bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2073: Childhood vaccine-specific CD4+T cell recall coordinates antitumor type I and II immunity
Authors: Brown Michael Clavon , Mckay Zachary P. , Yang Yuanfan , Bigner Darell D. , Nair Smita K. , Gromeier Matthias 
Published: June 2022

Abstract
A recombinant poliovirus (rPV) derived from the live-attenuated Sabin oral polio vaccine strain, is being tested in multi-institutional phase II clinical trials for recurrent glioblastoma (NCT04479241); unresectable, anti-PD-1 refractory melanoma (NCT04577807); and bladder cancer and head and neck squamous cell carcinomas (NCT04690699) in combination with PD-1/PD-L1 blockade. rPV capsid is identical to that of childhood polio vaccines, against which public health mandated vaccination is near universal. In non-vaccinated mice, rPV mediates antitumor efficacy in a replication-dependent manner via engaging innate inflammation and antitumor T cells. Accordingly, it was anticipated that pre-existing immunity to rPV impedes antitumor therapy.
Strikingly, despite curtailing intratumor viral replication, prior polio vaccination in mice substantially bolstered the antitumor efficacy of rPV relative to mice vaccinated with a control antigen (KLH). Intratumor recall responses induced by polio and tetanus antigens also delayed tumor growth. Recall antigen therapy was associated with marked intratumor influx of eosinophils, PD1 and Granzyme B expressing type 2 innate lymphoid cells (ILC2s), conventional CD4+ T cells, and increased expression of IFN-γ, TNF, and Granzyme B in tumor infiltrating T cells. The antitumor efficacy of polio recall antigen was mediated by CD4+ T cells, partially depended upon both CD8+ T cells and eosinophils, and was independent of B cells. Intratumor polio and tetanus recall antigen therapy bolstered the antitumor function of tumor-specific OT-I CD8+ T cells, indicating that intratumor CD4+ T cell recall provides help to antitumor CD8+ T cells. Recall antigen therapy complemented antitumor effects of immune checkpoint blockade and innate stimulating immunotherapy.
This work reveals that childhood vaccine-specific CD4+ T cells hold cancer immunotherapy potential and represent a novel mechanism to simultaneously engage both type I and II antitumor immunity.
Citation Format: Michael Clavon Brown, Zachary P. Mckay, Yuanfan Yang, Darell D. Bigner, Smita K. Nair, Matthias Gromeier. Childhood vaccine-specific CD4+T cell recall coordinates antitumor type I and II immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2073.
Abstract 2134: Discovery and structure activity relationships of BAY 2666605: PDE3A-SLFN12 complex inducer for cancer therapy
Authors: Gradl Stefan 
Published: June 2022

Abstract
Velcrin compounds are small molecules which act as molecular glues to form a PDE3A-SLFN12 complex. This complex formation induces apoptosis in cancer cells expressing elevated levels of PDE3A and SLFN12 (de Waal et al., Nat Chem Biol 2016; Wu et al., J Bio Chem 2020). Unlike traditional targeted therapies that leverage dependencies created by genomic alterations in cancer cells, velcrins instead kill cancer cells by a gain-of-function mechanism dependent on stimulation of SLFN12 RNase activity by complex formation with PDE3A (Garvie et al., Nat Commun 2021).
Based on in-vivo tool compounds which were discovered by hit-to-lead optimization from a phenotypic screen (Lewis et al., ACS Med Chem Lett 2019), the team set out to optimize the properties of the tool compounds. While already showing excellent potency and in-vivo efficacy in various tumor models, the compounds were only approximately tenfold selective against PDE3A when compared to their cell killing activity. PDE3A/B activity most notably influences cardiohemodynamics and inhibition of PDE3A/B was to be reduced to generate a larger safety window. Co-crystallization of analogs with PDE3A showed the binding mode of the velcrin class and changes in the solvent exposed region of the PDE3A binders led to steep activity changes in complex formation and cell killing. Careful optimization of the ratio of cell killing to PDE3A activity while optimizing DMPK and safety pharmacology led to the discovery of BAY 2666605.
BAY 2666605 has recently entered a First-in-Human study (NCT04809805) in patients with advanced solid tumors that co-express PDE3A and SLFN12, including melanoma, ovarian cancer, and sarcoma. We will discuss the discovery and structure activity relationships of BAY 2666605.
Citation Format: Stefan Gradl. Discovery and structure activity relationships of BAY 2666605: PDE3A-SLFN12 complex inducer for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2134.
Abstract 2153: ATR inhibition augments the efficacy of the lurbinectedin in small cell lung cancer
Authors: Schultz Christopher William , Zhang Yang , Fu Haiqing , Murai Yasuhisa , Wangsa Darawalee , Atkinson Devon , Saha Liton , Elenbaas Brian , Lee Chien-Fei , Zimmerman Astrid , Ried Thomas , Zenke Frank , Weaver Zoe , Elmeskini Rajaa , Pommier Yves , Thomas Anish 
Published: June 2022

