bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7603: Targeting MTAP-deleted tumor via synthetic lethality with a combination of a PRMT5i and an MAT2Ai
Authors: Zhang Guiping , Li Jiapeng , Li Jie Jack 
Published: March 2024

Abstract
MTAP (methylthioadenosine phosphorylase) is located adjacent to the tumor-suppressor gene CDKN2A (cyclin-dependent kinase inhibitor 2A) and sometimes co-deleted in 10-15% of all cancers, especially in glioblastoma, mesothelioma, and pancreatic cancers. Recent studies shown that MTAP deletions in cancer create vulnerability to synthetic lethal with the MAT2A/PRMT5/RIOK1 axis. Herein, we report the discovery of a PRMT5 inhibitor GH56, and an MAT2A inhibitor GH31, both showed promising single agent efficacy and synergy in MTAP loss tumor models. GH56 is an MTA-Cooperative PRMT5 inhibitor. In vitro, GH56 showed potent SDMA inhibition in MTAP-deleted cancer cells with an IC50 from 0.8‒3 nM. It also showed excellent selectivity with more than 100-folds in MTAP-WT cells. In a cell panel with more than 100 cell-lines, GH56 selectively inhibited the growth of cells with MTAP-deletion while separated the cells with MTAP-WT. In the safety panel and kinase panel, GH56 all showed good selectivity. In addition, GH56 had an IC50 &gt; 10 μM for hERG. In vivo, GH56 showed dose-dependent efficacy in a series MTAP-deleted models and were well tolerated. In U87MG glioblastoma CDX model, NCI-H838 NSCLC CDX model, BXPC-3/HupT4 PDAC CDX models and RT112-84 BLCA model, TGI for GH56 at high dose were all &gt;100%. On the other hand, GH31 is a potent and selective MAT2A inhibitor. GH31 also showed excellent selectivity with MTAP-deleted and MTAP-WT cell lines. The combination of GH56 and GH31 showed synergy both in vitro and in vivo. The low dose GH31 combination with low-dose GH56 achieved the similar efficacy as high dose GH56 and a more rapid tumor regression. In view of the delayed onset of the tumor response and high dose needed by PRMT5 inhibitor (reported by clinic stage compounds), the combination of PRMT5i and MAT2Ai will be advantageous. Furthermore, both GH56 and GH31 are brain penetrant, especially for GH31, with a Kpuu &gt; 0.6 and B/P &gt; 2. The combination of GH56 and GH31 in a brain metastasis model and a glioblastoma in situ model all showed strong synergy, demonstrated the potential for the treatment of glioblastoma and other cancer with brain metastasis. In summary, we discovered potent, selective and brain penetrant PRMT5 inhibitor GH56 and MAT2A inhibitor GH31. Both compounds are currently under evaluation in IND-enabling studies and will provide more options for MTAP-deleted cancers.
Citation Format: Guiping Zhang, Jiapeng Li, Jie Jack Li. Targeting MTAP-deleted tumor via synthetic lethality with a combination of a PRMT5i and an MAT2Ai [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 7603.
