bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1048: Genomic analysis of patients with relapsed ovarian cancer enrolled in a phase II trial of nivolumab and bevacizumab
Authors: Stover Elizabeth H. , Tyekucheva Svitlana , Liu Yiwen , Curtis Jennifer D. , Penson Richard T. , Liu Joyce F. 
Published: September 2020

Abstract
We analyzed genomic alterations in patients with relapsed ovarian cancer treated with combined nivolumab and bevacizumab in a phase II clinical trial, in order to identify potential biomarkers of response. Thirty-eight patients were treated with nivolumab and bevacizumab and the previously reported overall response rate was 28.9% (Liu et al, JAMA Oncology, 2019). Formalin-fixed paraffin-embedded patient tumor samples (acquired pre-treatment) underwent whole-exome sequencing, followed by quality control filtering and analysis of mutations, insertions/deletions, copy-number alterations, and mutational signatures using established methods. Differences in genomic event rates were assessed between response groups, as defined by presence or absence of objective response or clinical benefit. We describe the genomic alterations in all patients treated with nivolumab and bevacizumab, including several long-term responders with treatment duration &gt;24 months. The observed alterations in the patient cohort reflected known patterns of common mutations (e.g. TP53) and copy-number alterations (e.g. MYC amplification) in ovarian cancer. Within the limits of sample size, no significant differences in frequency of specific mutations were observed between response groups, with the possible exception of mutations in SETD1B, a histone methyltransferase, which were more frequent in the subset of patients lacking clinical benefit. BRCA1/2 mutation rate was similar between groups. Tumor mutational burden was not significantly different between groups. Initial exploratory analysis for copy-number alterations did not reveal genes with differential copy-number alterations between the response groups, and further analyses of copy-number alterations and mutational signatures are in progress. In summary, we describe genomic biomarker analysis from tumors of patients with relapsed ovarian cancer receiving treatment with nivolumab and bevacizumab. Taken together, we did not identify genomic alterations that clearly distinguish responding and non-responding patients in the data evaluated to date. Analysis of targeted RNA-sequencing data is planned as a next step. Further studies are needed to identify genomic or transcriptomic biomarkers of responses to checkpoint blockade and anti-angiogenic therapy in ovarian cancer.
Citation Format: Elizabeth H. Stover, Svitlana Tyekucheva, Yiwen Liu, Jennifer D. Curtis, Richard T. Penson, Joyce F. Liu. Genomic analysis of patients with relapsed ovarian cancer enrolled in a phase II trial of nivolumab and bevacizumab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1048.
Abstract 106: The inhibitory effects of baicalein on cell proliferation in breast cancer cells
Authors: Monear Nicodemus C. , Kantola Austin L. , Xhabija Besa 
Published: September 2020

Abstract
Baicalein is a naturally occurring substance found in certain herbaceous species such as Scutellaria baicalensis and Oroxylum indicum, as well more well-known species such as Thymus vulgaris (thyme). Classified as a flavonoid derivative, baicalein has been shown to inhibit cell proliferation by signaling apoptotic pathways in cell lines typically resistant to induced cell death. In this analysis, we have assessed cell viability by methylene blue staining and have shown that T47D breast cancer cells exhibit stunted proliferation patterns within 24 hours of exposure to baicalein at concentrations as low as 100 µM. Additionally, we have performed an analysis of the cell cycle by flow cytometry for which we have observed an arrest in the S phase, further indicating inhibited cell proliferation.
Citation Format: Nicodemus C. Monear, Austin L. Kantola, Besa Xhabija. The inhibitory effects of baicalein on cell proliferation in breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 106.
Abstract 1061: Increasing potency of anticancer drugs through Sortilin receptor-mediated cancer therapy: A new targeted approach for the treatment of ovarian cancer
Authors: Demeule Michel , Currie Jean-Christophe , Charfi Cyndia , Larocque Alain , Zgheib Alain , Kozelko Sophie , Béliveau Richard , Marsolais Christian , Annabi Borhane 
Published: September 2020

Abstract
Rational : The development of personalized therapies against ovarian cancer remains highly challenging even in current modern oncology. One strategy to achieve greater selectivity and better anticancer drug delivery into cancer cells is to conjugate cytotoxic agents to peptide ligands that selectively target receptors abundantly and/or exclusively expressed in these tumor cells. Increased expression of Sortilin (SORT1), a scavenging receptor also known as neurotensin receptor-3, has been observed in invasive ovarian cancer biopsies. In addition, increased SORT1 expression correlated with breast tumor grades.
Procedures : In light of these observations, we developed a peptide conjugation platform to target SORT1 and to increase cell selectivity and internalization of anticancer agents. As a proof-of-concept, doxorubicin and docetaxel were conjugated to a Sortilin-binding proprietary peptide (TH19P01).
Results : In vitro, significant intracellular delivery of the doxorubicin-TH19P01 conjugate (TH1904) and docetaxel-TH19P01 conjugate (TH1902) were observed in a ES-2 ovarian cancer cell line model while preserving efficient doxorubicin or docetaxel cytotoxic mechanism. TH19P01 and drug conjugate uptake in ovarian cancer cells assays were reduced when SORT1 expression was specifically silenced using siRNA or upon competition with the SORT1 ligands neurotensin and progranulin. Importantly, drug-TH19P01 conjugates were found to bypass the P-glycoprotein (P-gp) efflux pump in MDCK-MDR1 cells overexpressing P-gp as the uptake of conjugates was unaffected by the P-gp inhibitor Cyclosporin A. In vivo, TH1904 and TH1902 caused a more potent inhibition of human ovarian tumor xenografts grown in mice and were better tolerated than their unconjugated parent drugs.
Conclusion : These results strongly support future clinical development of this targeted technology platform to generate novel personalized therapeutics with specific indications in Sortilin-positive cancers.
Citation Format: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Larocque, Alain Zgheib, Sophie Kozelko, Richard Béliveau, Christian Marsolais, Borhane Annabi. Increasing potency of anticancer drugs through Sortilin receptor-mediated cancer therapy: A new targeted approach for the treatment of ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1061.
Abstract 107: Data mining analysis of the PP2A-cell cycle axis in breast and prostate cancer patients
Authors: Cendon-Florez Ylenia , Pippa Raffaella , Boffo Silvia , Odero Maria D. , Giordano Antonio 
Published: September 2020