Abstract
Small cell lung cancer (SCLC) is a recalcitrant disease with only a 9% five-year survival rate. SCLCs display intertumoral heterogeneity; high neuroendocrine (NE) tumors evolve with treatment and time in a largely MYC driven manner to a chemotherapy resistant non-NE state. Lurbinectedin, an RNA Pol-II inhibitor which causes DNA damage through binding ERCC5 was approved as second line therapy in 2020, with an overall response rate of 35% in patients with relapsed SCLC. However, these responses are short-lived and the majority of patient still succumb to their disease. A trial testing the combination of lurbinectedin and doxorubicin failed to improve survival compared with standard-of-care. We assessed lurbinectedin in combination with 43 other agents in SCLC cells. The top synergistic hit was the clinically relevant ATR inhibitor berzosertib which was 4-fold more synergistic than doxorubicin. Compared with lurbinectedin alone, the combination with berzosertib caused a 3.5-fold increase in DNA damage while significantly reducing the ability of cells to sense this damage by inhibiting γH2AX induction. This led to continued DNA replication even in the presence of lurbinectedin induced DNA damage, causing mitotic catastrophe and cell death. The combination was highly synergistic in 6 of 9 SCLC cell lines tested. Synergy was inversely correlated with p21 RNA and protein expression. The canonical role of p21 is to inhibit G1/S transition, and we found that thymidine induced G1 arrest inhibited synergy, while p21 knock-down increased the synergy. Interestingly, we observed synergy was inversely correlated with NE differentiation. In a high NE high p21 mouse model of SCLC, lurbinectedin alone was highly effective, with the combination showing little improvement. Conversely in a non-NE low p21 mouse model, lurbinectedin treatment alone was less effective, however the addition of berzosertib was synergistic and significantly improved efficacy. Overall, this work demonstrated berzosertib augments lurbinectedin efficacy in the recalcitrant non-NE SCLC subsets, and supported the development of a clinical trial testing lurbinectedin and berzosertib in SCLC patients NCT04802174.
Citation Format: Christopher William Schultz, Yang Zhang, Haiqing Fu, Yasuhisa Murai, Darawalee Wangsa, Devon Atkinson, Liton Saha, Brian Elenbaas, Chien-Fei Lee, Astrid Zimmerman, Thomas Ried, Frank Zenke, Zoe Weaver, Rajaa Elmeskini, Yves Pommier, Anish Thomas. ATR inhibition augments the efficacy of the lurbinectedin in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2153.
Abstract 2174: Sirpiglenastat (DRP-104), a novel broad acting glutamine antagonist, has therapeutic potential in targeting KEAP1-mutant lung cancer
Authors: LeBoeuf Sarah , Pillai Ray , Huang Shih Ming , Karakousi Triantafyllia , Wu Warren , Sayin Volkan , Wild Robert , Papagiannakopoulos Thales 
Published: June 2022

Abstract
Treating KRAS mutant lung adenocarcinoma (LUAD) remains a major challenge for clinical oncology. Approximately 20% of KRASmutant LUAD tumors carry loss-of-function mutations in KEAP1, a negative regulator of NRF2, which is the master transcriptional regulator of the endogenous antioxidant response. Emerging clinical studies demonstrate that KEAP1-mutant tumors are refractory to standard-of-care chemotherapy, immunotherapy, radiation and more recently KRASG12C inhibitors. Using a genetically engineered mouse model of KRAS-driven LUAD we demonstrated that loss of Keap1 hyper-activates Nrf2 and accelerates KRAS-driven LUAD. We observe that the ability of KEAP1 mutant tumors to divert their metabolism towards antioxidant production comes with a cost, generating multiple metabolic vulnerabilities, including a dependency on glutamine metabolism that can be therapeutically exploited through the pharmacological inhibition of glutaminase and other glutamine metabolizing enzymes. Using sirpiglenastat (DRP-104), a novel broad acting glutamine antagonist which inhibits all glutamine-consuming reactions, we demonstrate robust anti-tumor efficacy in multiple mouse and human pre-clinical KEAP1-mutant NSCLC models. Furthermore, we have characterized the metabolic mechanisms underlying DRP-104 sensitivity. Our studies demonstrate that DRP-104 has a distinct and broader mechanism of action compared to glutaminase selective inhibition, suggesting broader inhibition of glutamine metabolism may be a more effective therapeutic approach against KEAP1-mutant tumors. We have recently demonstrated that KEAP1-mutant tumors evade anti-tumor immune responses and do not respond to immune checkpoint blockade, which is also supported by clinical observations. We are currently assessing whether DRP-104 is able to promote anti-tumor immune responses as a single agent or in combination with immune checkpoint blockade in KEAP1-mutant tumors. Our studies will provide a rationale for sub-stratification of KEAP1-mutant patients with hyperactivation of the NRF2 pathway, which is a genetic subset of NSCLC with great clinical need, as treatment candidates for sirpiglenastat. A first-in-human clinical trial of sirpiglenastat (DRP-104) is currently ongoing and will further explore this hypothesis in a LUAD cohort (NCT04471415).
Citation Format: Sarah LeBoeuf, Ray Pillai, Shih Ming Huang, Triantafyllia Karakousi, Warren Wu, Volkan Sayin, Robert Wild, Thales Papagiannakopoulos. Sirpiglenastat (DRP-104), a novel broad acting glutamine antagonist, has therapeutic potential in targeting KEAP1-mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2174.
Abstract 2226: Using functional biomarkers to accurately predict advanced neoplasia in pancreatic cystic lesions
Authors: Caiazza Francesco , Lourenco Andre , Conroy Patricia , Hoffmann Thomas , Ivry Sam L. , York Tyler , Zhu Gina , Mustoe Audrey , O'Donoghue Anthony J. , Craik Charles S. , Kirkwood Kimberly 
Published: June 2022

