bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6147: Genome-wide association study identifies new genetic susceptibility loci for multiple primary cancers
Authors: He Shisi , Perry James , Li Shengchao , Mitchell Braxton D. , Zhang Yuji , Chen Shuo , Beane-Freeman Laura , Barry Kathryn Hughes , Berndt Sonja I. 
Published: March 2024

Abstract
Objectives: Genetic susceptibility is thought to contribute to the development of multiple primary cancers (MPC), often called secondary cancers. Although rare variants contribute to risk, these only account for a small fraction of MPC cases. The contribution of common variants to risk is unknown.
Methods: To identify common genetic variants associated with the risk of MPC, we conducted a trans-ancestry meta-analysis of genome-wide association studies (GWAS), including 7,360 MPC cases and 138,684 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and UK Biobank (UKBB). Association analyses were performed separately by genetic ancestry, genotype platform, and study, adjusting for age, sex, and principal components, and the results were meta-analyzed together using a fixed effects model. Genome-wide SNP heritability was estimated using GCTA. Pathway and functional enrichment analyses were conducted to gain insights into potential biological mechanisms underlying discovered loci.
Results: We identified one novel locus at chromosome 3q26.2 (LRRC34, rs7621631) that was associated with MPC risk (P=1.16x10-8). Variants in this region have been previously associated with telomere length, suggesting a possible underlying mechanism. In sex-stratified analyses, we identified an additional locus at chromosome 12q24.33 (intergenic, rs10466868) associated with MPC in men (P= 7.76x10-8), but not women. Although the risk associated with these two discovered loci was small, the genome-wide SNP heritability was estimated to be 12%, suggesting that there are likely more common variants to be discovered for MPC risk.
Conclusions: Our study demonstrates that common genetic variation contributes to the risk of multiple primary cancers and suggests additional loci are likely to be identified with larger studies.
Citation Format: Shisi He, James Perry, Shengchao Li, Braxton D. Mitchell, Yuji Zhang, Shuo Chen, Laura Beane-Freeman, Kathryn Hughes Barry, Sonja I. Berndt. Genome-wide association study identifies new genetic susceptibility loci for multiple primary cancers [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 6147.
Abstract 6303: Innovative strategies for managing chemotherapy-induced alopecia: Scalp cooling
Authors: Gaumond Simonetta I. , Abdin Rama , McPhillips Rory O. , Ferrari Lina M. , Mufarrej Sammya , Jimenez Joaquin J. 
Published: March 2024

Abstract
Chemotherapy-Induced Alopecia (CIA) is a visibly distressing consequence of chemotherapy. Although it does not pose a life-threatening risk, CIA can significantly affect patient’s self-esteem. Regarding the mechanism of action, stress induced by chemotherapy treatment can lead to the shedding of hair follicles, generating varying degrees of hair loss. In recent years, scalp cooling has emerged as a beneficial preventative agent for CIA due to its ability to induce vasoconstriction in the scalp and reduce follicular metabolic rate. To assess the efficacy of scalp cooling in preventing CIA, we conducted a review of randomized control trials published on PubMed in the last 10 years. Five studies met our inclusion criteria, in which three examined hair preservation and two evaluated treatment duration efficacy. All studies investigating hair preservation with scalp cooling reported highly significant results from the cooling device when compared to a placebo (56.3% vs. 0%, 39.3% vs. 0%, and 50.5% vs. 0%, respectively). Additionally, one of these studies also assessed hair regrowth, revealing higher rates in the scalp cooling group compared to the control at 6 weeks (89% vs. 12%) and at 12 weeks (100% vs. 59%). Both studies evaluating the effectiveness of scalp cooling based on treatment duration concluded that 20 minutes of cooling was as effective as 45 and 90 minutes in preventing CIA. Collectively, these findings add to the mounting evidence endorsing scalp cooling as a powerful management strategy in averting CIA.
