bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5029: VAF in ctDNA correlated with advanced breast cancer tumor burden and prognosis
Authors: Zhong Jianxin , Li Huiping , Shao Bin , Jiang Hanfang , Liu Xiaoran , Tang Haoran , Jia Shidong 
Published: March 2024

Abstract
Purpose: In patients with first-line advanced breast cancer (ABC), the correlation between ctDNA variant allele frequency (VAF) and tumor disease burden, and its prognostic value remains poorly investigated.
Methods: This study included patients with ABC diagnosed at Peking University Cancer Hospital who performed ctDNA test before receiving first-line treatment. Baseline plasma samples were collected for assessing ctDNA alterations and VAF with next-generation sequencing. The sum of tumor target lesion diameters (SLD) was measured with imaging methods according to RECIST 1.1 criteria.
Results: The final cohort included 184 patients. The median age of the cohort was 49.4 (IQR: 42.3-56.8) years. The median VAF was 15.6% (IQR: 5.4%-33.7%). VAF showed positive correlation with SLD in patients with relatively large tumor lesions (r = 0.314, p = 0.003), but not in patients with small tumor lesion (p = 0.226). VAF was associated with multiple metastasis sites (p = 0.001). Multivariate Cox regression analysis showed that high VAF was associated with shorter overall survival (OS) (HR: 3.519, 95% confidence interval (CI): 2.149-5.761), and first-line progression-free survival (PFS) (HR: 2.352, 95%CI: 1.462-3.782).
Conclusion: ctDNA VAF associated with tumor disease burden, and was a prognostic factor for patients with ABC. A combination of ctDNA test and radiographic imaging might enhance tumor burden evaluation, and improve prognosis stratification in patients with ABC.
Citation Format: Jianxin Zhong, Huiping Li, Bin Shao, Hanfang Jiang, Xiaoran Liu, Haoran Tang, Shidong Jia. VAF in ctDNA correlated with advanced breast cancer tumor burden and prognosis [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 5029.
Abstract 5047: Identifying genomic features associated with pathologic lymph node metastasis in lung adenocarcinoma patients
Authors: Wang Shijie , Zhou Zhiwei , Wang Song , Guo Rongyun , Ma Zeming , Zhao Dachuan , Wang Liang , Liu Yinan , Ma Yuanyuan , Zhang Jianzhi , Wang Sha , Chen Yedan , Tang Haimeng , Ou Qiuxiang , Chen Jinfeng 
Published: March 2024

Abstract
Introduction: Lymph node metastasis evaluation in solid tumors is mainly complicated by the diagnostic yield of standard imaging modalities and tumor size contradictions. Exploring clinical/molecular features that complement the use of radiologic and bronchoscopy findings may provide significant values for a more accurate pathologic determination of nodal metastasis.
Methods: We analyzed surgery-resected tumor samples from 72 treatment-naïve lung adenocarcinoma (LUAD) patients via whole-exome sequencing (WES). Mutational profiles of patients categorized based on their pathologic lymph node metastasis (pN) status were assessed, and the association between metastatic-driving features and overall survival (OS) was then explored in both the study cohort and the Cancer Genome Atlas Program (TCGA) external cohort.
Results: Among all 72 patients, 41 (56.9%) were pathologically confirmed as positive for lymph node metastasis (pN-positive), while 31 (43.1%) were categorized as pN-negative. The most frequently mutated gene was TP53 in both subgroups (54.8% and 53.7%, respectively), and the aberrant KEAP1-NRF2 signaling pathway was found significantly more enriched in pN-negative patients. Copy-number variant analysis showed that chromosome 7p amplifications (X7p_amp) at the arm level and EGFR amplifications at the focal gene level were more frequently identified in pN-positive patients (P=0.008 and P=0.004, respectively). Importantly, these amplifications were associated with worse OS in both the study cohort and the TCGA external dataset. Consistent with the unfavorable prognosis, pN-positive patients demonstrated a higher chromosome instability score (CIS) (median: 0.32 vs. 0.14, P=0.14) and a lower tumor mutation burden (TMB) (median: 1.83 vs. 3.85 muts/Mb, P=0.048) compared to pN-negative patients.
Conclusion: Our findings suggest that X7p_amp, particularly EGFR amplification, might be associated with pathologic involvement of lymph nodes and an unfavorable prognosis in LUAD patients. Our study highlights the importance of integrating clinical and genomic data into conventional radiologic modalities for a more accurate determination of pathologic nodal involvement.
Citation Format: Shijie Wang, Zhiwei Zhou, Song Wang, Rongyun Guo, Zeming Ma, Dachuan Zhao, Liang Wang, Yinan Liu, Yuanyuan Ma, Jianzhi Zhang, Sha Wang, Yedan Chen, Haimeng Tang, Qiuxiang Ou, Jinfeng Chen. Identifying genomic features associated with pathologic lymph node metastasis in lung adenocarcinoma patients [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 5047.
Abstract 5079: Comparative studies of chemotherapy and immuno-oncology combinations in multiple mouse syngeneic tumor models
Authors: Park Eunsil , Hinton Marlene , Cai Mingmei , Gil Malgorzata A. , Hebert Gustave , Cui Long , Linn Doug , Long Brian J. , Barry Evan R. 
Published: March 2024

