bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4654: Targeting poly-resistant stem cells in high-grade serous ovarian cancer via synthetic lethal drugs
Authors: Xian Wa , McKeon Frank , Crum Christopher , Ajani Jaffer , Davies Peter , Vincent Matthew , Bachovchin William , Lai Hung-Sen , Pan Shuang , Khorrami Melina , khorrami Melika , Montes Raul caballero , Mosaffa Paria , Hoffman Ashley , Su Amber 
Published: March 2024

Abstract
High-grade serous ovarian cancer (HGSOC) is remarkably responsive to chemotherapy and yet recurs at high rates as resistant disease. Using novel technology that selects for rare clonogenic cells which recapitulate HGSOC in immunodeficient mice, we have identified, in therapy-naive HGSOC, a minor population of clones that are intrinsically resistant to paclitaxel/carboplatin as well as to a broad spectrum of oncology drugs. These intrinsic "polyresistant" cells are a common, albeit minor, component of clonogenic cells in all therapy-naive tumors analyzed. Importantly, the polyresistant clonogenic cells share a gene expression signature distinct from the majority of clonogenic cells that are exquisitely sensitive to paclitaxel/carboplatin, and this gene signature of polyresistant cells extends to all polyresistant clones within a patient and across HGSOC cases. We have exploited these polyresistant clones to perform high-throughput screening of small molecule "bioactive" libraries to identify compounds that circumvent this resistance. While single agent "hits" were obtained, these showed minimal therapeutic windows relative to normal stem cells of the liver and gastrointestinal tract. Adaptations of synthetic lethal strategies have yielded lead drug combinations that eliminate polyresistant clones from all four cases tested at low nanomolar concentrations in vitro. We have improved these combinations via the synthesis of new chemical entities that show potent effects against both subcutaneous and peritoneal tumor models in immunodeficient mice derived from polyresistant HGSOC clones. Clonogenic analyses of these treated and untreated xenografts support the notion that these drug combinations are targeting the stem cell populations within these tumors. We anticipate that these drug combinations will assist in preventing or treating recurrent HGSOC.
Citation Format: Wa Xian, Frank McKeon, Christopher Crum, Jaffer Ajani, Peter Davies, Matthew Vincent, William Bachovchin, Hung-Sen Lai, Shuang Pan, Melina Khorrami, Melika khorrami, Raul caballero Montes, Paria Mosaffa, Ashley Hoffman, Amber Su. Targeting poly-resistant stem cells in high-grade serous ovarian cancer via synthetic lethal drugs [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 4654.
Abstract 4676: 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2) is a novel paclitaxel chemosensitizer to inhibit growth in Taxol non-resistant and Taxol resistant cancers
Authors: Cheng Ka Ming , Wu Gui yun , Cheung Kowk Kuen , Shen Xiao-Ling , Hu Ying-Jie , Lui Ki 
Published: March 2024

Abstract
11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2) is a single molecule isolated from a traditional Chinese Medicinal herb Marsdenia tenacissima (MT). Recently, our group has isolated a few single molecules from the MT herb, they have shown significant anti-tumor activity in vitro and MT2 has the highest potential among all. We have performed MTT viability assay and clonogenic assay to demonstrate that MT2-alone is non-cytotoxic, but the cytotoxicity of the paclitaxel+MT2 combination treatment was more significant than that of paclitaxel, a microtubule stabilizing chemotherapeutic agent. The underlying mechanism of such growth inhibition is contributed by the down-regulation of the pro-survival signaling and up-regulation of the apoptotic signaling such as an increase in cleaved caspase 3 and decrease in anti-apoptotic Bcl-2 proteins when cancer cells are co-treated with MT2+paclitaxel. More importantly, intraperitoneal administration of the combination treatment 5 times of MT2+paclitaxel (30mg/kg, 8mg/kg) has a more significant anti-tumor effect than the paclitaxel-alone (8mg/kg) or MT2-alone (30mg/kg) treatments using the wild-type hepatic HepG2 xenograft model in nude mice. Besides the wild-type HepG2 cancer cells, we have further demonstrated that MT2 is able to resensitize paclitaxel-resistant HepG2 cancer cells by inhibiting the activity of p-glycoprotein (Pgp), a key drug efflux transporter in chemotherapy resistance cancer cells. Also, the combination treatment has shown a significant anti-tumor effect in HepG2/DOX Pgp-overexpressed xenograft in nude mice. Taken together, MT2 is a novel chemosensitiser in combination use with paclitaxel to treat cancer. It enhances cancer apoptosis by suppressing the anti-apoptotic and survival signaling pathways in cancer cells.
