial analyses show that the intratumoral microbiota are not distributed randomly within human tumors; instead, they localize to distinct microniches that promote immune and epithelial cell functions supportive of cancer progression. These bacterial-colonized microniches are characterized by myeloid cell infiltration, upregulation of MAPKs and immune checkpoint proteins, and reduced T-cell levels. Furthermore, INVADEseq single-cell RNA sequencing has enabled us to identify the dominant host cell-associated bacteria, the human cell types they infect, and their impact on the transcriptional programs of infected cells from patient tumor specimens. In oral squamous cell carcinoma, Fusobacterium and Treponema species have been identified as the dominant cell-associated bacterial taxa, primarily infecting subsets of macrophages and aneuploid cancer epithelial cells and upregulating pathways associated with cancer progression. Our findings offer insights into the complex interplay between intratumoral microbiota and human components of the TME, emphasizing their role in supporting intratumoral heterogeneity and influencing cancer progression. Understanding these dynamics holds significant promise for the development of targeted therapeutic strategies aimed at disrupting bacterial-human spatial and cellular interactions within the TME.

Citation Format: Susan Bullman. From microniches to single cells: Understanding the impact of intratumoral microbes on spatial and cellular heterogeneity in 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 PL03-02.
Abstract SY03-03: Thinking outside the chromosome: Interrogating epigenetic mechanisms in noncanonical chromatin species
Authors: David Yael
Published: April 2024

The epigenetic regulation of DNA-templated processes is intricately tied to numerous events that determine cell phenotype and fate. The abrogation of epigenetic cascades drives various disease states, including cancer. Many of these pathological phenomena involve major chromosomal arrangements that can include the generation of non-canonical chromatin structures existing in the primary nuclei or encapsulated in spatially distinct micronuclei. Recently, we undertook a mechanistic approach to investigate the properties of unique non-chromosomal structures, revealing significant epigenetic contributions to their regulation. We found that micronuclei, the result of chromosomal instability in cancer, assume altered epigenetic landscapes upon departure from the nucleus. Moreover, chromosomes sequestered in micronuclei retain the epigenetic "scars" after reintegration into the primary nucleus, contributing to epigenetic reprogramming and heterogeneity in cancer. Additionally, we turned our attention to the Hepatitis B Virus' (HBV) covalently closed circular DNA (cccDNA) minichromosome, which forms from viral DNA and human histones following infection. We found that chromatinization drives the expression of the key viral oncogene, HBx, and thus promotes viral infection. Elucidating this new mechanism enabled us to halt infection by inhibiting histone remodeling, creating a potential first-in-class therapy for HBV. These exciting findings demonstrate the key role of chromatin in biomedical events and how a fundamental understanding of these processes can lead to the identification of new therapeutic avenues.

Citation Format: Yael David. Thinking outside the chromosome: Interrogating epigenetic mechanisms in noncanonical chromatin species [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 SY03-03.