Abstract
The development of immune checkpoint inhibitors (ICIs) and combinations of immuno-oncology therapies with standard-of-care (SoC) chemotherapeutic agents has shifted therapeutic paradigms for patients with multiple cancer indications. For many patients, these combinations have shown a beneficial effect on clinical outcomes and disease management. However, additional combination therapies are still needed. Preclinically, a comparison of responses from SoC chemotherapies and ICI combinations in multiple disease models may be helpful in identifying optimal treatment combinations in the clinic. Here we report the results of multiple SoC/ICI in vivo combination efficacy studies in a large panel of mouse syngeneic models spanning seven tissue origins: 1) Colon: CT26, MC38; 2) Breast: EMT6, 4T1; 3) Kidney: Renca; 4) Bladder: MB49, MBT2; 5) Skin: B16F10, CM3; 6) Lung: TC1, LL/2, M109; 7) Brain: GL261. The advantage of using syngeneic models is not limited to the rapid and reproducible tumor growth, but importantly that the animals also have an intact immune system and clinically relevant tumor microenvironment, which are required for ICI combination studies. We tested &gt; 10 chemo SoC combinations with a murinized anti-PD-1 antibody (DX400) in 14 syngeneic mouse models. We found that multiple SoC regimens combined well with DX400 treatment, including FOLFIRI, FOLFOX (colon), Carboplatin/Paclitaxel, Carboplatin/Pemetrexed (lung), Capecitabine/Docetaxel, Cisplatin/Gemcitabine (bladder), Cisplatin/5-FU/or capecitabine, and Oxaliplatin/5-FU/or capecitabine (gastric). Specifically, we observed that the SOC/ICI combinations resulted in enhanced antitumor activities compared to single-agent treatments in many of the models. These data, particularly specific SoC combination regimens that combine well with ICIs in each disease, are useful for optimizing promising combination approaches for clinical development and will be presented here.
Citation Format: Eunsil Park, Marlene Hinton, Mingmei Cai, Malgorzata A. Gil, Gustave Hebert, Long Cui, Doug Linn, Brian J. Long, Evan R. Barry. Comparative studies of chemotherapy and immuno-oncology combinations in multiple mouse syngeneic tumor models [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 5079.
Abstract 5081: Immune sensitization of melanoma to checkpoint inhibitor therapy using acoustically active nanoparticles
Authors: Henderson Michael Ian , Xiang Li , Drennan Samuel , Yi Xin , Fischer Jared , Yildirim Adem 
Published: March 2024

