bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5955: In vivo precision therapy for glioblastoma using a nanodrug targeting microRNA-10b
Authors: Kim Bryan Doyun , Kenyon Elizabeth , Chen Ming , Mondal Sujan , Carvalho Ana de , Moore Anna 
Published: March 2024

Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain malignancy, which accounts for about half of all brain tumors. Notably, GBM has been shown to express high levels of microRNA-10b (miR-10b) compared to normal brain tissue, which expresses virtually no miR-10b. Importantly, the mounting body of evidence suggests that suppressing miR-10b in glioblastoma cells disrupts various pathways involved in tumor formation, ultimately leading to the suppression of tumor growth and an increase in apoptosis. We have recently reported that our experimental nanodrug targeting miR-10b (MN-anti-miR10b) effectively suppresses miR-10b expression, inhibits tumor cell migration and invasion, and decreases GBM cell viability in vitro. MN-anti-miR10b consists of an iron oxide core with cross-linked dextran, which acts as the delivery vehicle, and is further conjugated with Cy5.5 fluorophores and therapeutic anti-miR-10b locked-nucleic acid antagomirs. The iron oxide core provides MR imaging contrast while Cy5.5 enables optical imaging modalities in vivo. In this study, U251, human GBM cells, were orthotopically implanted in nude, athymic mice and injected via tail vein with PBS, scrambled antagomir vehicle control (MN-Scr), or MN-anti-miR10b (10 and 20 mg Fe/kg), beginning on day 7 post-implantation. Mice were injected with respective treatments once a week for 6 weeks before assessing changes in survival and expression of miR-10b. In one trial, we assessed the differences in survival between treatment groups after completion of the injection regimen and found that MN-anti-miR10b can increase survival compared to control groups. In another trial, mice were euthanized one week after the last injection and GBM tissues were assessed for miR-10b expression by qRT-PCR. RNA samples extracted from this trial have been submitted for RNA sequencing and differential gene expression analysis will be performed. Here, we demonstrated in vivo that MN-anti-miR10b can efficiently decrease miR-10b expression (57%) and increase median survival (MN-anti-miR10b: 54.5 days vs MN-Scr: 44 days vs PBS: 44 days) compared to PBS and MN-Scr treatment groups. These studies suggest the use of MN-anti-miR10b can be effective in the treatment of GBM in vivo.
Citation Format: Bryan Doyun Kim, Elizabeth Kenyon, Ming Chen, Sujan Mondal, Ana de Carvalho, Anna Moore. In vivo precision therapy for glioblastoma using a nanodrug targeting microRNA-10b [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 5955.
Abstract 5963: VGLL1-derived peptides demonstrated anticancer effect by inhibiting VGLL1-TEAD4 interaction
Authors: Ock Sangmi , Lee Changsub , Jung Wongi , Whang Ina , Kim Kyung-Soo , Han Jongmin , Yim Sujin , Kim Bo-Kyung , Lee Hong-Sub , Chang Kwan-Young , Won Misun 
Published: March 2024

Abstract
YAP/TAZ, cofactors of TEA domain-containing transcription factor TEADs (TEAD1-4), play a key role in the HIPPO pathway, which is involved in various function including embryonic development, organ size, cell proliferation, tissue regeneration, and the development and progression of several cancers. YAP/TAZ is therefore considered as master regulators of various cancers. However, we are interested in VGLL1, a cofactor of TEAD4, because it is mainly involved in the proliferation and metastasis of various cancers, including gastric, breast, pancreatic, and ovarian cancers. In gastric cancer, VGLL1 expression is regulated by the PI3K/AKT/β-catenin pathway. VGLL1 is then phosphorylated at S84 by TGF-β/ribosomal S6 kinase 2 (RSK2) and interacts with TEAD4 to express target genes such as MMP9, cyclin D1, IGFBP3, IGFBP5 and ITGαV. which are involved in cancer malignancy. We designed