bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT217: First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b-2 trial
Authors: Thibaudin Marion , Fumet Jean-David , Limagne Emeric , Hampe Léa , Daumoine Susy , Derangère Valentin , Laheurte Caroline , Adotevi Olivier , Truntzer Caroline , Ghiringhelli François 
Published: April 2024

Abstract
Metastatic colorectal cancer (mCRC) remains a difficult-to-treat disease. While patients with microsatellite instable metastatic colorectal cancer (mCRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was the primary objective of phase IB; no safety issue was observed. The phase II primary objective of efficacy in terms of 3-month PFS in MSS patients was met, with 3-month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objectives, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9-8.6] and overall survival was not reached in MSS patients. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response, associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758.
Citation Format: Marion Thibaudin, Jean-David Fumet, Emeric Limagne, Léa Hampe, Susy Daumoine, Valentin Derangère, Caroline Laheurte, Olivier Adotevi, Caroline Truntzer, François Ghiringhelli. First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b-2 trial [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 CT217.
Abstract CT252: Nicotinamide in combination with EGFR-TKIs for the treatment of stage IV lung adenocarcinoma with EGFR mutations: A randomized double-blind (Phase IIb) trial
Authors: Park Cheol-Kyu , Oh Hyung-Joo , Bae Suk-Chul , Oh In-Jae , Jung Kyoung-Mi , Kim Da-Mi , Lee Jung-Won , Kang Chang Kyun , Park Il Yeong , Kim Young-Chul 
Published: April 2024

Abstract
Background: RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR-TKIs for patients with stage IV lung cancer carrying EGFR mutations.
Patients and Methods: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively.
Results: After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months (95% CI, 10.4-18.3), while the placebo group had a PFS of 10.9 months (9.0-13.2; p = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; p = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (p = 0.01) and never-smokers (p = 0.03) treated with nicotinamide.
Conclusion: The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked.
(ClinicalTrials.gov Identifier: NCT02416739)
Citation Format: Cheol-Kyu Park, Hyung-Joo Oh, Suk-Chul Bae, In-Jae Oh, Kyoung-Mi Jung, Da-Mi Kim, Jung-Won Lee, Chang Kyun Kang, Il Yeong Park, Young-Chul Kim. Nicotinamide in combination with EGFR-TKIs for the treatment of stage IV lung adenocarcinoma with EGFR mutations: A randomized double-blind (Phase IIb) trial [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 CT252.
Abstract LB013: Characterizing the role of exosomal miRNAs in metastasis
Authors: Agrawal Piyush , Olgun Gulden , Singh Arashdeep , Gopalan Vishaka , Hannenhalli Sridhar 
Published: April 2024

Abstract
Background: Exosomal microRNAs (Ex-miRs) play a pivotal role in intercellular communication, being transported via extracellular vesicles. In cancer, Ex-miRs influence tumor progression by regulating key cellular processes such as proliferation, angiogenesis, and metastasis. Their role in mediating communication between cancer cells and the tumor microenvironment highlights their significance as potential diagnostic and therapeutic targets.
Methodology: In this study, we aimed to characterize the role of Ex-miRs in influencing the pre-metastatic niche (PMN) across 7 tumor types. We extracted high-confidence Ex-miRs (Log FC &gt;= 2 in exosomes relative to expectation) and their targets (experimentally proven and targeted by at least 2 Ex-miRs) from various studies. Subsequently, we conducted gene ontology analysis to identify enriched pathways and selected the top 100 high-confidence Ex-miR targets based on the frequency of their appearance in the enriched pathways. These top 100 targets were consistently used throughout the analysis.
Results: Pathway enriched among the top Ex-miR targets included common ones such as “wound healing” and “regulation of epithelial cell proliferation”, as well as cancer-specific, like “regulation of angiogenesis in kidney” (KIRC), “ossification” in lung (LUAD), and “positive regulation of cytokine production” in pancreatic cancer (PAAD). Similarly, 'Pathways in cancer' and 'MicroRNAs in cancer' ranked among the top 10 enriched KEGG pathways for all cancer types. Ex-miR targets exhibited cancer-specific downregulation of gene expression in TCGA-Normal Adjacent Tumors (NATs), taken as proxy for PMN, compared to healthy tissue samples in GTEx. We further examined the 3’UTR GC content of these targets and found that Ex-miR targets are GC-rich, consistent with the previous findings stating that Ex-miR bind to the 3’UTR region of the target gene, downregulating their expression. Fisher’s exact test revealed a significant overlap of cancer-specific tumor suppressor genes (TSG) with Ex-miR targets. Cox regression indicated that Ex-miR targets are associated with better survival in certain cancer types, such as BRCA, COAD and KIRC. Lastly, a Support Vector Machine (SVM) model using Ex-miR target gene expression classified responders and non-responders to neoadjuvant chemotherapy with a high AUROC compared to other gene signatures.
Conclusion: Our study unveils the pivotal role of exosomal microRNAs in shaping the PMN in diverse cancers, underscoring the diagnostic and therapeutic potential of Ex-miRs.
Citation Format: Piyush Agrawal, Gulden Olgun, Arashdeep Singh, Vishaka Gopalan, Sridhar Hannenhalli. Characterizing the role of exosomal miRNAs in 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 LB013.
Abstract LB016: Spatial transcriptomics-based platform for pathological diagnosis and research of colorectal cancer
Authors: Qu Chi , Huang Huaqiang , Quan Yan , He Xuqing , Zhang Weifeng , Duan Tianbi , Zhang Jiajun , Gu Jiang 
Published: April 2024