Abstract
Advanced melanoma remains the most fatal form of skin cancer with novel therapeutic approaches required to treat inoperable metastatic lesions. While immunotherapies have shown promise in improving long-term melanoma survival, its treatment efficacy is limited, with only 50% of patients responding. Focused ultrasound (FUS) offers as a non-invasive strategy for targeted tumor ablation, thereby strengthening immunotherapy efficacy by release of tumor associated materials. However, control over tumor material release through FUS, without causing excessive thermal damage to surrounding healthy tissue remains challenging. To address this challenge, our group has previously developed acoustically active nanoparticles (AANPs) responsive to low intensity ultrasound for mechanical tumor ablation by generating strong and durable acoustic cavitation in the tumor tissue. Building upon previous success with AANPs, our current work focuses on sensitizing melanoma tumors to checkpoint inhibitor therapy by releasing tumor antigens into circulation using AANPs and FUS. Our findings revealed sensitization of an immunologically cold B16-F10 metastatic melanoma tumors following treatment, which resulted in a notable 12-day stall in tumor growth. When combined with immune checkpoint inhibitors α-PD-L1 and α-CTLA-4, this approach showed a complete response in B16-F10 bearing mice with impressive memory immune response upon a tumor rechallenge. Herein, these novel AANPs represent a promising advancement to enable accurate immune surveillance by boosting the release of tumor antigens and offers new strategies for improved immunotherapy of melanoma and other solid tumors.
Citation Format: Michael Ian Henderson, Li Xiang, Samuel Drennan, Xin Yi, Jared Fischer, Adem Yildirim. Immune sensitization of melanoma to checkpoint inhibitor therapy using acoustically active nanoparticles [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 5081.
Abstract 5090: Development of HSPG2 targeted glycoengineered antibody-drug conjugates
Authors: Li Xiaolei , Prabha Swayam 
Published: March 2024

Abstract
Ovarian cancer is associated with poor outcomes and aggressive behaviors. Although surgical removal of tumors and chemotherapy can initially eradicate cancer, many patients eventually experience relapse with chemotherapy-resistant tumors, resulting in poor long-term outcomes and chemotherapy complications. Antibody-drug conjugates (ADCs) are formed by integrating the tumor specificity provided by antibodies (Ab) and small molecule cytotoxicity drugs and can facilitate highly targeted delivery with minimal toxicity to normal tissues. Our group has identified that the overexpression of a novel target, heparan sulfate proteoglycan 2 (HSPG2), is associated with poor prognosis and survival of high grade serous ovarian cancer (HGSOC) patients. We have developed a monoclonal antibody (AM6) that effectively targets HSPG2-expressing tumors. In this study, we used a novel glycoengineering strategy to introduce artificial azide groups at the N-glycan sites of AM6 without affecting its antigen affinity and intracellular localization. The azide groups were then used for site-specific conjugation of the cleavable dibenzyl cyclooctyne - monomethyl auristatin E (DBCO-PAB-MMAE) linker (drug conjugate) to form an AM6 antibody-drug conjugate (AM6 ADCs). Hydrophobic interaction chromatography (HIC) and liquid chromatography/quadrupole time-of-flight/mass spectrometry (LC/Q-TOF/MS) confirmed the successful conjugation of the DBCO-PAB-MMAE to the AM6. In-vitro cytotoxicity studies of AM6 ADCs in OVCAR8 (high HSPG2 expression) and CAOV3 (regular HSPG2 expression) showed the cell line dependent response with lower IC50 in OVCAR8. These results suggest that the effectiveness of AM6 ADCs is proportional to the HSPG2 expression levels of the cells. Future studies will be aimed at the in-vivo evaluation of optimized antibody-drug conjugates.
Citation Format: Xiaolei Li, Swayam Prabha. Development of HSPG2 targeted glycoengineered antibody-drug conjugates [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 5090.
Abstract 511: Cell cycle inhibitors exhibit anti-tumor immunomodulatory roles through the HIF-1-DDX41 cytosolic DNA sensing pathway in HCC
Authors: Chan Cerise Yuen Ki , Wong Po Yee , Xue Helen Do Gai , Goh Chi Ching , Cheu Jacinth Wing Sum , Tse Aki Pui Wah , Zhang Misty Shuo , Wong Carmen Chak Lui 
Published: March 2024