Abstract 7607: Single-cell genomics study before and after neoadjuvant therapy for triple-negative breast cancer
Authors: Shao Yingkuan , Xu Kailun 
Published: March 2024

Abstract
Breast cancer has become the most common malignant tumor globally. Neoadjuvant chemotherapy (NAC) has become an important treatment option for locally advanced breast cancer, capable of eliminating circulating tumor cells (micrometastases) and achieving downstaging objectives. However, even after completing neoadjuvant chemotherapy or receiving local treatment, some patients may still have residual lesions, which are a key factor in distant recurrence and metastasis. The existing clinical biomarker tests such as CEA, CA-153, and imaging methods are unable to accurately assess the condition early on. Although tissue pathology biopsy of tumor specimens is the gold standard for clinical pathological diagnosis, it also has certain limitations. Traditional high-throughput sequencing technology for breast cancer primarily identifies "driver genes" associated with the occurrence and development of breast cancer. However, it has limitations in identifying genomic structural changes and subclones of breast cancer, and it overlooks the heterogeneity among tumor cells. The emergence of single-cell RNA sequencing (scRNA-seq) technology can detect these heterogeneous individuals, decode the heterogeneity of breast cancer cells, refine molecular subtypes, and open up new pathways to overcome drug resistance. We collected samples from 6 patients with locally advanced triple-negative breast cancer (ER-, PR-, HER2-negative, defined as HER2 immunohistochemistry 0, 1+ or 2+ but FISH-negative). We compared the cell subgroups and their gene expression in biopsy specimens before neoadjuvant chemotherapy with those in post-treatment specimens obtained during surgery, analyzing changes in cell composition in the tumor microenvironment before and after immunotherapy to identify specific cell types potentially contributing to the outcome of immunotherapy, particularly cell subtypes associated with T-cell clonal proliferation. We found that in the group with good neoadjuvant treatment response (Miller-Payne grade 4-5), B cells, CD4+ T cells, CD8+ T cells, and Tregs cells were all significantly downregulated, while endothelial cells and aSMA-positive fibroblast cells were significantly upregulated. By comparing changes in the immune microenvironment between patients with and without T-cell clonal proliferation before and after treatment, we revealed the differentiation patterns of various immune cells in immunotherapy and potential mechanisms of action.
Citation Format: Yingkuan Shao, Kailun Xu. Single-cell genomics study before and after neoadjuvant therapy for triple-negative breast 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 7607.
Abstract 7650: An analysis of the prognostic role of sarcopenia derived with fully automated deep learning slice-based muscle estimation in patients with metastatic non-small cell lung cancer (NSCLC)
Authors: Safta Wiem , Santana-Davila Rafael , Paulucci David , Geese William J. , Grootendorst Diederik J. 
Published: March 2024

Abstract
Introduction: Sarcopenia, progressive and generalized loss of skeletal muscle mass, is difficult and labor intensive to directly measure as it requires manual segmentations by radiologists from computed tomography (CT) scans. Sarcopenia has been shown to be a prognostic factor in some metastatic cancers. We evaluated the impact of sarcopenia derived via an automated segmentation algorithm on outcomes in the Phase 3 NSCLC clinical trial, CheckMate 227 (NCT02477826)
Methods: The sarcopenia score assessment involves automated selection of the L3 vertebra level slice from abdominal or chest, abdomen, and pelvis (CAP) CT scans, followed by automated segmentation of the muscle area from that slice. Sarcopenia scores were derived from previously established definitions of sarcopenia, with values below 41 cm2/m2 for female patients (regardless of BMI) and below 43 cm2/m2 or 53 cm2/m2 for male (based on BMI &lt; 25 kg/m2 or ≥ 25 kg/m2). Among the 967 patients with evaluable scans, sarcopenia at baseline was identified in 68.39% (n=329/481) patients receiving nivolumab (NIVO) with ipilimumab (IPI) and 70.2% (n=341/486) receiving chemotherapy (Chemo).
Results: There was a trend of worse overall survival (OS) in patients with baseline sarcopenia across both treatment arms (minimum follow up 49.4 months). In patients with baseline sarcopenia vs ITT, median OS was 16.5 mo vs. 21.8 mo (p= 0.219) within the NIVO + IPI arm and 12.9 mo vs.15.0 mo (p= 0.273) within the Chemo arm respectively. Any increase in muscle mass from baseline to week 12 was associated with better OS for patients treated with NIVO+IPI (n=98) with sarcopenia at baseline compared to those without an increase in muscle mass (median OS 45.3 mo vs.19.5 mo, p= 0.012). This was not seen in those who received Chemo (n=87). Weight and muscle mass were moderately correlated at baseline (r=0.60).
Conclusions: We found that in CheckMate 227, baseline sarcopenia is associated with numerically worse OS, regardless of treatment, leading to potential use as a negative prognostic biomarker. Patients with NSCLC receiving immunotherapy might benefit from changes in muscle mass being monitored during treatment. Validation of these findings in other studies and other tumor types is warranted.
Citation Format: Wiem Safta, Rafael Santana-Davila, David Paulucci, William J. Geese, Diederik J. Grootendorst. An analysis of the prognostic role of sarcopenia derived with fully automated deep learning slice-based muscle estimation in patients with metastatic non-small cell lung cancer (NSCLC) [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 7650.