S84-containing VGLL1-derived peptides (VGLL1S84 peptides, SCVP), which consist of 7 to 15 amino acids linked to CPP, a cell-penetration peptide. We evaluated SCVP to inhibit the VGLL1-TEAD4 interaction and their therapeutic potential as anticancer agents. SCVP suppressed the growth of gastric and breast cancer cells expressing high levels of VGLL1, EGFR, and/or HER2. In the RNA-seq analysis of NUGC3 to elucidate the molecular mechanisms of SCVP induced cell death, SCVP-treated cells showed gene expression changes in metabolic pathway, RAS signaling, PI3K-AKT signaling, Wnt signaling, TNF signaling, and mTOR signaling. However, RNA-seq analysis of breast cancer cells treated with SCVP showed changes in the expression of genes involved in cell cycle, DNA replication, DNA repair, and apoptosis. Then, we performed CRISPR/Cas9 screening using SCVP and sgRNA library to explore companion biomarkers and genetic interactors of VGLL1 for targeted cancer therapy. As a result, we identified several candidate genes, including ZNF292 and PLK1, as synthetic lethal genes of VGLL1. As expected, HCC70 cells with ZNF292 mutation showed increased sensitivity to SCVP. We also found that SCVP in combination and the PLK inhibitor volasertib resulted in a synergistic effect on the growth inhibition of breast cancer cells. In conclusion, we demonstrated VGLL1 as a novel target for anticancer drug development, and elucidated the molecular mechanism and therapeutic potential of the SCVP in gastric and breast cancers.
Citation Format: Sangmi Ock, Changsub Lee, Wongi Jung, Ina Whang, Kyung-Soo Kim, Jongmin Han, Sujin Yim, Bo-Kyung Kim, Hong-Sub Lee, Kwan-Young Chang, Misun Won. VGLL1-derived peptides demonstrated anticancer effect by inhibiting VGLL1-TEAD4 interaction [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 5963.
Abstract 6029: 225Ac/89Zr labeled anti nectin 4 radioimmunoconjugates as theranostics against nectin 4 positive triple negative breast cancer
Authors: Babeker Hanan , Njotu Fabrice , Ketchmen Jessica , Tikum Florence , Doroudi Alireza , Nwangele Emmanuel , Uppalapati Maruti , Fonge Humphrey 
Published: March 2024

Abstract
Nectin4 (N4) is a biomarker that is overexpressed in ~62% of triple negative breast cancer (TNBC) and its lack of expression in normal tissues makes it an ideal target for the therapy and PET imaging of TNBC. Methods: We developed a fully human antibody against nectin 4 (anti N4) using phage display. Anti N4 was radiolabeled with 89Zr & 225Ac, respectively, for imaging & radiotherapy using TNBC xenograft & syngeneic mouse models. TNBC murine 4T1 cells were transduced with human N4 and N4 expression was confirmed by FACS. Biodistribution & PET imaging of 89Zr anti N4 radioimmunoconjugate (RIC) was studied in mice bearing N4 positive xenografts. Dosimetry of 225Ac anti N4 was studied in healthy mice & the therapeutic efficacy was evaluated for 90 days in mice bearing MDA MB 468 xenograft & transduced 4T1 syngeneic models. Mice were treated with 2 doses of 350 nCi administered at 10 days apart. Tumor growth was monitored by a digital caliper. Results: The pharmacokinetic profile of 89Zr-anti-N4 RIC showed biphasic distribution with a moderate elimination of 63 h. PET imaging & biodistribution of 89Zr anti N4 in mice bearing MDA MB 468 xenograft showed high tumor uptake of 13.2 ± 1.12 %IA/g at 120 h. 225Ac anti N4 was effectively internalized in MDA MB 468 and was cytotoxic to the cells with IC50 of 1.2 kBq/mL. Treatment with 225Ac anti N4 led to complete tumor remission in all mice bearing MDA MB 468 xenografts and 4T1 syngeneic model by day 20 and 28, respectively. Conclusions: 89Zr anti N4 was an effective PET imaging probe with specific uptake in tumor. 225Ac anti N4 was effective as a therapeutic agent resulting in complete remission of tumors in both mouse xenograft & syngeneic models. These results are promising for the development of anti-N4 RICs as theranostics for TNBC.