Abstract
Cell cycle inhibitors have a long history as anti-cancer therapeutics in clinical applications. Uncontrolled and infinite cell cycles are hallmarks of cancer, which enable them to proliferate rapidly and survive. To target these key features of cancer cells, cell cycle inhibitors are used to arrest their active cell cycle and induce cell death. In this study, beyond the known primary effect on cell cycle control, we identified that an expected and a secondary effect in immune modulation by the cell cycle inhibitors. Anti-mitotic agents including Paclitaxel (microtubule stabilizer), Palbociclib (CDK4/6 inhibitor) and AZD1152 and GSK1070916 (Aurora Kinase B inhibitors) can also eliminate cancer cells via an alternative mechanism - the activation of STING signaling. Our results demonstrated that these anti-mitotic agents caused DNA damage and cytosolic DNA accumulation. The cytosolic DNA was captured by a cytosolic DNA sensor DDX41,which triggered STING-TBK1-IRF3/7 pathway to upregulate secretion of pro-inflammatory senescence-associated secretory phenotype (SASP) factors in cancer cells. In addition, we revealed that transcription of DDX41 was mediated by the transcription factor known ashypoxia-inducible factor (HIF). In HCC, hypoxia induced DDX41 expression through HIF-1,thus hypoxic HCC cells were more prone to STING activation and SASP production under mitotic stress induced by cell cycle inhibitors. In the tumor microenvironment, the SASP enhanced infiltration of immune cells into the tumor core to eliminate cancer cells. We also observed the additive effects of cell cycles inhibitors (Paclitaxel, Palbociclib, and AZD1152)with anti-PD-1 mAb to arrest growth of HCC in mouse models. In summary, this study exhibited the novel immune-mediated aspect of cell cycle inhibitors in suppressing tumor growth. Our data suggested the potential combination regimen of cell cycle inhibitors and currently available immunotherapy with promising result.
Citation Format: Cerise Yuen Ki Chan, Po Yee Wong, Helen Do Gai Xue, Chi Ching Goh, Jacinth Wing Sum Cheu, Aki Pui Wah Tse, Misty Shuo Zhang, Carmen Chak Lui Wong. Cell cycle inhibitors exhibit anti-tumor immunomodulatory roles through the HIF-1-DDX41 cytosolic DNA sensing pathway in HCC [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 511.
Abstract 5124: A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics
Authors: Wright William C. , Geeleher Paul 
Published: March 2024

Abstract
Combination chemotherapy is crucial for successfully treating cancer. However, the enormous number of possible drug combinations means discovering safe and effective combinations remains a significant challenge. To improve this process, we conduct large-scale targeted CRISPR knockout screens in drug-treated cells, creating a genetic map of druggable genes that sensitize cells to commonly used chemotherapeutics. We prioritize neuroblastoma, the most common extracranial pediatric solid tumor, where ~50% of high-risk patients do not survive. Our screen examines all druggable gene knockouts in 18 cell lines (10 neuroblastoma, 8 others) treated with 8 widely used drugs, resulting in 94,320 unique combination-cell line perturbations, which is comparable to the largest existing drug combination screens. Using dense drug-drug rescreening, we find that the top CRISPR-nominated drug combinations are more synergistic than standard-of-care combinations, suggesting existing combinations could be improved. As proof of principle, we discover that inhibition of PRKDC, a component of the non-homologous end-joining pathway, sensitizes high-risk neuroblastoma cells to the standard-of-care drug doxorubicin in vitro and in vivo using patient-derived xenograft (PDX) models. Our findings provide a valuable resource and demonstrate the feasibility of using targeted CRISPR knockout to discover combinations with common chemotherapeutics, a methodology with application across all cancers.
Citation Format: William C. Wright, Paul Geeleher. A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics [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 5124.
Abstract 5193: Molecular evolution of chemoresistance acquisition and predictive insights into the progression of bladder cancer
Authors: Yang Gi-Eun , Kim Jae-Jun , Shin Tae Hwan , Leem Sun-Hee 
Published: March 2024

