bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA12: Poverty and pediatric leukemia outcomes
Authors: Bona Kira 
Published: February 2019

Abstract
Novel efforts to identify and address residual drivers of morbidity and mortality in pediatric cancer are essential. Poverty, in addition to biology, is emerging as a target for improvement in childhood cancer outcomes. While population-based evidence has suggested that poverty negatively impacts overall survival (OS) in childhood leukemia, limited data have explored the relationship between poverty and disease outcomes in the standardized care setting of clinical trials. Furthermore, measures of poverty amenable to targeted intervention have not been previously described in the pediatric oncology setting. We examined overall survival (OS), event-free survival (EFS), and cumulative incidence and timing of relapse by community-level poverty for 575 children with newly diagnosed acute lymphoblastic leukemia (ALL) treated on consecutive phase III multicenter consortium protocols between 2000-2010. Children were categorized as living in a high- or low-poverty area using aggregate U.S. Census data linked to zip code. Children from high-poverty areas experienced inferior OS as compared to those in low-poverty areas (85% vs. 92%, p=0.02), which remained marginally significant after adjustment for NCI risk criteria. Among children who relapsed, children from high-poverty areas were significantly more likely to experience early relapse (&lt;36 months in complete remission; 92% vs 48%, p=0.008), which is more challenging to salvage. These data identified poverty-related disparities in childhood leukemia outcomes, suggesting a need for further investigation of poverty measures amenable to intervention. We subsequently sought to describe the prevalence of a concrete measure of poverty termed household material hardship (HMH)--defined as food, energy, and housing insecurity--in a cohort of newly diagnosed pediatric oncology families. HMH in primary care is associated with inferior health outcomes, remediable with targeted intervention, and associated with improved health outcomes when remediated. We conducted a single-site prospective cohort study of 99 families of newly diagnosed pediatric cancer families receiving chemotherapy. We found that 20% of families reported pre-existing HMH at the time of diagnosis, and 29% of families reported HMH following 6 months of chemotherapy despite existing psychosocial supports. These data suggest that a quantifiable and remediable measure of poverty is present in a significant proportion of children undergoing cancer therapy in the U.S. and represents a potential target for future intervention.
Citation Format: Kira Bona. Poverty and pediatric leukemia outcomes [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA12.
Abstract IA19: Cancer chemotherapy and the tools needed to advance treatment in a medical diverse population
Authors: Williams Jennie L. 
Published: February 2019

Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and is the third leading cause of cancer-related deaths in the Western world. The mortality from colorectal cancer in Caucasian American (CAs) has been declining, but the death rate continues to be higher in African Americans (AAs), maintaining the racial disparity. In addition, AAs more often present with CRC at advanced stages contributing to the lower five-year survival rate. Hispanic-Americans (HAs) have significantly lower CRC incidence and mortality rates when compared with non-Hispanic AA (NH-AA) and non-Hispanic CA (NH-CA) populations. However, rates among HAs are significantly higher than those among residents of Puerto Rico and other Spanish-speaking countries in South and Central America. Furthermore, preliminary data and documented results show that for HA the age at presentation is lower and the stage of the disease is higher than that of AA and CAs. We hypothesize that various factors (i.e., familial, socioeconomic, environmental, and dietary) may contribute to the underlying problem of colon cancer racial/ethnic health disparity. Also, it has been noted that the response to chemopreventive agents differ as to the biologic/genetic heterogeneity of the tumors of NH-AAs, Has, and NH-CAs. Since chemopreventive agents exert their effect through a molecular target, this disparity would suggest differences at the genetic level. Therefore, the formulation and evaluation of chemopreventive/chemotherapeutic agents that address the issue of differential chemoresponse and chemoresistance is essential to survival. To study, in vitro and in vivo, the development of and chemoresponsiveness of therapeutic agents to colonic diseases in diverse populations, the availability of the appropriate cells (cell lines/organoids) and animal (PDX) models is critical. Our overarching goal is to assess racial and ethnic genetic/epigenetic dysregulations and associate these changes to chemoresponse and colon cancer racial disparity. The availability of these biologic tools will facilitate overcoming differential incidence and outcome seen among racial and ethnic groups for CRC. To achieve this goal, we are generating and characterizing novel cell lines, PDXs, and organoids derived from NH-CAs, Has, and AAs patients with colorectal cancer. Downstream use of these biologic tools will assist our group and the scientific community at large in improving targeted personal cancer treatment. This research effort is inclusive of all and will benefit a diverse population.
Citation Format: Jennie L. Williams. Cancer chemotherapy and the tools needed to advance treatment in a medical diverse population [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA19.
Abstract IA21: NCI's Patient-Derived Models Repository: Generating models from racial and ethnic minorities
Authors: Evrard Yvonne A. 
Published: February 2019