Abstract
Background: The accurate identification of high-grade dysplasia (HGD) or invasive cancer (advanced neoplasia, AN) in pancreatic cystic lesions (PCLs) is needed to identify PCLs that warrant surgical intervention. Cytologic evaluation of cyst fluid is widely-used but has poor sensitivity. We previously found that activity of the lysosomal serine protease tripeptidyl peptidase 1 (TPP1) is associated with mucinous PCLs that harbor AN (AUC 0.72). We aimed to identify additional functional biomarkers that would improve performance of our classifier for dysplastic grade in mucinous PCLs.
Methods: We used a combination of global protease activity profiling and shotgun proteomics to identify differentiating markers between PCLs with low-grade dysplasia (LGD, n=3) and HGD (n=3). Candidate biomarkers were validated in an independent cohort of 28 clinically-annotated mucinous PCLs (HGD n=12, LGD n=16), by measuring both protein concentration (using ELISA) and enzymatic activity (using internally-quenched fluorescent substrates). We used a nested cross-validation approach to iteratively split our cohort into training and validation sets to predict HGD. Model accuracy was evaluated using area under the curve (AUC), sensitivity, specificity, and accuracy.
Results: We identified 8 proteins that were highly abundant in mucinous PCLs with HGD. Among these were the inflammatory enzymes myeloperoxidase (MPO) and neutrophil elastase (ELANE), suggesting that differential activity levels could be exploited that would minimize fluid requirements and cost. Among 28 mucinous PCLs, a composite score that included both activity and mass of MPO performed the best for HGD in mucinous cysts (AUC 0.955, sensitivity 98%, specificity 93%). ELANE activity (AUC 0.76, sensitivity 69%, specificity 59%) and TPP1 activity (AUC 0.765, sensitivity 71%, specificity 74%) had modest performance.
Conclusions: Our functional biomarkers accurately classified HGD among mucinous cysts. Functional biomarkers that require low sample volumes (&lt;10μl) of cyst fluid have the potential to substantially improve clinical decision-making for patients with PCLs.
Citation Format: Francesco Caiazza, Andre Lourenco, Patricia Conroy, Thomas Hoffmann, Sam L. Ivry, Tyler York, Gina Zhu, Audrey Mustoe, Anthony J. O'Donoghue, Charles S. Craik, Kimberly Kirkwood. Using functional biomarkers to accurately predict advanced neoplasia in pancreatic cystic lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2226.
Abstract 2242: Impact of low-dose computed tomography screening for lung cancer at a community oncology clinic on stage of lung cancer diagnosis in the catchment area
Authors: Ellis Edgar T. , Bauer Michael A. , Beck Thaddeus , Bradford Daniel S. , Thompson Joanna , Kulik Margarete C. , Su Joseph L. 
Published: June 2022