Citation Format: Hanan Babeker, Fabrice Njotu, Jessica Ketchmen, Florence Tikum, Alireza Doroudi, Emmanuel Nwangele, Maruti Uppalapati, Humphrey Fonge. 225Ac/89Zr labeled anti nectin 4 radioimmunoconjugates as theranostics against nectin 4 positive triple negative 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 6029.
Abstract 6091: Multi-cancer early cancer detection and cancer-type identification with high sensitivity non-invasive using urine: Pancreatic lung cancer early detection
Authors: Luccio Eric Di , Hirotsu Takaaki 
Published: March 2024

Abstract
N-NOSE, a breakthrough cancer detection test from HIROTSU BIO SCIENCE, utilizes the unique chemotactic behavior of the nematode C. elegans. This nematode is drawn to the urine of individuals with 15 different types of cancers (including stomach, colon-rectum, lung, breast, pancreas, liver, prostate, uterus, esophagus, gallbladder, bile duct, kidney, urinary bladder, ovary, oropharynx) while avoiding urine from healthy persons, making N-NOSE a comprehensive primary screening tool. It has a high accuracy rate, with 87.5% sensitivity and 90.2% specificity for early-stage cancers. Being non-invasive and reasonably priced, N-NOSE has been a significant success in Japan since its 2020 launch, with over 500,000 screenings.This presentation delves into the technology aspect of N-NOSE in Japan, comparing its clinical research and key findings with competitors to underscore its effectiveness in early cancer detection. Furthermore, N-NOSE now advances to not only detect cancer but also identify its type in a noninvasive way, using urine and with high PPV.With pancreatic cancer being particularly lethal, we outline “N-NOSE plus pancreas,” the world’s first pancreatic cancer detection test at an early stage. This involves genetically modifying C. elegans to react specifically to early-stage pancreatic cancer urine samples, a development centered on the newly identified cr-4 GPCR in AWC neurons. Next, we profile our newest liver-cancer-specific test, “N-NOSE plus liver,” which offers early liver cancer detection with high sensitivity and specificity using urine.Finally, we highlight how N-NOSE bridges the gap in cancer screening and type identification, offering a complete, non-invasive solution.
Citation Format: Eric Di Luccio, Takaaki Hirotsu. Multi-cancer early cancer detection and cancer-type identification with high sensitivity non-invasive using urine: Pancreatic lung cancer early detection [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 6091.
Abstract 6099: Identification of intrinsic precursors of Barrett's and gastric intestinal metaplasia
Authors: Xian Wa , McKeon Frank , Yamamoto Yusuke , Khorrami Melika , Khorrami Melina , Mory Zaal , Siegelman Jeremy , Su Amber , Montes Raul Caballero , Hoffman Ashley , Ajani Jaffer , Crum Christopher , Bachovchin William , Wang Shan , Vincent Matthew , Nguyen Crystal 
Published: March 2024

Abstract
The origin of Barrett's esophagus (BE) and gastric intestinal metaplasia (GIM), obligate precursors of esophageal adenocarcinoma (EAC) and intestinal gastric cancer (iGC), has intrigued investigators for decades and would likely guide preemptive strategies. From endoscopic biopsies of clinically confirmed BE and GIM, we have cloned stem cells committed to intestinal metaplasia in vitro. Remarkably, the gene expression profiles of BE and GIM stem cells are highly related down to broad arrays of transcription factors compared with stem cells of the normal gastric mucosa. Using cell surface markers in common between BE and GIM stem cells, we have identified clusters of cells at the squamocolumnar junction and the distal stomach in mice and have used Fluorescence-activated cell sorting (FACS) to clone these cells from both sites. These murine clones can be differentiated in air-liquid interface cultures, and both are committed to intestinal metaplasia marked by goblet cells and Alcian blue staining. To ask whether similar cells exist in humans, we generated stem cell libraries from endoscopic biopsies taken from the gastroesophageal junction (GEJ) and the antrum-body junction (ABJ) in patients without BE or GIM. FACS sorting of these stem cell libraries using the same cell surface markers common to BE and GIM stem cells and the murine precursors, we have identified stem cells from the GEJ and ABJ that show similar gene expression profiles and share a commitment to intestinal metaplasia upon in vitro differentiation. Using identical transformation protocols involving retrovirally transduced protooncogenes, we find that these transformed intrinsic cells give rise to tumors with expression profiles similar to EAC and iGC in TCGA datasets, whereas transformed gastric mucosal stem cells yield tumors marked by signet ring cells typical of diffuse gastric cancer. Lastly, we find that drugs we have developed that target the stem cells of BE and GIM also eliminate the putative precursor cells of BE and GIM, suggesting the potential of therapeutics that might eliminate the emergence of intestinal metaplasia and the cancers derived from them.