Citation Format: Simonetta I. Gaumond, Rama Abdin, Rory O. McPhillips, Lina M. Ferrari, Sammya Mufarrej, Joaquin J. Jimenez. Innovative strategies for managing chemotherapy-induced alopecia: Scalp cooling [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 6303.
Abstract 6356: Novel antibody targeting tumor NKG2D ligand MIC: Preclinical studies and clinical development plan for mCRPC
Authors: Wu Jennifer Donglan , Sosman Jeff , Kocherginsky Masha , Serritella Anthony , Hussian Maha , Vanderweele David J. 
Published: March 2024

Abstract
In response to genomic insults and DNA double-strand breaks, the stressed epithelial cells express the MHC I-chain related molecule (MIC) on the surface as a byproduct of activating the ATM pathway. The MIC molecule itself has no known impact on tumor survival or growth. In the context of immune microenvironment, tumor cell surface MIC can activate NK cells and co-stimulate CD8 T cells by engaging in the activating receptor NKG2D to hinder the early tumorigenesis. However, in established malignancies, in particular metastatic diseases, tumor cells shed surface MIC to release the soluble form MIC (sMIC). It has been well demonstrated that, in contrary to cell surface MIC, sMIC is highly immune suppressive by disturbing NK cell homeostasis and repolarizing NK cells function, impairing antigen-specific CD8 T cell function by downmodulating NKG2D expression and CD3z expression, and facilitating immune suppression of MDSCs and TAMs in tumor microenvironment. We have demonstrated that MIC is prevalently expressed by prostate tumor cells and significantly upregulated in mCRPC tumors. We have shown significantly elevated levels of serum sMIC in prostate cancer patients with metastatic diseases. We have developed a novel class of clinical candidate monoclonal antibody huB10G5 that can target both sMIC and surface MIC to re-invigorate both NK and CD8 T cell function and inhibit MDSCs and TAMs in preclinical models. The huB10G5 has an acceptable safety profile and is currently completing CMC for IND enabling. We hypothesize that huB10G5 is a novel immune therapeutic reagent for mCRPC patients. To test our hypothesis, we first conducted serial studies of the clinical candidate huB10G5 in pre-clinical models of prostate cancers. We found that huB10G5 can effectively induce 100% long-term tumor complete regression (CR) as low as 1.0 mg/KG. These animals are fully protected from tumor re-challenge. The anti-tumor effect is mediated by the combined action of NK and CD8 T cells. With the support of our pre-clinical efficacy and safety data, we have planned to initiate Phase I clinical trial with huB10G5 for mCRPC patients in 2024.
Citation Format: Jennifer Donglan Wu, Jeff Sosman, Masha Kocherginsky, Anthony Serritella, Maha Hussian, David J. Vanderweele. Novel antibody targeting tumor NKG2D ligand MIC: Preclinical studies and clinical development plan for mCRPC [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 6356.
Abstract 6380: Exploring immune checkpoint inhibitor-related adverse events in pediatric cancer patients: A pharmacovigilance analysis of VigiBase and the FDA adverse event reporting system (FAERS) database
Authors: Shen Junyi , Lin Anqi , Cheng Quan , Zhang Jian , Luo Peng 
Published: March 2024

Abstract
Background: With the widespread use of immune checkpoint inhibitors (ICIs) in the treatment of childhood cancers, their associated ICIs-related adverse events (irAEs) have become an important challenge. Our study was conducted to explore the pediatric high-risk ICIs-related AEs (pediatric irAEs) and explore the underlying mechanisms of pediatric irAEs.
Methods: We analyzed ICIs-related adverse reaction reports in VigiBase from 1967 to 2023 and the FDA Adverse Event Reporting System (FAERS) database from 2013 to 2022. Using three methods, the reporting odds ratio (ROR), the proportional reporting ratio (PRR), and the information component (IC), we conducted a disproportionality analysis between pediatric and adult cancer patients using ICIs to discover pediatric irAEs. Furthermore, we explored the impact of clinical factors on the occurrence of pediatric irAEs and their subsequent prognosis through univariate and multivariate logistic regression analyses. Finally, combining these data with pan-cancer transcriptome data from the Gene Expression Omnibus (GEO) database, we explored the potential biological mechanisms related to pediatric irAEs.