Abstract
The National Cancer Institute (NCI) has developed a Patient-Derived Models Repository (PDMR) comprising quality-controlled, early-passage, clinically annotated patient-derived xenografts (PDXs) to serve as a resource for public-private partnerships and for academic drug discovery efforts. The first 100 models were released in May 2017, are clinically annotated with pathologic and molecular information available in a publicly accessible database, and are available to the extramural community for research use (pdmr.cancer.gov). The PDMR was established by NCI at the Frederick National Laboratory for Cancer Research (FNLCR) in direct response to discussions with academia and industry; the oncology community's highest-priority need was identified as better preclinical models that more faithfully reflect the patient's tumor and are associated with the patient's treatment history. NCI has focused on collecting specimens from patients with cancers that are under-represented in many other PDX collections such as head and neck, pancreatic, bladder and gynecologic cancers, melanomas, and sarcomas. Recently, NCI has also increased its focus on generation of PDXs from racial and ethnic minorities through new funding opportunities. The initial goal is to have 20-25% of the models in the PDMR from racial and ethnic minorities in diagnoses that are most pertinent to cancer health disparities. The overall goal of NCI is to create a long-term home for at least 1,000 models such that sufficient biologic, clinical, and population diversity is represented to allow researchers to ask questions such as: what is the impact of tumor heterogeneity on target qualification or clinical response; do PDXs more faithfully represent the human tumor for pharmacodynamic assay and predictive marker development; or can an adequately powered preclinical PDX clinical trial lead to better evaluation of therapies for future clinical use?
Grant Support: This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.
Citation Format: Yvonne A. Evrard. NCI's Patient-Derived Models Repository: Generating models from racial and ethnic minorities [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA21.
Abstract A01: Stem cell signals in the initiation and progression of non-small cell lung cancer
Authors: Barber Alison G. , Husain Hatim , Valasek Mark A. , Scadeng Miriam , Reya Tannishtha 
Published: February 2019

Abstract
Lung cancer is most commonly diagnosed at a late stage when the disease is in its most aggressive state. To define the key regulators of lung cancer, we have focused on how stem cell signals are hijacked to drive progression to an undifferentiated state. Using a novel reporter mouse designed to reflect expression of the stem cell fate determinant Musashi-2 (Msi2), we found that Msi2 is highly expressed in tumors derived from the KrasG12D/+; p53fl/fl (KP) mouse model of lung adenocarcinoma. To test if Msi2-expressing cells preferentially act as the cell of origin in lung cancer, we isolated lung epithelial cells and tested their tumorigenic potential in vitro and in vivo following activation of Kras and loss of p53. Importantly, Msi2+ cells preferentially formed tumorspheres in vitro as well as tumors in vivo, indicating that Msi2+ tumor cells have increased tumor-initiating capacity. To determine whether Msi2 is required for lung cancer growth and progression, we crossed KP mice to Msi2 knockout mice and monitored tumor growth over time. Loss of Msi2 led to a reduction in both the number of tumors that formed and in overall tumor burden. Moreover, the mice exhibited a reduced frequency of high-grade tumors and an increase in overall survival, suggesting that loss of Msi2 impairs tumor development and disease progression. Finally, inhibition of Msi2 in a primary lung adenocarcinoma cell line led to reduced tumor volume in vivo, suggesting that Msi2 continues to be a dependency in established disease. Collectively, our data identify Msi2 as a stem cell signal that is critically required in lung cancer development and progression.
Citation Format: Alison G. Barber, Hatim Husain, Mark A. Valasek, Miriam Scadeng, Tannishtha Reya. Stem cell signals in the initiation and progression of non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A01.
Abstract B07: Characterization of branched-chain aminotransferase 1 as a novel therapeutic target for small cell lung cancer
Authors: Butler Napoleon B. , Kim Keebeom , Kim Dong-wook , Park Kwon 
Published: February 2019