Abstract
The application of spatial transcriptomic (ST) in contemporary pathology is promising yet rarely validated. We herein established a ST-based platform to analyze colorectal cancers following the logic and workflow of routine histopathological diagnosis. By integrating spatial coordinate traits with in-situ gene expression matrix, we reproduced and extended key diagnostic features for tumor diagnosis and molecular analysis including proliferation evaluation, vasculature identification, immune scoring and dMMR/pMMR molecular subtyping. Meanwhile, spatial and morphological distinction ST co-dominated broadened avenues for targeted cancer therapy and research. In hyperplasia/carcinoma confusion sites, we detected mixed cnv patterns in single crypt with distinct spatial distributions; Meanwhile, RNA-based molecular subtypes prevailed with intratumor heterogeneity and concurrently exhibited uniformed histological characteristics; Moreover, landscape of temporal molecular variation during cancer infiltration stages revealed potential metastatic biomarkers and mechanisms. In conclusion, we have herein established a comprehensive platform to perform and extensely extend assessment for tumor diagnosis. Additionally, by aligning histological features and gene expression profiles, we excavated significant opportunity for pathological investigation and coordination of multimodal molecular pathology dimensions, which is suitable and ideal for scientific discoveries and molecular diagnosis. With improvement in efficiency and cost-effectiveness, we foresee that this de novo platform will significantly advance pathological diagnosis and research of cancer tissue.
Citation Format: Chi Qu, Huaqiang Huang, Yan Quan, Xuqing He, Weifeng Zhang, Tianbi Duan, Jiajun Zhang, Jiang Gu. Spatial transcriptomics-based platform for pathological diagnosis and research of colorectal 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 LB016.
Abstract LB029: Degraders of TEAD transcription factors based on interface 3 binders
Authors: Sawant Rajiv , Geitmann Matthis , Gossas Thomas , Emond Wei B. , Bremberg Ulf , Koehler Konrad , Ceribelli Michele , Thomas Craig J. , Brandt Peter 
Published: April 2024

Abstract
TEAD transcription factors have emerged as clinically validated targets for Hippo-altered cancers, e.g. mesothelioma driven by NF2 inactivation/deficiency. We have developed a series of novel small molecule targeted protein degraders of TEAD based on pan-TEAD interface 3 ligands. In cells, the compounds induce degradation of TEAD by formation of a ternary complex with Cereblon, leading to ubiquitination of TEAD and subsequent proteasomal degradation. In a cell-based luciferase reporter assay the degraders show low nanomolar activity. The downstream effects of TEAD degradation were further investigated by qPCR and WB analyses of bona fide YAP-TEAD target genes such as CTGF, Cyr61 and AMOTL2. The effectiveness of the TEAD degraders were compared to other classes of TEAD modulators such as palmitoylation inhibitors and YAP-TEAD protein-protein inhibitors by means of cellular viability assays using various mesothelioma cell lines. Finally, we performed an unbiased, quantitative high-throughput drug combination screening by combining a TEAD degrader with a library of approximately 2,800 oncology-focused drugs. This research was supported in part by the Intramural/Extramural research program of the NCATS, NIH.
Citation Format: Rajiv Sawant, Matthis Geitmann, Thomas Gossas, Wei B. Emond, Ulf Bremberg, Konrad Koehler, Michele Ceribelli, Craig J. Thomas, Peter Brandt. Degraders of TEAD transcription factors based on interface 3 binders [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 LB029.
Abstract LB060: Engineering KRAS mutation-specific affinity binders: A new frontier in cancer research
Authors: Serrano Ramon , Wallace Ryan , Bibikov Sergei , Weiner Michael , Harvey Kevin J. 
Published: April 2024