Abstract 783: Early impact assessment of in-house EGFR testing for NSCLC in Kenya
Authors: Njau Allan , Nguku Samuel , Abuodha Joseph 
Published: March 2024

Abstract
Introduction: Quality of life and survival among non-small cell lung cancer (NSCLC) patients have improved in the last two decades owing mainly to use of tyrosine kinase inhibitors (TKIs) and other targeted therapies. Low and middle-income countries (LMICs) especially in Africa, are lagging in realizing these benefits largely due to hurdles in molecular testing. In addition, quality histology and molecular data from LMICs is deficient. The aim of this study is to assess the immediate impact of improved access to epidermal growth factor receptor (EGFR) testing in Kenya, and to establish a long term-lung cancer data base.
Methods: Staring mid-June 2023, an in-house PCR-based method was adopted for EGFR testing of NSCLC in order to side step the challenges of out-of-country send outs which was until then, the only option for EGFR testing. Further, a sponsored access program was created. From prospectively accrued samples, we performed a before-and-after assessment of the number of NSCLC cases intercepted, cost and turnaround times (TAT) as measures of impact. Demographic, histopathology, and EGFR mutation profiles were analyzed in comparison to Asia, USA and European data. Whole slide histology scanned images are made to compliment the database.
Results: Over the four-month period, 62 NSCLC cases were accrued, median age at diagnosis was 63 with a range of 24 - 93. The male to female ratio was 1: 1.5. Adenocarcinomas comprised 89%, squamous cell carcinoma 5% and 3% were not classifiable. Metastatic disease was reported in 14 (22%) with the brain being the commonest site. EGFR mutations were identified in 16 (25%) with exon 19 deletions and L858R mutations constituting 94% of them. Monthly requisitions for EGFR have increased 3-fold, and the average TAT has been halved to 7 days.
Conclusion: Similarities between our data and global patterns are noted; median age is in the seventh decade, NSCLC is more common in women, and so are the rates of EGFR mutations, adenocarcinomas are the predominant type, and there are high rates of brain metastasis at diagnosis. EGFR mutation rates appear to be higher than USA and European data but lower than Asian data. In-house and sponsored testing has had an immediate impact in reduction of costs and TAT and increased requisitions. Assessment of access to targeted therapy, clinical outcome, survival, expansion of molecular profiling beyond EGFR, and build-up of the database including virtual histology images for exploring artificial intelligence algorithms are our next steps.
Citation Format: Allan Njau, Samuel Nguku, Joseph Abuodha. Early impact assessment of in-house EGFR testing for NSCLC in Kenya [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 783.
Abstract 788: Leveraging multi omics approach to examine the potential role of causative viruses in glioblastoma
Authors: Gunasegaran Bavani , Alnakli Aziz Abdullah A , Guillemin4 Gilles J. , Ahn Seong Beom , Heng Benjamin 
Published: March 2024

Abstract
Glioblastoma (GB), a grade IV brain cancer, has the lowest survival rate. Despite aggressive and targeted therapies, patients remain to have the worst prognosis. More than 16% of cancer incidence worldwide has been attributed to infectious agents, raising uncertainties about the role of infections in the development of brain cancer. While numerous studies have suggested potential viral involvement in GB pathogenesis, a common limitation is the reliance on a singular technology, such as DNA/RNA sequencing or immunohistochemistry, within each study. This approach may restrict the comprehensive exploration of viral contributions, as different technologies offer distinct insights into the complex mechanisms underlying GB development. Utilizing a combination of techniques could provide a more holistic understanding, enhancing the robustness of findings and potentially uncovering nuanced aspects of viral influence that a single technology might overlook. To clarify the role of viruses in GB pathology, our study employs a comprehensive approach integrating three distinct research methods. We screened 178 publicly accessible raw mass spectrometry (MS) data of GB tumors from three independent publications (PMID: 31331834, 31154438, 36720864) by employing our internally developed data identification pipeline. The pipeline transforms raw MS data for downstream analysis, conducts database searches against the latest viral protein databases and undergoes peptide validation for enhanced robustness. Subsequent analysis filters duplicate hits and consolidates nested peptides. The final protein list includes only those identified with two or more peptides of over eight amino acids. The pipeline concludes by inferring and listing the corresponding viruses, ensuring a comprehensive and refined approach to the identification and analysis of viral proteins in the context of MS data. To enhance this dataset, we incorporated whole-genome metagenomics and MS-based proteomics, examining a preliminary cohort of15 GB tumor tissues. This approach explored a wide range of viral encoded proteins. Our comprehensive analysis, integrating bioinformatics, genomics, and proteomics, identified multiple herpesvirus species across our cohorts. This potential identification of viruses within GB has the capacity to redefine the stratification of tumor types in GB patients, signaling a significant development in our understanding of the disease.