Citation Format: Wa Xian, Frank McKeon, Yusuke Yamamoto, Melika Khorrami, Melina Khorrami, Zaal Mory, Jeremy Siegelman, Amber Su, Raul Caballero Montes, Ashley Hoffman, Jaffer Ajani, Christopher Crum, William Bachovchin, Shan Wang, Matthew Vincent, Crystal Nguyen. Identification of intrinsic precursors of Barrett's and gastric intestinal metaplasia [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 6099.
Abstract 6145: A trans-ethnic meta-analysis identified additional novel genomic loci associated with cervical cancer
Authors: Kamiza Abram Bunya , Brandenburg Jean-Tristan , Ramsay Michele , Mathew Christopher 
Published: March 2024

Abstract
Introduction: Cervical cancer is the second most common cause of cancer-related deaths among women worldwide. Genome-wide association studies (GWAS) have identified genetic variants associated with cervical cancer. However, these discoveries have been limited by the small sample sizes of the individual cohorts. To identify additional novel loci associated with cervical cancer, we performed a trans-ethnic meta-analysis.
Methods: GWAS summary data for trans-ethic meta-analysis were identified in women of European ancestry from the UK Biobank, East Asian ancestry from Biobank Japan, and African ancestries from the pan-UK Biobank and Johannesburg cancer study. Meta-analyses were performed using fixed effect inverse variance weighted method implemented in GWAMA. To localize putative genomic loci associated with cervical cancer, we performed fine mapping using the Bayesian approach by calculating the marginal posterior probability of causality for each single nucleotide polymorphisms (SNPs) and 99% credible set size.
Results: Our meta-analysis identified four additional novel genomic loci associated with cervical cancer. These loci include: rs147778467 (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.08-1.16, P-value = 3.12 x 10-08) in RGS21, rs53150478 (OR =1.03, 95%CI = 1.01-1.05, P-value = 4.48 x 10-08) in MAN1C1, rs113842373 (OR = 0.68, 95%CI = 0.56-0.81, P-value = 2.31 x 10-09) in LINCO1850 and rs75372437 (OR = 0.80, 95%CI = 0.72-0.88, P-value = 3.32 x 10-08) in RNU6-356P. These loci are implicated in carcinogenic pathways. Moreover, our Bayesian fine mapping identified five loci with a marginal posterior probability of causality &gt; 1 and reduced the 99% credible set sizes.
Conclusion: We identified additional novel loci associated with cervical cancer and our fine mapping identified loci with a high posterior probability of being causal.
Citation Format: Abram Bunya Kamiza, Jean-Tristan Brandenburg, Michele Ramsay, Christopher Mathew. A trans-ethnic meta-analysis identified additional novel genomic loci associated with cervical 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 6145.
Abstract 6216: Single cell DNA sequencing of BRAF treatment resistant anaplastic thyroid cancer
Authors: Thennavan Aatish , Tarabichi Maxime , Wu Per , Martin Meghan , Dadu Ramona , Cabanillas Maria , Busaidy Nafia , Henderson Ying C. , Zafereo Mark , Williams Michelle D. , Lai Stephen , Navin Nicholas , Wang Jennifer R. 