Abstract
Few studies have explored tumor metabolism to target small cell lung cancer (SCLC), for which treatment options are limited and eventually fail with resistance. The objective of this study is to identify novel biomarkers and therapeutic targets among molecular changes specific to the cancer cells relative to precancerous precursor cells. In our previous study, comparative profiling of precancerous cells with SCLC cells revealed branched-chain aminotransferase1 (Bcat1) as one of the most upregulated genes in the cancer cells relative to their precursors as well as normal lung. Based on this result, we hypothesize that the elevated Bcat1 plays a role in promoting SCLC. Here, we confirmed elevated Bcat1 protein expression in mouse SCLC cells relative to precancerous cells and in human SCLC lines. Targeting Bcat1 in mouse and human SCLC cells with shRNA or small-molecule inhibitors significantly reduced colony expansion in soft agar and formation of subcutaneous tumors in athymic nude mice. Inhibition of Bcat1 also reduced protein synthesis rate as measured by puromycin incorporation into protein. Additionally, we found Bcat1 plays a significant role in leucine catabolism in mouse SCLC using a coupled enzymatic assay. Taken together, these novel findings suggest that elevated Bcat1 promotes SCLC growth by supporting protein synthesis, which is necessary for proliferating cells. Given the proven safety profile of existing inhibitors of Bcat1, our findings are significant in supporting the concept of targeting Bcat1 as a novel and particularly valuable therapeutic strategy for SCLC.
Citation Format: Napoleon B. Butler, Keebeom Kim, Dong-wook Kim, Kwon Park. Characterization of branched-chain aminotransferase 1 as a novel therapeutic target for small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B07.
Abstract B08: Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition
Authors: Augert Arnaud , Eastwood Emily , Ibrahim Ali H. , Wu Nan , Grunblatt Eli , Basom Ryan , Eaton Keith D. , Martins Renato , Poirier John , Rudin Charles M. , Milletti Francesca , Mack Fiona , MacPherson David 
Published: February 2019

Abstract
Small cell lung cancer (SCLC) is a recalcitrant, lethal tumor type for which little change to first-line standard-of-care treatment has been made over the last few decades. Unlike non-small cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Activation of NOTCH signaling impairs neuroendocrine differentiation and suppresses SCLC, but there are no therapeutic strategies to activate NOTCH in SCLC. LSD1 inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was unknown. Here we demonstrate that exposure to the highly potent and selective LSD1 inhibitor, RG6016/ORY1001, induces NOTCH pathway activation, resulting in the suppression of ASCL1, a regulator of neuroendocrine cell state critical for SCLC oncogenesis. LSD1 binds to the NOTCH1 locus, modulating NOTCH1 expression in SCLC cells. In vivo, sensitivity to LSD1 inhibition in SCLC patient-derived xenograft (PDX) models correlates with the extent of NOTCH pathway activation and repression of a neuroendocrine phenotype. LSD1 inhibition represents a novel therapeutic approach to target the activation of NOTCH and suppression of ASCL1 in SCLC.
Citation Format: Arnaud Augert, Emily Eastwood, Ali H. Ibrahim, Nan Wu, Eli Grunblatt, Ryan Basom, Keith D. Eaton, Renato Martins, John Poirier, Charles M. Rudin, Francesca Milletti, Fiona Mack, David MacPherson. Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B08.
Abstract B10: Radiomics signatures on the region defined by using multi-window CT to improve detection lung cancer screening
Authors: Lu Hong , Mu Wei , Balagurunathan Yoganand , Qi Jin , Schabath Mathew , Gillies Robert James 
Published: February 2019

Abstract
Purpose: To evaluate the utility of defining a region using complementary information provided by different CT windows on the lung nodules to predict malignancy.
Methods: We obtained 50 cases from National Lung Screening Trial (NLST) with 23 malignant and 27 benign patients. We segmented lung nodules using lung and mediastinal window independently and obtained the difference region (3D). About 260 quantitative radiomics features were exacted on the voxels segmented from different windows and the difference region. We used support vector machines (SVM) to build a predictive model to identify malignancy. We compared the effectiveness of the multi-window based features against single-lung window features using a 2-fold cross validation.
Results: We find several radiomics features in the difference region to be predictive of malignancy; the best univariate features was Run_Length_Nonuniformity differnce region had an AUC of 0.911.The best feature in the lung window was defined by Sum_Entropylung window, which had an AUC of only 0.825. While using cross-validataion (2-fold) we obtained a mean accuracy of 80.97% and an AUC of 0.8 (specificity and sensitivity of 0.887 and 0.712). Compared to single-window, the best predictive features had accuracy of 78.17% and AUC of 0.772 (specificity and sensitivity of 0.876 and 0.667).
Conclusions:The multi-window based radiomics features, especially the features from difference area, can improve diagnostic performance in differentiation of benign and malignant lung nodules to great extent.
Citation Format: Hong Lu, Wei Mu, Yoganand Balagurunathan, Jin Qi, Mathew Schabath, Robert James Gillies. Radiomics signatures on the region defined by using multi-window CT to improve detection lung cancer screening [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B10.
Abstract B18: Characterization and therapeutic harnessing of TRAIL’s pro-tumorigenic and pro-apoptotic functions in cancer
Authors: Montinaro Antonella , Hartwig Torsten , Karstedt Silvia von , Zubiaur Itziar Areso , Lemke Johannes , Taraborelli Lucia , Surinova Silvia , El-Bahrawy Mona A. , Walczak Henning 
Published: February 2019