Results: We identified 4 categories of pediatric irAEs in the VigiBase and FAERS databases, including cytokine release syndrome (RORVigiBase = 17.05; RORFAERS = 14.17), acute respiratory distress syndrome (RORVigiBase = 10.26; RORFAERS = 12.39), seizure (RORVigiBase = 7.18; RORFAERS = 10.63) and febrile neutropenia (FN) (RORVigiBase = 3.01; RORFAERS = 4.84). The occurrence of pediatric irAEs may be related to mechanisms such as activation of immune cells, imbalance of inflammatory factors, activation of pathogen recognition, downregulation of inhibitory synapses, excitation/inhibition imbalance and central nervous system dysfunction.
Conclusion: This study systematically analyzed the high-risk irAEs that may occur after using ICIs in pediatric cancer patients. Next, we explored the possible biological mechanisms of these pediatric irAEs to provide certain theoretical guidance for the prevention and treatment of adverse reactions in pediatric cancer patients after treatment with ICIs.
Citation Format: Junyi Shen, Anqi Lin, Quan Cheng, Jian Zhang, Peng Luo. Exploring immune checkpoint inhibitor-related adverse events in pediatric cancer patients: A pharmacovigilance analysis of VigiBase and the FDA adverse event reporting system (FAERS) database [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 6380.
Abstract 6509: GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors
Authors: Hou Xiaodan , Yan Honghua , Zhang Xin , Qian Weidong , Chen Dong , Ren Zhihua , Tong Youzhi 
Published: March 2024

Abstract
Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is the central signal molecule in regulating cell growth, metabolism, angiogenesis, and survival. The first generation of mTOR inhibitors specifically inhibit mTORC1 but are insensitive to mTORC2 and cannot eliminate the downstream signaling cascade in cancer. GT0486, a second-generation mTORC1/2 dual inhibitor, can selectively suppress mTOR kinase activity while has no inhibitory effect on other kinase receptors. We investigate the anti-tumor efficacy of GT0486 in a variety of tumor cells and xenograft animal models in vitro and in vivo. The combination effects of GT0486 and BTKi (BTK inhibitor) were also evaluated. Compared with other mTOR inhibitors (GDC-0349, AZD-2014, Rapamycin, GDC-0941, and CC-223), GT0486 exhibits the stronger inhibitory activity on human tumor cells, such as U87(glioma), PC-3(prostate cancer), MDA-MB-468(breast cancer) and Huh-7(liver cancer). In B-cell lymphoma, compared with the CC-223, GT0486 shows greater inhibitory potency against TMD8, DoHH2 and WSU-DLCL2, with IC50 values of 85nM, 96nM and 83nM, respectively. Moreover, in the U87 and the PC-3 xenograft animal models, GT0486 strongly reduced tumor growth in dose dependent manner. High synergistic effects were observed with GT0486 in combination with BTK inhibitors, including Acalabrutinib, Ibrutinib, Zanubrutinib and Orelabrutinib in the BTKi sensitive TMD8 cells. In BTKi resistant DoHH2 cells, GT0486 also enhanced the drug sensitivity of BTKi. The possible biomarkers on the synergistic mechanism were further studied. GT0486 improves the role of BTKi on cell cycle arrest in phase G1. At the same time, the phosphorylation levels of mTOR downstream effectors AKT, 4EBP1 and S6 were dose-dependently downregulated after GT0486 treatment, and a significant reduction were observed when combined with BTKi. These results demonstrate that GT0486 is a promising dual mTOR1/2 inhibitor, which is currently undergoing clinical phase I study in China for the treatment of solid tumors. Strong synergistic effects observed with GT0486 in combination with BTKi in this study might open a way for a novel treatment strategy in clinical trials.