Abstract
Introduction: Arkansas has the second-highest incidence of lung cancer in the U.S., with a largely rural and medically underserved population. Low-dose computed tomography (LDCT) is a well-established procedure for lung cancer screening in academic medical centers, but few local community oncology centers utilize this technology. Highlands Oncology Group (HOG), located in Northwest Arkansas (NWA), took the initiative to bring LDCT screening to a non-academic medical center and provide routine LDCT screening to a rural population. The objective of this study is to evaluate the benefits of free LDCT screening at a community oncology clinic.
Methods: The study compared for-fee and free periods of LDCT screening at HOG and their impact on identifying cancer in NWA. The study population was patients in HOG’s catchment area who fell into the risk categories set by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology to be eligible for screening between March 2013 and February 2020.
Results: A total of 5,402 eligible participants enrolled in the study. During ten months of for-fee screening (n=60), 3.3% of patients diagnosed had Stage I lung cancer, and 1.7% were diagnosed with Stages II-IV. During the first ten months of free screening (n=729), 3% of patients were diagnosed with Stage I lung cancer, 1.8% were diagnosed with Stages II-IV, and 1.1% were diagnosed with other cancers. Over the entire program until February 2020 (n=5,402), a total of 76 patients were diagnosed with Stage I lung cancer, 52 were diagnosed with Stage II-IV, and 35 were diagnosed with other cancers.
Conclusion: The result of this study suggests that eligible patients are more receptive to free lung cancer screening, even though most insurance coverage does not have a required co-pay for eligible patients. We also observed an increased diagnosis rate for early-stage lung cancers due to increased patient influx with free LDCT screening. The state central registry data showed a decline in distant lung cancer after the free LDCT screening offered in the northwestern counties in the HOG catchment area. At the same time, no such trend is visible for the entire state, suggesting a stage shift in lung cancer due to free LDCT screening.
Citation Format: Edgar T. Ellis, Michael A. Bauer, Thaddeus Beck, Daniel S. Bradford, Joanna Thompson, Margarete C. Kulik, Joseph L. Su. Impact of low-dose computed tomography screening for lung cancer at a community oncology clinic on stage of lung cancer diagnosis in the catchment area [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2242.
Abstract 2252: Predicting second breast cancers among women diagnosed with primary breast cancer using patient-level data and machine learning algorithms
Authors: Syleouni Maria Eleni , Karavasiloglou Nena , Manduchi Laura , Wanner Miriam , Korol Dimitri , Rohrmann Sabine 
Published: June 2022

Abstract
In 2020 2.3 million women were diagnosed with breast cancer. About 7.4% of women who have been diagnosed with primary breast cancer will have a second primary breast cancer within 10 years. This study builds a prediction model for second breast cancer for women who have had primary breast cancer. Readily available cancer registry data with machine learning methods for classification are employed. The best-performing model is selected based on the area under the receiver operator curve, and the key characteristics contributing to a high risk for second breast cancer are identified based on the prediction model. Using extreme gradient boosting (XGBoost) with limited patient features we find an area under the curve of 0.65-0.70 for the testing set. Among the most important features are days from incidence to treatment, size of primary tumor based on the pathology report, and oestrogen receptor status.This research is a step towards the development of a tool that will help doctors identify women very likely to develop second breast cancer, which will prioritize their follow-up or inform their course of treatment depending on their characteristics.
Citation Format: Maria Eleni Syleouni, Nena Karavasiloglou, Laura Manduchi, Miriam Wanner, Dimitri Korol, Sabine Rohrmann. Predicting second breast cancers among women diagnosed with primary breast cancer using patient-level data and machine learning algorithms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2252.
Abstract 2275: Transcription factor landscape cataloguing highlights key insights in inflammatory breast cancer (IBC)
Authors: Rosado-Tristani Diego A. , Morales Carlos S. , Peterson Esther A. , Rodríguez-Martínez Jose A. 
Published: June 2022

Abstract
Transcription factors are proteins that bind to DNA in a sequence-specific manner to regulate gene expression for normal cellular functions. Cancers have been shown to have aberrant transcriptional regulation. Therefore, identifying transcription factor landscapes will aid in characterizing complex diseases. As an example, breast cancer has many subtypes that are phenotypically and molecularly distinct. Inflammatory Breast Cancer (IBC) is rare, and the most aggressive form of breast cancer currently known. It is a poorly characterized subtype, and diagnosis often results in poor prognosis for patients. As such, we decided to explore the transcription factor landscape in IBC. This was accomplished employing the following strategy: 1) We assembled de novo transcriptomes for SUM149, an IBC cancer line and MCF7, a non-IBC cancer line using Trinity; 2) We translated the assembled transcriptomes using getORF from EMBOSS; 3) We identified putative transcription factors in the translated transcriptomes using CREPE. We then identified differentially expressed genes between SUM-149 and MCF-7 using DEseq2. Our results highlight differences in the transcription factor catalogues between IBC and non-IBC cancers. Of interest in SUM-149 is the gene BNC1, a member of the C2H2 zinc finger family of transcription factors. Dysregulation of this gene is associated with brain metastasis in breast cancers which is a common phenotype in IBC. BNC1-associated genes are linked to GO terms such as, epithelial cell differentiation, and regulation of alternative mRNA splicing, via spliceosome; however, BNC1 functions in IBC are yet to be determined. This analysis will bridge the gap in knowledge of key transcriptional regulators in IBC.
Citation Format: Diego A. Rosado-Tristani, Carlos S. Morales, Esther A. Peterson, Jose A. Rodríguez-Martínez. Transcription factor landscape cataloguing highlights key insights in inflammatory breast cancer (IBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2275.