bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5995: How FDA-approved drug, Aprepitant, induces immunogenic death of cancer cells
Authors: Dai Xinyi , Zhu Junyao , Perry Sofia , Jiang Qianjin , Shapiro David J. 
Published: March 2024

Abstract
Aprepitant is a long-standing FDA approved anti-nausea drug, recently re-purposed as an early-stage anticancer agent; how aprepitant kills cancer cells was not well studied. We find that aprepitant kills human and mouse cancer cells by hyperactivating the stress response pathway, the anticipatory unfolded protein response (a-UPR), thereby inducing immune cell activating necrotic cell death. Aprepitant is a small molecule neurokinin-1 receptor (NK-1R) antagonist widely used to prevent nausea and vomiting in cancer patients undergoing chemotherapy. Recently aprepitant has shown promise in mouse xenograft studies of colon, lung and pancreatic cancer and melanoma. Since aprepitant was thought to trigger release of calcium stored in the lumen of the endoplasmic reticulum, the step that we showed triggers hyperactivation of the a-UPR by ErSO family anticancer agents, we explored the role of the a-UPR in aprepitant action. Aprepitatnt robustly activates the PERK arm of the UPR increasing p-PERK and peIF2α, inhibiting protein synthesis. Notably, aprepitant treatment results in ATP depletion and activation of AMPK. Aprepitant induced rapid cell death was not blocked by apoptosis inhibitors or necroptosis inhibitors. In both standard 2-dimensional cell culture and 3-dimensional organoid culture aprepitant-treated breast cancer cells displayed typical features of necrotic cell death, including cell swelling, membrane rupture, and cytoplasmic vacuolization. Cell death by necrosis and membrane rupture leads to release of immune cell activating cell contents termed damage-associated molecular patterns (DAMPs). Aprepitant treatment induces release of the classic DAMPs, HMGB1 and ATP and medium from aprepitant-treated breast cancer cells enhances migration of differentiated human THP-1 macrophage. Thus aprepitant and other necrosis inducing therapies elicit immunogenic cell death (ICD) and may have the potential to enhance adjuvant immunotherapy. Genome-wide CRISPR screens with negative selection against aprepitant and other studies are being used to explore the pathways of aprepitant induced cell death and evaluate its therapeutic efficacy. Since FDA-approved aprepitant has been widely used for many years, identifying its pathway of action will both accelerate its clinical transition as an anticancer agent and help identify patients whose genetic profiles make them most likely to benefit from aprepitant therapy.
Citation Format: Xinyi Dai, Junyao Zhu, Sofia Perry, Qianjin Jiang, David J. Shapiro. How FDA-approved drug, Aprepitant, induces immunogenic death of cancer cells [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 5995.
Abstract 6028: Preferential tumor-to-normal tissue biodistribution and single-dose efficacy with ABD147, a DLL3-targeted engineered antibody-based radiotherapeutic, in preclinical small cell lung cancer models
Authors: Kulic Iva , Melese Etienne S. , Cummins Emma , Mandel Alex , Viswas Raja , Abrams Michael , Judge Adam 
Published: March 2024