Abstract
Cancer heterogeneity arises from cellular features, suggesting that distinct molecular drivers may be latent within cancers diagnosed at different clinicopathological stages. We thoroughly assessed phenotypic traits and molecular alterations linked to chemoresistance and constructed chemoresistant bladder cancer cell lines representing the stepwise transformation. Model cell lines (5637GRCs, gemcitabine-resistant cells) with stepwise gemcitabine resistance representing early, intermediate, and late resistance phases were developed from non-muscle-invasive bladder cancer (NMIBC) cells. Notably, an increase in cell motility was observed at a relatively early phase. The results from the time-course analysis of molecular evolution showed changes in focal adhesion kinase signaling, PI3K-Akt signaling, and TGF-β signaling pathways during the phase of increasing cell motility. As chemoresistance increased, the levels of genes related to differentiation and MAPK signaling gradually increased. A 63-gene chemoresistance-motility (CrM) signature was constructed and weighted according to cell motility, and a strong correlation was observed between cancer metastasis and drug resistance; the signature also showed prognostic relevance in patients with NMIBC. This study affords a significant understanding of the molecular evolution of chemoresistance acquisition and enables prediction of cancer progression during chemotherapy treatment. Moreover, it provides insights into the progression of cells through all chemoresistance stages from NMIBC to MIBC. Therefore, this study proposes the feasibility of utilizing biomarkers correlated with cancer motility to predict cancer progression in the early phase of chemotherapeutic intervention in patients with non-muscle-invasive bladder cancer.
Citation Format: Gi-Eun Yang, Jae-Jun Kim, Tae Hwan Shin, Sun-Hee Leem. Molecular evolution of chemoresistance acquisition and predictive insights into the progression of bladder 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 5193.
Abstract 5261: Immunologic signatures of peripheral blood cells in patients with advanced pancreatic cancer under lenvatinib-pembrolizumab maintenance therapy
Authors: Chung Vincent , Kos Ferdynand , Manual Edwin , Dempsey Shannon , Diamond Don J. 
Published: March 2024

Abstract
Background: The treatment of pancreatic cancer is limited by chemotherapy toxicities which impacts quality of life. This is a phase 2 clinical trial of lenvatinib and pembrolizumab as maintenance therapy in patients with advanced pancreatic cancer. We observed preclinical activity of this combination in pancreatic mouse models. We hypothesize that this combination may address unmet needs to minimize toxicities associated with standard treatments, stimulate anti-tumor T cell immunity, and improve the progression free and overall survival. Exploratory studies aim to characterize immune-related systemic changes in peripheral blood over the course of therapy and to identify global changes in expression of tumor-related genes in needle biopsy samples of liver metastatic lesions.
Methods: Multiplex gene expression analysis of unsorted peripheral blood mononuclear cells (PBMC) was performed using PanCancer Immune Profiling Panel on NanoString nCounter platform. PBMC samples from pre- through week 32 of treatment were assessed for differential expression of 730 immune profiling genes defining T cell functions and associated immune categories.
Results: PBMC immune profiling from 4/5 patients show a distinctive pattern of increased activation of T cells during the first 9 weeks of treatment followed by a sharp inhibition starting at weeks 9-12 after 3-4 cycles of treatment (CD3E, CD247, LCK, TBX1, TCF7, STAT4, IL2RG). Subsequent upregulation of macrophage-derived scavenger, inflammatory, and immunosuppressive gene expression patterns continued for the remainder of treatment (CD14, MSR1, MARCO, CD68, TGFB1, IL10RA). The median PFS of first 10 patients was 21.5 (9-32) weeks.
Conclusions: Immunotherapy resistance may be related to rapidly developing terminal differentiation and unresponsiveness of T cells in parallel with upregulation of macrophage-derived inflammatory and immunosuppressive processes. Studies are on-going to prevent inhibition of the T-cells.
Citation Format: Vincent Chung, Ferdynand Kos, Edwin Manual, Shannon Dempsey, Don J. Diamond. Immunologic signatures of peripheral blood cells in patients with advanced pancreatic cancer under lenvatinib-pembrolizumab maintenance therapy [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 5261.