Citation Format: Ka Ming Cheng, Gui yun Wu, Kowk Kuen Cheung, Xiao-Ling Shen, Ying-Jie Hu, Ki Lui. 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2) is a novel paclitaxel chemosensitizer to inhibit growth in Taxol non-resistant and Taxol resistant 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 4676.
Abstract 4727: Large scale drug response comparison across different neuroblastoma cell model systems
Authors: Park Se Whee , Liu Ernest , Los Aironas , Seashore-Ludlow Brinton , Östling Päivi , Molenaar Jan , Kallioniemi Olli , Stenman Jakob , Karlsson Kasper 
Published: March 2024

Abstract
Traditionally neuroblastoma research has predominantly used 2D cell lines, which, despite their simplicity, often fall short in mirroring the physiological complexity of actual tumors. Recently, 3D models like patient-derived tumor organoids (PDO) and patient-derived xenografts (PDX) have emerged as superior alternatives, offering more realistic predictions of patient treatment responses. This study aims to discern the differences in drug response between conventional 2D cell lines and the more advanced 3D neuroblastoma models - specifically, patient-derived organoids (nPDO) and patient-derived xenograft organoids (nPDXO). Employing high-throughput drug screening of 528 cancer drugs, we evaluated the drug responses across traditional 2D cell lines, nPDOs, and nPDXOs. Additionally, focused experiments with 29 selected drugs were conducted to determine the influence of culture topology on drug efficacy. The findings were compared to a study by Hansson et al.1 that used nPDXO. Our study discovered a pronounced difference in drug sensitivity between 2D cell lines and 3D models, with 3D models showing heightened sensitivity. Interestingly, 2D cell cultures had a more heterogenous drug response compared to 3D models. The drug response correlation between nPDOs and nPDXOs was relatively high (Spearman ~0.8), indicating consistent responses across these models. Our comparison underscores the impact of model system choice on drug response studies in neuroblastoma. The study highlights important differences in drug response between neuroblastoma 2D and 3D cell culture models. However, only subtle differences were found between PDO and PDX-derived organoid lines, despite differences in treatment centers and media compositions. This suggests that while the choice of cell culture topology greatly impacts drug response, PDO and PDX derived lines can largely be used interchangeably for drug screening experiments.
References: 1. Hansson et al, ﻿Therapeutic targeting of KSP in preclinical models of ﻿high-risk neuroblastoma, Science Translational Medicine(2020)
Citation Format: Se Whee Park, Ernest Liu, Aironas Los, Brinton Seashore-Ludlow, Päivi Östling, Jan Molenaar, Olli Kallioniemi, Jakob Stenman, Kasper Karlsson. Large scale drug response comparison across different neuroblastoma cell model systems [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 4727.