Abstract
Targeted radiotherapies represent an emerging treatment modality for aggressive cancers with limited treatment options, such as small cell lung cancer (SCLC). ABD147 is a Delta Ligand 3 (DLL3)-targeted antibody conjugate designed to carry and deliver cytotoxic radioactive isotopes to DLL3-expressing tumor cells. DLL3 is commonly expressed on the cell surface of neuroendocrine cancer cells, including SCLC, but has limited and predominantly intracellular expression in non-malignant tissues. The ABD147 antibody specifically binds human DLL3 with high affinity and is internalized by DLL3-expressing cancer cells. To minimize radiation exposure to normal tissue, ABD147 has been engineered to clear quickly from the blood compartment. Using indium-111 to determine ABD147 pharmacokinetics and biodistribution in mice, we demonstrate rapid blood and normal tissue clearance of 111In-ABD147, as designed, following a single intravenous dose administration. However, 111In-ABD147 retains high tumor accumulation (activity concentration of up to 30% ID/g) in xenograft mouse models of SCLC despite low DLL3 surface antigen expression on tumor cells (≤ 3000 copies). 111In-ABD147 shows a favorable tumor-to-normal tissue distribution with predominant liver clearance. Following ABD147 therapeutic radioisotope delivery of actinium-225 or lutetium-177 (225Ac-ABD147, 177Lu-ABD147), we demonstrate single-dose tumor regression and dose-dependent sustained anti-tumor efficacy, corresponding to an extension of survival out to 84 days in multiple SCLC xenograft models. In summary, ABD147 can preferentially deliver radionuclides to DLL3-expressing tumor tissue while substantially reducing the systemic radioactive exposure typical of conventional IgG radioconjugates. Following promising results in preclinical models, including potent anti-tumor activity, 225Ac-ABD147 is now progressing into clinical development.
Citation Format: Iva Kulic, Etienne S. Melese, Emma Cummins, Alex Mandel, Raja Viswas, Michael Abrams, Adam Judge. Preferential tumor-to-normal tissue biodistribution and single-dose efficacy with ABD147, a DLL3-targeted engineered antibody-based radiotherapeutic, in preclinical small cell lung cancer 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 6028.
Abstract 6059: Discovery of ETS-007, a first-in-class degrader targeting N-terminal domain of androgen receptor derived from AR liquid-liquid phase separation inhibitor
Authors: Li Yingjie , Fei Mingyue , Miao Yingke , Feng Lijian , Fan Xiaofei , Li Jinping , Chen Yaozhong , Xu Ming , Cui Wenqi , Zheng Qiangang , Zhu Jidong 
Published: March 2024

Abstract
Patients with advanced prostate cancer inevitably acquire resistance to anti-androgen therapies, and progress to lethal castration-resistant prostate cancer (CRPC). The resistance mechanisms involve AR gene amplification and overexpression, constitutively active ligand-independent splice variants such as AR-V7, and the mutations in the AR ligand-binding domain (LBD). Our previous study has shown that the AR N-terminal domain (NTD) is responsible for AR liquid-liquid phase separation (LLPS) capability, which is essential for AR/AR-V7 transcriptional activity. We conducted a compound library screening using an AR LLPS phenotypic assay and identified ET0516 as a hit to specifically inhibit AR LLPS and its downstream gene expression, indicating that inhibition of AR. LLPS through targeting its NTD is a feasible approach to overcome the resistance to current anti-androgens therapy. Here we report the identification of a novel AR degrader, ETS-007 which is originated and evolved from internal LLPS phenotypic screening, that effectively degrades both AR and AR-V7 proteins with DC50 of single-digit nM by inducing a protein-protein interaction between AR NTD and an E3 ligase complex. ETS-007 induced AR and AR-V7 polyubiquitination, followed by degradation which could be blocked by the protease inhibitor MG132. ETS-007 significantly inhibited cell proliferation in AR and/or AR-V7 positive cell lines, e.g. LNCaP and 22RV1, and downregulated the androgen responsive genes such as PSA and TMPRSS2. Compared with enzalutamide and ARV-110, ETS-007 could block transcriptional activities of AR-V7, and AR mutants in luciferase report assay. Oral administration of ETS-007 in an enzalutamide-resistant 22RV1 xenograft model led to intratumoral AR-V7 degradation and concomitant decrease in PSA protein levels, resulting in a remarkable tumor regression. Taken together, our findings provide preclinical evidence that ETS-007 as a potent AR-NTD degrader derived from our LLPS platform can effectively block the transcriptional activities of both AR and AR-V7 for the treatment of metastatic CRPC.
Citation Format: Yingjie Li, Mingyue Fei, Yingke Miao, Lijian Feng, Xiaofei Fan, Jinping Li, Yaozhong Chen, Ming Xu, Wenqi Cui, Qiangang Zheng, Jidong Zhu. Discovery of ETS-007, a first-in-class degrader targeting N-terminal domain of androgen receptor derived from AR liquid-liquid phase separation inhibitor [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 6059.
Abstract 6150: MMP14 and MKLN1 as colorectal cancer susceptibility genes and a drug repurposing candidate from genome-wide association study in South Korea
Authors: Yun Dabin , Yang Jung-Ho , Kweon Sun-Seong , Sim Jin-ah , Kim Minjung , Park Ji Won , Jeong Seung Yong , Shin Aesun , Song Nan 
Published: March 2024