Citation Format: Bavani Gunasegaran, Aziz Abdullah A Alnakli, Gilles J. Guillemin4, Seong Beom Ahn, Benjamin Heng. Leveraging multi omics approach to examine the potential role of causative viruses in glioblastoma [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 788.
Abstract 798: Increasing breast cancer incidence across generation status in Mexican American women: The Multiethnic Cohort
Authors: Zhang Xinman , Cheng Iona , Paik Adelynn , Huang Brian , Setiawan Veronica Wendy 
Published: March 2024

Abstract
Background: Breast cancer (BC) is the most commonly diagnosed cancer among Latino women in the US. Compared to foreign-born Latino women, US-born Latino women have a higher incidence of BC. While prior studies have suggested this difference in incidence may be explained by risk factors such as unhealthy lifestyle behaviors, reproductive history, and neighborhood socioeconomic status, it is unclear how the risk of BC has changed over generations among Latinos women. In this study, we investigated the association between generational status and BC incidence among Mexican American women within the Multiethnic Cohort (MEC).
Methods: The study population included 15,303 self-reported Mexican Americans from the MEC. Generational status was categorized as: 1st generation (Mexico-born, n = 6,347), 2nd generation (US-born with one or two parents born in Mexico, n = 6,390), or 3rd generation (US-born with both parents born in the US, n = 2,566). Multivariable Cox models were used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of BC incidence by generational status. All models were adjusted for relevant risk factors including age, physical activity, smoking, alcohol intake, education, body mass index, diet, family history of BC, menopausal status, age at menarche, parity, mammography history, hormone use, neighborhood socioeconomic status, and Hispanic ethnic enclave.
Results: During an average 21.5-year follow-up, 815 incident BC cases were identified. The age-adjusted incidence rate (per 100,000) of BC increased by generation (1st: 191.9; 2nd: 265.3; 3rd: 284.0). Third (70.4%) and 2nd (66.5%) generations had a larger proportion of localized disease at diagnosis compared to 1st generation women (59.7%). Compared to 1st generation Mexican Americans, 2nd (HR = 1.24; 95% CI: 1.03-1.49) and 3rd generation (HR = 1.28; 95% CI: 1.02-1.60) had elevated risks of BC (p-trend: 0.02) The positive association with generational status remained significant when restricting to women who reported mammogram use (HR 2nd vs. 1st = 1.27, 95% CI: 1.04-1.55; HR 3rd vs. 1st = 1.34, 95% CI: 1.06-1.70) (p-trend: 0.01).
Conclusions: Our findings suggest that generational status among Mexican American women is associated with risk of BC, after adjusting for sociodemographic, lifestyle, neighborhood, and reproductive risk factors. Further studies are warranted to discover the potential factors that contribute to this increased risk and elucidate the underlying etiology.
Citation Format: Xinman Zhang, Iona Cheng, Adelynn Paik, Brian Huang, Veronica Wendy Setiawan. Increasing breast cancer incidence across generation status in Mexican American women: The Multiethnic Cohort [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 798.
Abstract 815: Leveraging clinical workflow for rapid integration of social needs assessment in a urologic oncology clinical practice
Authors: Washington Samuel L. , Rhoads Kim F. , Carroll Peter R. , Shariff-Marco Salma , Chan June M. 
Published: March 2024

Abstract
Introduction: Social determinants of health and resulting social needs are known to impact cancer care, yet characterization of social needs within a specific clinic’s population remains in its infancy. We aim to characterize early findings from social needs screening in patients seen in a tertiary urologic oncology clinic.