Abstract 4738: Overcoming therapy resistance in rhabdomyosarcoma by targeting the PI3K-MAPK pathway
Authors: Wang Yadong , Chen Eleanor 
Published: March 2024

Abstract
Rhabdomyosarcoma (RMS) is a devastating pediatric cancer. There has not been any significant change in the treatment options for the last 4 decades, especially for relapsed or advanced disease. There is an urgent need to identify alternative treatment options to improve survival outcomes of RMS patients. RMS is comprised of two major subtypes as defined by the presence or absence of PAX3/PAX7-FOXO1 gene fusion. Fusion-negative RMS (FN RMS) is characterized by alterations in the RAS-PI3K-MAPK pathway in &gt;90% of the cases. However, the role of the PI3K-MAPK pathway in therapy resistance and disease relapse remains poorly characterized. We have generated two FN-RMS lines, RD and SMS-CTR, with resistance to the standard-of-care chemotherapeutic agent, vincristine, through long-term culturing in incrementally increased concentrations of the drug. By RNA sequencing, vincristine-resistant RD and SMS-CTR cells demonstrated increased expression of genes in the RAS-PI3K-MAPK pathway compared to the parental lines. We hypothesize that increased activity of the PI3K-MAPK pathway contributes to therapy resistance in FN RMS. To test the hypothesis, we first showed that targeted disruption of PIK3CA by shRNA inhibited the cell growth of vincristine-resistant FN RMS cells. The same cells also showed increased sensitivity to the MEK inhibitor, trametinib, as well as the PIK3Cα inhibitor, alpelisib, compared to the parental cells. We then showed that zebrafish FN-RMS tumors treated with the combination of vincristine and alpelisib significantly inhibited tumor growth compared to the treatment with each agent alone. Through integrative analysis of RNA sequencing and ATAC-seq data, we identified MYOD1 and NFATC2 as among the top candidate upstream regulators. Targeted disruption of either MYOD1 or NFATC2 by CRISPR/Cas9 reduced cell growth of vincristine-resistant FN RMS cells and altered expression of the genes in the PI3K-MAPK pathway, implicating MYOD1 and NFATC2 in driving abnormal activity of this pathway. To assess the relevance of our findings in the clinical settings, we showed that selective components in the PI3K-MAPK pathways are up-regulated in 3 matched primary-recurrence/metastasis paraffinized tissue samples of human FN RMS by the NanoString GeoMx Digital Spatial Profiler (DSP) platform. Our findings indicate that targeting the PI3K-MAPK pathway is a promising targeted therapy option for overcoming therapy resistance in RMS.
Citation Format: Yadong Wang, Eleanor Chen. Overcoming therapy resistance in rhabdomyosarcoma by targeting the PI3K-MAPK pathway [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 4738.
Abstract 4793: Effects of treatment delays on lung cancer survival
Authors: Montero Percy Guzman , Cordero Sharon Segura 
Published: March 2024

Abstract
Background: Previous studies have established a link between treatment initiation delays and reduced overall survival in individuals diagnosed with lung cancer. These delays are often influenced by diagnostic complexities, logistical hurdles, and patient-related factors. However, the association between treatment delays and survival outcomes has yet to be extensively investigated using data from a large national cohort. This study aims to fill this research gap and provide unique insights into the relationship between treatment delays and lung cancer survival by utilizing data from a substantial national cohort.
Methods: The study population consisted of 3,723 lung cancer patients participating in the NCI PLCO Cancer Screening Trial. Cox Proportional Hazards (PH) Regression analyses examined the time between cancer diagnosis and treatment initiation using several measures including intervals from tumor doubling/stage progression time models by Spratt et al. (1964) and Detterbeck et al. (2008). Analyses controlled for patient and clinical characteristics including age, sex, race/ethnicity, smoking status, histopathologic type, cancer stage, and treatment modality. Data analysis was conducted using Microsoft Excel, STATA, and IBM SPSS software.
Results: PH Regression analyses demonstrated a clear association between longer time intervals from diagnosis to treatment initiation and increased risk of mortality. Patients with time intervals exceeding 20 days exhibited a hazard ratio (HR) for mortality of 1.21 (p &lt; 0.001, 95% confidence interval [CI] 1.1158-1.3176). The Spratt tumor progression model, considering intervals exceeding 88 days, revealed a HR of 1.22 (p = 0.03, 95% CI 1.0146-1.4885). On the other hand, the Detterbeck model, which considered intervals exceeding 118 days, did not show a statistically significant association with increased mortality risk. Furthermore, PH analysis identified cigarette smoking status, marital status, and tumor grade as significant predictors of mortality risk.