Abstract
Cancer is a complex disease involving genetic and proteomic dysregulation. Better understanding of this disease requires precise tools to analyze how cells change from a normal to a diseased state. Among the genes implicated in cancer, the checkpoint inhibitor KRAS is notable for its frequent cancer causing mutations. These mutations, especially in glycine codon 12, are a driving force in several cancers, including those of the pancreas, lung, and colon. Recently, researchers have made significant strides in treating one variant, targeting G12C, using small molecules. However, other mutations, including the G12D and G12V variants, which are more common in disease, still lack targeted treatments. To overcome this challenge, we are using a unique immunization and screening strategy to identify a series of KRAS mutant-specific binders. These affinity binders, targeting the wild-type glycine and variants like G12D, G12S, G12C, G12A, G12R, and G12V, are being designed for research purposes to dissect cancer pathways and understand the spatial organization of cancer cells. They may also hold potential for clinical use as tools for prognosis and therapy. Deep characterization of these and other potentially widely used tools will be critical for advancing their uptake in the laboratory and clinic.
Citation Format: Ramon Serrano, Ryan Wallace, Sergei Bibikov, Michael Weiner, Kevin J. Harvey. Engineering KRAS mutation-specific affinity binders: A new frontier in cancer research [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 LB060.
Abstract LB106: Ultra-short ctDNA: A new paradigm for ctDNA liquid biopsy
Authors: Li Feng , Wei Fang , He Hua-Jun , Lin Chien-Chung , Yang Szu-Chun , Huang Allen Wei-Lun , Tang Cheuk Ying , Kim Yong , Wong David T. 
Published: April 2024

Abstract
Mononucleosomal ctDNA (mnctDNA, 157-bp, double-stranded) spearheads liquid biopsy (LB) for cancer detection, treatment and clinical care. The bottleneck of mnctDNA LB are low copy number of ctDNA and limit of detection of platform technologies. Recent discovery of ultra-short ctDNA (usctDNA, 52-54 nt, single-stranded) that harbors somatic mutations prompted us to explore the quantification and stoichiometry of usctDNA to mnctDNA in plasma and saliva of NSCLC patients.
Paired plasma and saliva from 20 advanced NSCLC patients with tissue genotyped positive for L858R were processed for cfDNA extraction and quantification with Qubit and Tape Station. Digital PCR assays targeting L858R somatic mutation to generate amplicons of 57-bp (usctDNA) and 100-bp (mnctDNA) were performed by UCLA and independently by NIST.
Results in Table 1 revealed that three findings of usctDNA that will have potential to impact ctDNA liquid biopsy. First, the somatic mutation (L858R) is present in usctDNA. Second, The stoichiometric ratio of usctDNA to mnctDNA is similar in plasma and saliva at 1.6X. For the wild-type counterpart, the ratio is 1.1X for plasma and 0.6X for saliva. Third, the copy number of usctDNA and mnctDNA in saliva to plasma is 7.8X and 7.7X.
Conclusion: Detection of tumor-associated/specific EGFR L858R somatic mutations in uscfDNA is translationally impactful, adding 1.6X of the ctDNA targets for molecular detection, effectively cumulating 2.6X of total ctDNA targets, permitting earlier cancer detection, treatment monitoring and therapy prognostication. The finding that saliva harbors 7X of the us- and mnctDNA further raises the prospect of advancing saliva ctDNA liquid biopsy for NSCLC detection as it may effectively allow 15.5X (7.8X+7.7X) ability to detect malignancy-associated ctDNA.
Table 1. Quantification of usctDNA and mnctDNA in Plasma and Saliva Mut usctDNA (L858R) WT cfDNA usctDNA mnctDNA U/M uscfDNA mncfDNA U/M Plasma 1555 ± 326 964 ± 209 1.6X 15201 ± 1509 13261 ± 1424 Saliva 12158 ± 1731 7442 ± 1020 1.6X 340896 ± 27170 601733 ± 71573 1.1X Saliva/Plasma (fold X) 7.8 7.7 1.6X 22.4 45.3 0.6X
Citation Format: Feng Li, Fang Wei, Hua-Jun He, Chien-Chung Lin, Szu-Chun Yang, Allen Wei-Lun Huang, Cheuk Ying Tang, Yong Kim, David T. Wong. Ultra-short ctDNA: A new paradigm for ctDNA liquid biopsy [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 LB106.
Abstract LB143: Environmental assessment of alcohol-related policies and practices at US cancer organizations
Authors: Si Meghan , Martch Stephanie , Shete Sanjay , Hawk Ernest 
Published: April 2024