Citation Format: Xiaodan Hou, Honghua Yan, Xin Zhang, Weidong Qian, Dong Chen, Zhihua Ren, Youzhi Tong. GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors [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 6509.
Abstract 6517: ALDOC as an indicator of HMGB1 blockade combined with checkpoint inhibitor based immunotherapy in GBM patients
Authors: Yang Yi-Fang , Chan Ming-Hsien , Chen Chi-Long , Hsiao Michael , Chang Yu-Chan 
Published: March 2024

Abstract
Aldolase is an enzyme that takes part in glycolysis by catalyzing a six-carbon intermediate to yield two three-carbon products, requiring ATP. The aldolase family comprises three members, namely ALDOA, ALDOB, and brain-specific ALDOC. Low-grade gliomas and glioblastoma (GBM) are characterized by shared genetic events, including chromosome 1p/19q codeletion, EGFR amplification, and ATRX loss of function, in which ALDOC plays a role. Additionally, ALDOC is responsive to IDH1 mutations. If patients display IDH1 mutations, it is expected that ALDOC performance will be relatively higher. This finding suggests a more favorable prognosis. The ALDOC promoter region's function is impeded by hypermethylation, which declines as glioma progresses. The regulatory mechanisms and implications remain unclear. We established a multi-omics profile and identified several crucial mechanisms activated upon the loss of ALDOC expression. Among these mechanisms, we found HMGB1 to have a key role in linking the immune response, tumor microenvironment, and epigenetic modifications. We compared the proteomic and secretomic platforms in an ALDOC overexpression/knockdown model, which showed abundant HMGB1 expression following ALDOC inhibition. Importantly, there is an inverse correlation between ALDOC expression and HMGB1 protein levels. Additionally, our findings reveal that upregulation of ALDOC promotes its translocation to the nucleus, thereby enhancing its binding affinity with HMGB1. This, in turn, enables extracellular release of HMGB1 in GBM, which triggers signaling via receptors for advanced glycation end-products (RAGE) and several cytokines. Moreover, HMGB1 remodels the immune microenvironment and upregulates multiple immune checkpoint molecules, including PD-L1, PD-L2, B7-H3, and MHCs. Not all GBM models exhibited significant effects when combined with immune checkpoint blockade using HMGB1 blockade. However, ALDOC knockout mice demonstrated poorer survival and treatment efficacy, suggesting that ALDOC may be crucial for a personalized immunotherapy strategy.
Citation Format: Yi-Fang Yang, Ming-Hsien Chan, Chi-Long Chen, Michael Hsiao, Yu-Chan Chang. ALDOC as an indicator of HMGB1 blockade combined with checkpoint inhibitor based immunotherapy in GBM 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 6517.
Abstract 6574: UCHL1 is a molecular indicator and a therapeutic target for neuroendocrine carcinomas
Authors: Liu Shiqin , Chai Timothy , Marques Fernando , Yin Qingqing , Hsu En-Chi , Shen Michelle , Toland Angus , Bermudez Abel , Hartono Alifiani B. , Massey Christopher F. , Lee Chung S. , Zheng Liwei , Baron Maya , Denning Caden J. , Aslan Merve , Nguyen Holly , Nolley Rosalie , Zoubeidi Amina , Das Millie , Kunder Christian , Howitt Brooke , Soh H Tom , Weissman Irving L. , Liss Michael A. , Chin Arnold I. , Brooks James D. , Corey Eva , Pitteri Sharon , Huang Jiaoti , Stoyanova Tanya Ivanova 
Published: March 2024

Abstract
Neuroendocrine carcinomas, such as neuroendocrine prostate cancer (NEPC), small cell lung cancer (SCLC), and neuroblastoma, share common histological features, including expression of neuroendocrine markers, rapid relapse after treatment, and poor prognosis. Due to the poor clinical outcome of patients with neuroendocrine carcinomas, there is a critical need to identify new drivers, therapeutic targets, and effective therapeutic strategies for these malignancies. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a protease that has a dual function in regulating protein stability. We demonstrated that UCHL1 is significantly elevated in tissues from patients with NEPC, SCLC, and neuroblastoma. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of key transcriptional factors, E2F1 and c-MYC. Conversely, UCHL1 binds p53 and promotes p53 degradation. Importantly, treatment with UCHL1 inhibitors significantly reduces tumor growth and metastasis of neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, halts tumor growth in pre-clinical settings. Our study reveals new mechanisms of UCHL1 function in neuroendocrine carcinomas tumorigenesis and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosis and monitoring treatment responses in neuroendocrine carcinomas.