Conclusions: Data from a large national cohort study indicate that delays in lung cancer treatment initiation have detrimental impacts on survival. Treatment initiation shortly after diagnosis had the most significant differential impact on mortality risk. Timely initiation of treatment is of utmost importance and should be prioritized in lung cancer care. By addressing factors contributing to treatment delays, it is likely possible to improve the survival rates of patients with lung cancer.
Citation Format: Percy Guzman Montero, Sharon Segura Cordero. Effects of treatment delays on lung cancer survival [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 4793.
Abstract 4854: Breast cancer incidence trends in Ukraine 2010-2019: Rising incidence at young ages
Authors: Verovkina Nataliia , Sumkina Olena , Syvak Liubov , El-Diery Wafik 
Published: March 2024

Abstract
Background. BC commonly affects women of older age, however, in developing countries around 20-25% cases of BC presented in young woman. Age-specific clinical characteristics or outcomes data for young women are lacking. Most of the standard treatments used in this subpopulation currently are derived from older patients. Early onset BC is often defined aggressive in nature. Several research have attributed this to a hidden unique biology. However, findings remain controversial.
Purpose: The aim of this study is to describe recent trends for BC incidence in Ukraine since 2010 by age groups and interpret them to seek clue for improvement.
Methods: We analyzed records from the NCR on 143420 BC cases (C50, International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10)) diagnosed in 2010-2019 in female Ukrainian population. The data were submitted on the beginning of 2022. We calculated annual age-standardized incidence rates (ASRWs) for three age groups. The estimated annual percent change (EAPC) of the rates was calculated using the generalized linear regression. The difference of the rates with its statistical significance was determined with the standardized rate ratio.
Results: During 2010-2019, the proportion of BC in all cancers detected at the age of 20-44 increased from 21.7% to 25.9%, while the frequency of BC detection at the age of 45+ did not change and ranged 19.3-20.2%. During the study period, the BC incidence rate has increased significantly (≤0.01): the ASRW of females aged 0-85+ grew with EAPC=0.6% amounting to 42.4-45.7 per 100,000 population, the incidence rate of women aged 45+ grew with EAPC=0.3% ranging from 130.0 to 139.6 per 100,000 population, while the incidence rate of women aged 20-44 grew with EAPC=1.8% amounting to 22.8-27.8 per 100,000 population. In age group 20-44 years, EAPC of BC incidence (1.8%) significantly exceeds the EAPC of the incidence for all cancers combined (0.2%). The dynamics of stage distribution showed increasing proportion of BC cases detected in women aged 20-44 in stage 1 (by 4.1% from 2010 to 2019) and its decreasing for BC cases detected in stage 2 by 4.5%; the proportion of cases diagnosed in stage 4 decreased by 0.5% along with increase in number of cases with undefined stage by 0.6%.
Conclusions: The obtained results indicate trends for increasing the incidence of Early Onset BC in Ukraine and justify need for the further research elucidating prognosis and validating novel biomarkers for customizing therapy for this patient group .
Citation Format: Nataliia Verovkina, Olena Sumkina, Liubov Syvak, Wafik El-Diery. Breast cancer incidence trends in Ukraine 2010-2019: Rising incidence at young ages [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 4854.
Abstract 4859: Mental health of early-onset and late-onset cancer survivors
Authors: Lee Jayden H. , An Jaejin 
Published: March 2024

Abstract
Background: Psychiatric disorders such as anxiety and depression are shown to be common when diagnosed with early-onset cancer, often defined as cancers diagnosed in adults &lt;50 years of age. We hypothesize that the mental health of early-onset cancer survivors is negatively affected compared to late-onset cancer survivors.
Methods: We identified cancer survivors in the Medical Expenditure Panel Survey 2021 Full Year Consolidated Data File. We categorized cancer survivors as early-onset (≤ 50 years of age) and late-onset (&gt; 50 years of age). We examined the proportion of mood and anxiety disorders, and the proportion of antidepressant and antianxiety medication use among the early and late-onset cancer survivors. We conducted chi-square tests and multivariable logistic regression models by adjusting for sex and race.