Abstract
Background: One of the major topics about colorectal cancer (CRC) is to find susceptible genes. Furthermore, functional interpretation of post-GWAS analysis gains attention and various approaches to find drug-repurposing candidates are used in cancer research. Our study aims to identify susceptible genes for CRC and provide drug-repurposing candidates.
Methods: CRC patients in Seoul National University Hospital with prospective follow-up were recruited. From blood-derived DNA, genome-wide SNPs were genotyped using the Korea Biobank Array and 409,063 SNPs were extracted. SNP-based logistic regression model was fit for the event of CRC estimating beta values. Furthermore, post-GWAS analysis was conducted using regulatory function, multiple annotation and gene expression database. Drug-repurposing candidate was identified through the pre-trained deep neural network with susceptible genes.
Results: We used 500 participants of CRC cases and 1,500 participants of healthy controls. For GWAS, statistically significant associations were mapped to MKLN1, MMP14, PTPN14 and MKL2 genes. For post-GWAS analysis, strong associations were found for MKLN1 (rs75170436, 7q32.3, Beta=-0.90, P-value=5.90×10-13) and MMP14 (rs3751489, 14q11.2, Beta=-1.91, P-value=2.31×10-12). From the drug-repurposing analysis, PPARδ/β agonist (GW0742; Binding score=3.79(MKLN1), 12.06(MMP14)) was identified for both genes with the highest score.
Conclusions: We revealed MKLN1 and MMP14 genes as susceptible genes associated with CRC development. Additionally, we identified PPARδ/β agonist (GW0742) as a drug-repurposing candidate for the treatment of CRC. These findings can promote the understanding of CRC development and provide a novel therapeutic candidate for CRC patients in the future.
Citation Format: Dabin Yun, Jung-Ho Yang, Sun-Seong Kweon, Jin-ah Sim, Minjung Kim, Ji Won Park, Seung Yong Jeong, Aesun Shin, Nan Song. MMP14 and MKLN1 as colorectal cancer susceptibility genes and a drug repurposing candidate from genome-wide association study in South Korea [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 6150.
Abstract 6205: Identify drugs for metastatic castration-resistance prostate cancer (mCRPC) patients with high glycolytic activity through in silico approach
Authors: Su Mei-Chi , Lee Adam M. , Huang R. Stephanie 
Published: March 2024

Abstract
Prostate cancer (PC) remains a prominent cause of cancer-related mortality among men in the United States. A significant factor contributing to the mortality of PC patients is the development of resistance to second-generation antiandrogen therapies, particularly androgen receptor-signaling inhibitors (ARSI), which is pronounced in patients with late-stage PC, metastatic castration-resistance prostate cancer (mCRPC). Therefore, there is an urgent need for novel therapeutics beyond AR signaling inhibition for patients with mCRPC. One of the key drivers of resistance to ARSI and a critical feature of CRPC is cancer metabolism reprogramming to elevated glycolysis. However, the current research on finding drugs to impede high-glycolytic tumor growth is hurdled by a resistance raised from metabolic plasticity. The aim of this research is to quickly repurpose existing drugs for inhibiting high-glycolytic mCRPC growth while proactively circumstancing resistance from metabolic plasticity through computational approaches. To do this, we imputed a large number of drug responses in patients with mCRPC using a computational algorithm (OncoPredict), identified drugs that were projected to show higher sensitivity in high-glycolytic tumors, and performed in vitro validation. Furthermore, to maximize drug efficacy, we identified biomarkers for drug candidates. By implementing this computational pipeline, we identified a number of drugs with various mechanisms of action that show higher efficacy in mCRPC with high glycolysis. Furthermore, we successfully validated the efficacy of these nominated drug candidates including an anti-parasitic agent, an HSP90 inhibitor, and a CDK inhibitor. These drug candidates exhibited superior tumor growth inhibition in in vitro models of high glycolysis-induced advanced PC. In conclusion, this study introduces an innovative in silico approach to unveil the existing drugs’ unknown potential for the treatment of patients with mCRPC. Our findings hold promise for development of effective therapeutics for combating this challenging disease.
Citation Format: Mei-Chi Su, Adam M. Lee, R. Stephanie Huang. Identify drugs for metastatic castration-resistance prostate cancer (mCRPC) patients with high glycolytic activity through in silico approach [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 6205.
Abstract 6226: Identifying nested spatial units as a conserved organizing principle of the spatial tumor microenvironment
Authors: Behera Vivek , Giba Hannah , Doran Benjamin A. , Kline Justin P. , Raman Arjun S. 
Published: March 2024