Abstract
In 1998, the International Agency for Research on Cancer (IARC) declared that the consumption of alcoholic beverages was a class I carcinogen to humans; the designation was reaffirmed in 2007 and 2010. Despite this, approximately 4% of new cancer cases worldwide in 2020 were attributable to alcohol intake. Growing evidence indicates that alcohol use increases the risk of cancers of the upper aerodigestive tract (oral cavity, pharynx, esophagus, and larynx) and lower digestive tract (colon, rectum, and liver). Over half of the 6.3 million cases of these cancers are considered preventable, underscoring notable gaps regarding alcohol consumption and cancer prevention. Despite (1) the longstanding designation of alcohol as an established carcinogen, (2) an increasing and consistent body of data noting alcohol as a leading contributor to the global cancer burden, and (3) the publication of policy statements by authoritative sources, it is unclear whether cancer-focused institutions are aware of these facts or are acting on these data (i.e., implementing evidence-based policies and practices to limit alcohol-related cancer risks for their employees, guests, or the public). Driven by these data and shortfalls, we developed a 22-item survey to inquire about cancer organizations' interpretation of current literature, existing policies, decision-making processes, inclination to act, and perceived responsibility to lead in the realms of public education and policy implementation to mitigate alcohol-related cancer risks in the public’s interest. The survey will be sent to over 100 leading U.S. cancer organizations, including NCI-designated- and other major cancer centers, cancer-oriented professional organizations, and cancer-research organizations. It underwent rigorous testing for clarity, brevity, and expected response time, also drawing upon the expertise of five survey-science professionals. The study is under institutional review board (IRB) review, and we anticipate the survey’s distribution in the first quarter of the calendar year 2024. We expect to share the survey instrument and results during the meeting.
Citation Format: Meghan Si, Stephanie Martch, Sanjay Shete, Ernest Hawk. Environmental assessment of alcohol-related policies and practices at US cancer organizations [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 LB143.
Abstract LB157: Discovery of HP537, a potent and selective p300/CBP inhibitor for the treatment of hematologic malignancies
Authors: Li Jing , Tu Zhilin , Peng Jian , Fan Lei , Yu Hua , Wang Fei , Li Xinghai 
Published: April 2024

Abstract
E1A-binding protein P300 (p300) and its paralog CREB binding protein (CBP) are key acetyl transferases (HAT) and transcriptional co-factors. p300/CBP bromodomain (BRD) inhibition reduces acetylation of H3K27 at enhancers, leading to suppression of enhancer-driven gene expression, such as MYC and IRF4 that are critical for the initiation, progression, and chemoresistance of hematological malignancies. Thus, p300/CBP inhibition is a highly potential therapeutic strategy for the treatment of hematological malignancies, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL) and leukemia. We have discovered HP537 that competitively inhibits an acetylated peptide substrate to bind BRD of p300/CBP with IC50 &lt; 5 nM. HP537 does not inhibit the enzymatic activity of HAT domain of p300/CBP and HAT1, nor has binding affinity for other BRD containing proteins including BRD4 and BRD9. HP537 inhibits proliferation of a wide range of cell lines derived from MM, leukemia and lymphoma with IC50 values ranged from 0.01 μM to 0.4 μM. Protein expression levels of acetylated H3K27, c-Myc and IRF4 are significantly decreased by HP537 in MM, NHL and acute myelogenous leukemia (AML) cell lines in a dose- and time-dependent manner. HP537 robustly and dose-dependently inhibits tumor growth in OPM-2 (MM), MOLM-16 (AML), and KARPAS-422 (NHL) cell line derived tumor xenograft (CDX) mouse models. Down-regulation of c-Myc and IRF4 are also observed in the tumor samples. In conclusion, HP537 is a novel, potent and selective inhibitor of p300/CBP BRD. The pre-clinical data supports the clinical development of HP537 for the treatment of hematological malignancies. A FIH study of HP537 in cancer patients is planned to start in 2024. HP537 structure will not be disclosed.
Citation Format: Jing Li, Zhilin Tu, Jian Peng, Lei Fan, Hua Yu, Fei Wang, Xinghai Li. Discovery of HP537, a potent and selective p300/CBP inhibitor for the treatment of hematologic malignancies [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 LB157.