Results: We identified 291 early-onset cancer survivors (mean age 41 years, 71% female) and 2556 late-onset cancer survivors (mean age 71 years, 56% female). Among the early-onset cancer survivors, 18% had mood disorders (17% took antidepressants) and 20% had anxiety disorders (6% took antianxiety medication). In comparison, 12% late-onset cancer survivors had mood disorders (21% took antidepressants) and 13% had anxiety disorders (8% took antianxiety medication). Early-onset cancer survivors were more likely to develop mood (Adjusted Odds Ratio (aOR)=1.45; 95% CI=1.06 - 1.99) and anxiety (aOR=1.42; 95% CI=1.05 - 1.92) disorders compared to late-onset cancer survivors. However, there were no differences in receiving antidepressants (aOR=0.79; 95% CI=0.57 - 1.09) or antianxiety (aOR=0.69; 95% CI=0.41 - 1.16) medication between early and late-onset cancer survivors when adjusting for sex and race.
Conclusion: Early-onset cancer survivors had an elevated risk of acquiring psychiatric disorders such as mood and anxiety disorders than late-onset cancer survivors, but treatment was suboptimal. Clinician and patient awareness can help narrow the gaps of treatment for early-onset cancer survivors.
Table 3. Odds Ratio for early-onset vs. late-onset cancer survivors (*Sex and Race adjusted) Variables Crude Odds Ratio Adjusted Odds Ratio * Mood Disorders 1.48 (1.09 - 2.00) 1.45 (1.06 - 1.99) Anxiety Disorder 1.52 (1.13 - 2.03) 1.42 (1.05 - 1.92) Antidepressants 0.80 (0.59 - 1.10) 0.79 (0.57 - 1.09) Antianxiety 0.70 (0.42 - 1.17) 0.69 (0.41 - 1.16)
Citation Format: Jayden H. Lee, Jaejin An. Mental health of early-onset and late-onset cancer survivors [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 4859.
Abstract 4860: Recommendations for enhancing inclusion and management of esophagus cancer clinical trials: Insights on mortality of esophagus cancer as a second primary malignancy
Authors: Zhou Haiyu , Leng Jinhang , Qiu Hongrui , Huang Qizhi , Zhang Jinqiang 
Published: March 2024

Abstract
Background: Esophagus cancer as a second primary malignancy (esophagus-2) is increasingly common, but its prognosis is poorly understood. This study aims to examine the overall, non-cancer related and cancer-specific survival of patients diagnosed with esophagus-2 compared to the first primary esophagus cancer (esophagus-1).
Methods: We included primary esophagus cancer patients diagnosed from 1975 to 2020 in the Surveillance, Epidemiology, and End Results program. Esophagus-2 was identified in patients with a previous diagnosis of non-esophageal primary malignancy. Hazard ratios of overall, esophagus cancer-specific and non-cancer related mortality were estimated among patients with esophagus-2 compared to esophagus-1, adjusting for age, sex, tumor stage and other demographic and clinical characteristics.
Results: A total of 74521 and 14820 patients were identified as esophagus-1 and esophagus-2. Esophagus-2 patients suffered lower risk of esophagus cancer-specific mortality in initial 5 years but similar risk thereafter, independent of tumor characteristics and treatment. In the first 5 years after diagnosis, patients with esophagus-2 had similar risk of overall mortality with those with esophagus-1 but increased risk thereafter. As for non-cancer related mortality, esophagus-2 patients had higher risk all along.
Conclusion: Patients diagnosed with esophagus-2 face a favorable esophagus cancer-specific survival within the early period after diagnosis. However, patients with esophagus-2 are more liable to die of non-cancer cause. A conservative approach to manage esophagus-2 solely based on malignancy history is not supported but effort should be put into surveillance, prevention and management of the comorbidities and complications for the first malignancy.
Citation Format: Haiyu Zhou, Jinhang Leng, Hongrui Qiu, Qizhi Huang, Jinqiang Zhang. Recommendations for enhancing inclusion and management of esophagus cancer clinical trials: Insights on mortality of esophagus cancer as a second primary malignancy [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 4860.