Abstract
Heterogeneity of therapeutic response amongst cancer patients has a profound impact on cancer-related mortality. It has been widely hypothesized that diversity in clinical outcomes is driven by variability in tumor biology at scales ranging from inter-patient to inter-cellular. Indeed, the advent of technologies describing the tumor microenvironment (TME) at cellular resolution has demonstrated that TME organization is heterogeneous with respect to intra-tumor spatial location, body tumor location (primary vs metastatic), patient, and tumor type. However, the organizing principles that govern TME heterogeneity remain unclear. Without such organizing principles, it remains an arduous task to link descriptions of tumor biology heterogeneity to clinical outcomes in a mechanistically explainable manner. Through the application of network statistical inference models to spatial transcriptomic data, we have identified that nested spatial units (NSUs) are a core organizing principle of the TME. We find that NSUs are widely conserved across 96 patient biopsies of 14 distinct tumor types and 3 body locations (primary, abdominal metastases, brain metastases). Moreover, NSUs represent a transferrable organizing blueprint that allows for the spatial location of individual spots (5-50 cells) in a tumor biopsy to be predicted by the NSUs of a secondary, unrelated biopsy (Pearson correlation of spot-spot distance: 0.04 - 0.71, median 0.25). By using NSUs as the organizing unit of comparison, we identify variation in gene expression, biological pathways, and multicellular structures occurring across tumors in a distance-dependent manner. In summary, NSUs provide a foundation for the comparative analysis of tumor spatial biology and a path by which spatial biology can be mechanistically linked to patient outcomes.
Citation Format: Vivek Behera, Hannah Giba, Benjamin A. Doran, Justin P. Kline, Arjun S. Raman. Identifying nested spatial units as a conserved organizing principle of the spatial 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 6226.
Abstract 6237: Large-scale imputation models for multi-ancestry proteome-wide association analysis
Authors: Wu Chong , Zhang Zichen , Yang Xiaochen , Zhao Bingxin 
Published: March 2024

Abstract
Proteome-wide association studies (PWAS) decode the intricate proteomic landscape of biological mechanisms for complex diseases. Traditional PWAS model training relies heavily on individual-level reference proteomes, thereby restricting its capacity to harness the emerging summary-level protein quantitative trait loci (pQTL) data in the public domain. Here we introduced a novel framework to train PWAS models directly from pQTL summary statistics. By leveraging extensive pQTL data from the UK Biobank, deCODE, and ARIC studies, we applied our approach to train large-scale European PWAS models (total n = 88,838 subjects). Furthermore, we developed PWAS models tailored for Asian and African ancestries by integrating multi-ancestry summary and individual-level data resources (total n = 914 for Asian and 3,042 for African ancestries). We validated the performance of our PWAS models through a systematic multi-ancestry analysis of over 700 phenotypes across five major genetic data resources. Specifically, we identified several novel and well-known genes for various cancers; we highlighted eight genes associated with six cancer traits across all three PWAS model cohorts, including CTSF, RSPO3, CRTAM, LAYN, CHRDL2, DPEP1, NFASC, and NAAA. Our results bridge the gap between genomics and proteomics for drug discovery, highlighting novel protein-phenotype links and their transferability across diverse ancestries. The developed PWAS models and data resources are freely available at www.gcbhub.org.
Citation Format: Chong Wu, Zichen Zhang, Xiaochen Yang, Bingxin Zhao. Large-scale imputation models for multi-ancestry proteome-wide association analysis [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 6237.
Abstract 6256: Prevalence of BRCA1 and BRCA2 proteins in breast cancer in a nigerian population and their relationship with different breast cancer morphological variants
Authors: Raphael Solomon , Oluwasesan Abdul 
Published: March 2024