Abstract
Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is known for specifically killing many cancer cells. This has led to the clinical development of several agonists for TRAIL-Rs. However, while some cancer cells die in response to TRAIL, most primary cancer cells are resistant to TRAIL-based monotherapy. In resistant cells, TRAIL signaling can induce non-apoptotic, tumor-supporting effects. Hence, efficient therapy design requires understanding of the bivalent nature of TRAIL signaling. Here we demonstrate that, on the one hand, TRAIL–TRAIL-R signaling in cancer cells elicits the production of cytokines, most importantly CCL2, which promote the accumulation of alternatively activated, M2-like myeloid cells in the tumor microenvironment, consequently promoting tumor growth via a CCL2/CCR2 axis. On the other hand, we identified CDK9 inhibition as a powerful means to render many TRAIL-resistant cancer cells highly sensitive to TRAIL-induced apoptosis. Importantly, this combination was also highly effective in vivo and led to significant tumor regression in mouse models of lung cancer. Therefore, in certain cancer patients antagonizing endogenous TRAIL–TRAIL-R signaling may modulate the tumor microenvironment in favour of tumor regression, while in other cancer patients the combination of TRAIL-R agonists with CDK9 inhibitors should be considered as a highly active alternative therapy.
Citation Format: Antonella Montinaro, Torsten Hartwig, Silvia von Karstedt, Itziar Areso Zubiaur, Johannes Lemke, Lucia Taraborelli, Silvia Surinova, Mona A. El-Bahrawy, Henning Walczak. Characterization and therapeutic harnessing of TRAIL’s pro-tumorigenic and pro-apoptotic functions in cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B18.
Abstract B27: Osimertinib (AZD9291) is sensitive and bound with affinity to EGFR exon 20 insertion mutant models
Authors: Lee Yusoo , Kim Tae Min , Kim Dong-Wan , Ahn Yong-Oon , Kim Soyeon , Keam Bhumsuk , Kim Miso , Heo Dae Seog 
Published: February 2019

Abstract
Background: Although EGFR exon 20 insertion mutation is the third most common among EGFR-mutant NSCLC, this mutation has not been well studied and the first-generation EGFR TKIs are ineffective. In addition, the efficacy of the third-generation EGFR TKIs is controversial.
Methods: Various EGFR exon 20 insertion mutation models were developed using Ba/F3 system as follows: C-helix (n=1, A763_Y764insFQEA) and loop following C-helix (n=7). In addition, SNU-3173 cell line was derived from NSCLC patient with EGFR exon 20 insertion mutation. Cell viability assays were performed using EGFR TKIs (gefitinib, erlotinib, dacomitinib, afatinib, rociletinib, olmutinib, nazartinib, and osimertinib). Immunoblotting was performed to evaluate the downstream signals of EGFR pathway. Additionally, the docking homology models of EGFR exon 20 insertion mutations with osimertinib were developed with SWISS-Model and SwissDock for estimation of the structural appropriateness.
Results: Cell viability assay showed that EGFR exon 20 insertion mutants are resistant to the first-generation EGFR TKIs, except for A763_Y764insFQEA mutant Ba/F3 cells. IC50 values of second-generation EGFR TKIs are five- to hundreds-folds lower than gefitinib and erlotinib. Dacomitinib and afatinib have good efficacy for the most of them, and regulated down signaling pathways. The third-generation TKIs showed moderate efficacy against EGFR exon 20 insertion mutants. Overall, osimertinib has the most successful inhibition of EGFR exon 20 insertion mutants (IC50 values for C-helix and loop following C-helix mutants for afatinib, &lt;0.1nM and 16.7-352.5nM; rociletinib 1022.1nM and 288.0-3034.6nM; olmutinib, 351.8nM and 30.4-626.7nM; osimertinib 131.6nM and 14.7-65.7nM; and nazartinib, 351.8nM and 36.3-509.9nM, respectively). Ribbon diagram with in silico homology docking simulations showed how exon 20 insertion mutations change the structures of kinase domain and the suitable binding values with various EGFR exon 20 insertion mutant subtypes with osimertinib.
Conclusions: Osimertinib showed an outstanding effectiveness against various EGFR exon 20 insertion mutations. In addition, docking simulation of in silico homology models corresponded with the in vitro results. Consequently, osimertinib is effective against EGFR exon 20 insertion mutant models.
Citation Format: Yusoo Lee, Tae Min Kim, Dong-Wan Kim, Yong-Oon Ahn, Soyeon Kim, Bhumsuk Keam, Miso Kim, Dae Seog Heo. Osimertinib (AZD9291) is sensitive and bound with affinity to EGFR exon 20 insertion mutant models [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B27.