Citation Format: Shiqin Liu, Timothy Chai, Fernando Marques, Qingqing Yin, En-Chi Hsu, Michelle Shen, Angus Toland, Abel Bermudez, Alifiani B. Hartono, Christopher F. Massey, Chung S. Lee, Liwei Zheng, Maya Baron, Caden J. Denning, Merve Aslan, Holly Nguyen, Rosalie Nolley, Amina Zoubeidi, Millie Das, Christian Kunder, Brooke Howitt, H Tom Soh, Irving L. Weissman, Michael A. Liss, Arnold I. Chin, James D. Brooks, Eva Corey, Sharon Pitteri, Jiaoti Huang, Tanya Ivanova Stoyanova. UCHL1 is a molecular indicator and a therapeutic target for neuroendocrine carcinomas [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 6574.
Abstract 6637: The Haemophilus influenzae vaccine mitigates pancreatic tumor progression and lowers immunoregulatory cell levels in the tumor microenvironment
Authors: Giurini Eileena F. , Pappas Sam G. , Gupta Kajal H. 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease projected to become the second leading cause of cancer deaths by 2030. First-line chemotherapies gemcitabine and FOLFIRINOX provide little therapeutic benefit and are accompanied by severe adverse toxicities, precluding long-term treatment. In addition, PDAC is notoriously refractory to checkpoint inhibitor immunotherapies, due to poor immunogenicity and a tumor microenvironment dominated by suppressive cell types. Thus, there is an unmet need for innovative, immune-based strategies to combat PDAC. A previous study utilized engineered bacteria to effectively kill PDAC tumor cells by directly delivering immunogenic tetanus toxoid to the tumor. Given the potential toxicity in using live bacteria, our group utilized a less toxic alternative, an FDA-approved Haemophilus influenzae type b vaccine (HibVx) also containing a tetanus toxoid component. To determine the antitumor potential of HibVx, our group used a physiologically relevant murine model, low T cell clone murine PDAC tumor model 641c95 and clinically relevant KPC mice model for PDAC. After tumors were established, animals received three consecutive daily treatments of HibVx via intraperitoneal injection. HibVx-treated animals experienced a dramatic reduction in tumor growth compared to PBS-treated controls (p&lt;0.001). Given that tetanus toxoid is highly immunogenic in nature, changes in intratumoral immune cell populations following HibVx treatments were of great interest. Using flow cytometry analysis, HibVx-treated tumors had a significant increase in natural killer cells compared to control tumors (p&lt;0.05). In addition, HibVx affected myeloid-derived suppressor cell populations (MDSCs), which are heavily implicated in the suppressive nature of PDAC tumors. HibVx also significantly decreased MDSCs within the tumor (p&lt;0.05). In all, these findings position HibVx as an effective immunostimulatory agent that can be used as an alternative to live bacteria-based therapy for the treatment of PDAC.
Citation Format: Eileena F. Giurini, Sam G. Pappas, Kajal H. Gupta. The Haemophilus influenzae vaccine mitigates pancreatic tumor progression and lowers immunoregulatory cell levels in the tumor microenvironment [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 6637.