Abstract
Background: Breast cancer is the commonest site specific cancer in women and a leading cause of cancer death among women in Nigeria and globally. The trend in Nigeria and Africa is that breast cancers are seen in younger age groups, are of higher grades and follow an aggressive course. It has been suggested that this may largely be due to mutation in BRCA genes with the attendant alteration in function of its proteins. This study aimed at determining the prevalence of BRCA1 and BRCA2 proteins in breast cancers seen in our environment as well as to see any association between these proteins and different morphological variants.
Materials and Methods: A descriptive study using tissue blocks of all histologically diagnosed breast cancer in our department between 2013 and 2017. Fresh sections were recut for histological grading and immunohistochemistry. Proteintech BRCA1 and BRCA2 polyclonal antibodies and detection kit were used.
Results: One hundred and thirty (130) cases met the inclusion criteria for this study. The mean (SD) age of the patients was 44.8 (10.3) years with ages ranging from 26 to 79 years. There were more cases of breast cancer (73.1%) seen before 50 years. Two (2) Male Breast Cancer (MBC) cases were seen, giving the female to male ratio of 64:1. The commonest morphological variant encountered was Invasive Carcinoma, No Special Type at 84.6% of cases. This was followed by invasive medullary (7.8%). The least common variant was papillary cancer at 0.8%. The tumors seen were mostly grade 3 (71.2%), followed by grade 2 at 22.7% and the least was grade 1 at 6.1%. Positivity for BRCA1 and BRCA2 proteins was seen in 27.7% and 30.0% of cases respectively. One of the MBC showed reactivity for BRCA1 protein. No significant relationship was seen between BRCA 1/2 proteins expression and age or breast cancer histotypes.
Conclusion: BRCA 1 and 2 proteins are an important risk factor for breast cancers seen in this environment. However, there is no association with age distribution and morphological variants of the breast cancer in our population.
Citation Format: Solomon Raphael, Abdul Oluwasesan. Prevalence of BRCA1 and BRCA2 proteins in breast cancer in a nigerian population and their relationship with different breast cancer morphological variants [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 6256.
Abstract 6302: Home-based supportive care programs for quality-of-life outcomes among patients with advanced cancer: A systematic review
Authors: Hwang Inyoung , Wo Go-Un , Lee Sun-Young , Yoo Shin Hye , Kim Kyae Hyung , Kim Min-Sun , Shin Jeongmi , Jeong Hyejin , Jang Min Seol , Baek Sun Kyung , Jung Eun Hee , Lee Dong-Wook , Cho Belong , Park Jin Ho , Kwon Hyuktae 
Published: March 2024

Abstract
Objectives This study systematically reviews the literature on the effect of home-based supportive care (HbSC) programs on the quality of life (QoL) of patients with advanced cancer.
Methods: The research question ‘Do home-based supportive care programs for patients with advanced cancer improve their QoL?’ was addressed. After registering the plan with PROSPERO (CRD42021235007), literature published from 1 January 1990 to 11 July 2022 was searched on Ovid Medline, Embase, Cochrane library, Web of Science, and Google Scholar and reviewed for inclusion based on predefined criteria. This review only included trial studies published in English.
Results: Of 5288 articles identified, 17 studies were judged suitable for inclusion in this review. The components of HbSC programs included home visits, patient and caregiver education, home nursing, psychotherapy, exercise, and telephone consultation. Eight programs included conducting multidisciplinary team meetings. Improvements in QoL were reported in six studies. Specific areas of QoL improved when interventions included home nursing, psychotherapy, patient and caregiver education, and exercise.
Conclusion: HbSC programs appear to enable the improvement of the QoL of patients with advanced cancer. The area of QoL that shows improvement could vary depending on the HbSC components. More studies that address HbSC programs are needed to select patients at the proper time and provide suitable programs for patients to benefit most.
Citation Format: Inyoung Hwang, Go-Un Wo, Sun-Young Lee, Shin Hye Yoo, Kyae Hyung Kim, Min-Sun Kim, Jeongmi Shin, Hyejin Jeong, Min Seol Jang, Sun Kyung Baek, Eun Hee Jung, Dong-Wook Lee, Belong Cho, Jin Ho Park, Hyuktae Kwon. Home-based supportive care programs for quality-of-life outcomes among patients with advanced cancer: A systematic review [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 6302.