Methods: Screening was conducted using survey questions about specific domains of social needs (e.g., financial strain, unmet transportation needs, and food insecurity) that were integrated into new patient and annual follow-up questionnaires for all patients seen within a urologic oncology faculty clinic, starting in January 2023. Screening items were rapidly implemented into workflow by taking advantage of existing processes. Clinical and demographic data and screening responses were abstracted from the electronic medical record. Summary statistics were calculated. P value&lt;0.05 was deemed statistically significant.
Results: A total of 2305 patients were included (4% Non-Hispanic Black, 11% Asian American, 8% Latinx, and 63% Non-Hispanic White). Responses increased from 30 in January to 399 in October. Respondent mean age was 67 years [standard deviation (SD) 12.3] with 87.8% identifying as male. Roughly 13% screened positive for at least one social need (one positive 8.1%, two positive 3.4%, three positive 1.2%) with variations by domain [transportation 3.6%, food insecurity 5.4%, 10.2%] and race and ethnicity (Figure 1, p&lt;0.001 for all).
Conclusions: By leveraging the existing clinical workflow, rapid uptake of social needs screening demonstrates variations by social needs domains and race and ethnicity within a urologic oncology patient population. These efforts represent institutional action towards characterizing the burdens faced by our patient population and inform the design of interventions to address social needs within the catchment area, to improve clinical care and clinical trial participation.
Citation Format: Samuel L. Washington, Kim F. Rhoads, Peter R. Carroll, Salma Shariff-Marco, June M. Chan. Leveraging clinical workflow for rapid integration of social needs assessment in a urologic oncology clinical practice [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 815.
Abstract 829: Phthalate exposure results in circadian rhythm-induced BBB dysfunction increasing the risk for breast cancer brain metastasis
Authors: Tiburcio Destiny , Adolphe Sarah , Akpu Ijeoma B. , Teglas Timea , Naranjo Oandy , George Sophia H. , Toborek Michal J. 
Published: March 2024

Abstract
Phthalates, classified as plasticizers, represent a group of chemicals pervasive in the general U.S. population, with notably higher levels in non-Hispanic Blacks compared to non-Hispanic Whites. These persistent organic pollutants (POPs) have been identified for their impact on the circadian rhythms of the brain and vascular system. Several studies indicate that phthalates can elevate neuroinflammation and reduce levels of the junctional protein ZO-1 in the hypothalamus, home to the master circadian clock known as the suprachiasmatic nucleus (SCN). The SCN regulates cellular and tissue circadian rhythms, including tight junction proteins essential for the blood-brain barrier's (BBB) main barrier function. Interestingly, experimental studies reveal that prolonged chronic circadian rhythm disruption (CRD) in mice leads to increased breast cancer metastasis. However, the effects of phthalates on CRD concerning brain cancer and metastasis remain poorly understood. Given their significant prevalence and biological impact, we hypothesize that phthalate exposure induces CRD through hypothalamic dysregulation, resulting in BBB dysfunction and an elevated risk of brain metastasis.
Results. We developed an in vitro BBB model using endothelial cells and exposed them to an environmentally relevant mixture of five phthalates simulating chronic low-grade exposure. Analysis showed dysregulation of critical clock genes (Bmal1 and Clock), along with a substantial decrease in BBB tight junction proteins (claudin-5 and occludin) at the protein and mRNA levels. The tumor trans-endothelial migration assay using breast adenocarcinoma cells along with endothelial cells demonstrated an increased metastatic potential following phthalate exposure.
Conclusion. These findings offer crucial insights into the molecular mechanisms underlying phthalate exposure, suggesting potential targets for future brain metastasis treatments. Additionally, they hold implications for the future regulation and management of phthalate usage and policy. This work was supported by the University of Miami U-LINK Resilience Challenge grant.
Citation Format: Destiny Tiburcio, Sarah Adolphe, Ijeoma B. Akpu, Timea Teglas, Oandy Naranjo, Sophia H. George, Michal J. Toborek. Phthalate exposure results in circadian rhythm-induced BBB dysfunction increasing the risk for breast cancer brain metastasis [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 829.