Published: March 2024

Abstract
Anaplastic thyroid cancer (ATC) is one of the most lethal cancers. Although dramatic responses to BRAFV600E-mutated ATC are seen with BRAF/MEK inhibition, treatment resistance inevitably develops, limiting survival. In this study we sequentially profiled BRAFV600E-mutated ATC at diagnosis, after BRAF/MEK targeted therapy and at the time of disease recurrence using both bulk and single-cell DNA/RNA sequencing. We profiled (~400-800 single cells) for each patient - Patient 1 (n = 704 cells); Patient 2 (n = 817 cells) and Patient 3 (n = 407 cells). At diagnosis, we show that tumor cell populations were characterized by a predominance of arm-level aneuploidies. Across all patients, there is a sharp decline in tumor cells post BRAF-targeted treatment. Interestingly, we observe at least 2 distinct tumor subclones present in the pre-treatment tumor and subsequently there was an expansion event that occurred in each patient after BRAF treatment. This was associated with acquiring unique copy number aberrations (CNA)events and the dominance of these subclones in the recurrent disease. For Patient 2, we also performed single-cell RNA sequencing and show that the recurrent tumor cells have high proliferation and stem-cell like cell states even though they had higher differentiation scores. Importantly, correlating the scDNAseq identified CNA with the inferred CNA from scRNAseq, we show proof of concept that copy number aberrations can be directly correlated with gene expression changes and gene dosage effects. Collectively our data reveal an early polyclonal dissemination model of clones in BRAF-mutated ATCs and suggests that treatment resistance to BRAF inhibition develops as a results of incomplete elimination of viable tumor cell reservoirs in ATC.
Citation Format: Aatish Thennavan, Maxime Tarabichi, Per Wu, Meghan Martin, Ramona Dadu, Maria Cabanillas, Nafia Busaidy, Ying C. Henderson, Mark Zafereo, Michelle D. Williams, Stephen Lai, Nicholas Navin, Jennifer R. Wang. Single cell DNA sequencing of BRAF treatment resistant anaplastic thyroid 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 6216.
Abstract 6239: Human computer interface guided approach to accelerate anticancer drug discovery: Application to human estrogen receptor interactome
Authors: Rajnarayanan Rajendram V. , Alsabagh Aya 
Published: March 2024

Abstract
Structure-based drug discovery of target specific drugs greatly rely on the existence of high resolution X-ray crystal structure of the target proteins. Flexible and dynamic regions including hinges and loops which constitute major protein-protein interaction sites as well as allosteric sites are often beyond the scope of current tools and techniques available for protein folding and modeling. Human ability in recognizing patterns and to solve complex puzzles are far superior to any existing computer program at folding these atypical regions of proteins. We have utilized an unconventional combination of using dynamic three-dimensional protein models as physical human computer interface (HCI) devices and integrated proteomics data to predict flexible and dynamic protein-protein interfaces and allosteric pockets of key regulatory proteins to accelerate compound discovery. To this end, we have successfully utilized 1) Flexible HCI devices to generate an ensemble of dynamic three dimensional structures which includes a subset of biologically active conformations among others (thereby exploring the viable chemical space) and 2) Structure refinement and efficient filtering of biologically active conformations can be accomplished by integrating protein-protein interface and fold proteomics data. Here we present AI ready, HCI guided exploration of human estrogen receptor interactome and early in vitro confirmatory analyses. AI approachs to predict 3D protein structures from amino acid sequences like AlphaFold are often on par with experimentally generated structures and AI-guided structure prediction or docking approaches have been reported to significantly reduce computer time utilization. Streamlining of HCIguided tools to enable access to dynamic druggable pockets in protein targets will accelerate drug discovery.
Citation Format: Rajendram V. Rajnarayanan, Aya Alsabagh. Human computer interface guided approach to accelerate anticancer drug discovery: Application to human estrogen receptor interactome [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 6239.