Abstract
Breast and prostate cancer are aggressive hormone-dependent diseases that affect thousands of people every year. Despite advances in early detection and the understanding of the molecular bases of both cancers' biology, resistance to therapy frequently occurs. Thus, the identification of novel therapeutic targets and pathways that contribute to breast and prostate cancer lethality is necessary for improving clinical outcomes. Here, we analyzed the gene expression of known inhibitors of the protein phosphatase 2A (PP2A) in both cancer patient samples. Our analysis disclosed a general over-expression of all PP2A negative regulators. Additionally, SET, CIP2A, ANP32E and TIPRL genes are frequently co-expressed, and their expression positively correlates with the ones of the main cyclins and CDKs, suggesting the existence of a feed-forward loop that might contribute to the cancer progression via PP2A inactivation. Overall, our study indicates the existence of a strategic and targetable axis between PP2A inhibitors (SET, CIP2A, ANP32E and TIPRL) and cell cycle regulators (Cyclin A, Cyclin E, Cyclin B and CDK1) and provides a valuable rationale for using a personalized combinational therapy approach to improve breast and prostate cancer patient survival. Keywords: Breast cancer, Prostate Cancer, PP2A, cell cycle
Citation Format: Ylenia Cendon-Florez, Raffaella Pippa, Silvia Boffo, Maria D. Odero, Antonio Giordano. Data mining analysis of the PP2A-cell cycle axis in breast and prostate cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 107.
Abstract 1078: The nucleosomal acidic patch helps anchor of de novo DNA methyltransferase DNMT3A2/3B3 complex
Authors: Xu Ting-Hai , Liu Minmin , Zhou Edward , Liang Gangning , Xu Eric H. , Melcher Karsten , Jones Peter A. 
Published: September 2020

Abstract
CpG methylation by de novo DNA methyltransferases (DNMT) 3A and 3B is essential for mammalian development and differentiation, and is frequently dysregulated in cancer. DNMT3s preferentially bind nucleosomes yet can not methylate the DNA wrapped around the nucleosome core, and favor the methylation of linker DNA at positioned nucleosomes. Here we present the cryo-EM structure of a ternary complex of catalytically active DNMT3A2, the catalytically inactive accessory subunit DNMT3B3, and a nucleosome core particle flanked with linker DNA. We find that the catalytic-like domain (CLD) of the accessory DNMT3B3 binds the acidic patch of the nucleosome core, which orients the binding of the catalyticaly active DNMT3A2 to linker DNA. The sterical constraints of this arrangement suggest that nucleosomal DNA must be moved relative to the nucleosome core for de novo methylation to occur.
Citation Format: Ting-Hai Xu, Minmin Liu, Edward Zhou, Gangning Liang, Eric H. Xu, Karsten Melcher, Peter A. Jones. The nucleosomal acidic patch helps anchor of de novo DNA methyltransferase DNMT3A2/3B3 complex [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1078.
Abstract 1092: A systematic analysis of BRAF mutations and their sensitivity to different BRAF inhibitors
Authors: Barbash Zohar , Haham Dikla , Hafzadi Liat , Zipor Ron , Barth Shaul , Aizenman Arie , Zimmerman Lior , Tarcic Gabi 
Published: September 2020

Abstract
The MAPK-ERK signaling cascade is among the most frequently mutated pathways in human cancer, with the BRAF V600 mutation being the most common alteration. FDA-approved BRAF inhibitors as well as combination therapies of BRAF and MEK inhibitors are available and provide survival benefits to patients with a BRAF V600 mutation in several indications. Yet non-V600 BRAF mutations are found in many cancers and are even more prevalent than V600 mutations in certain tumor types. As the use of NGS profiling in precision oncology is becoming more common, novel alterations in BRAF are being uncovered. This has led to the classification of BRAF mutations, which is dependent on its biochemical properties and affects it sensitivity to inhibitors. Therefore, annotation of these novel variants is crucial for assigning correct treatment. Using a high throughput method for functional annotation of MAPK activity, we profiled 151 different BRAF mutations identified in the AACR Project GENIE dataset, and their response to 4 different BRAF inhibitors- vemurafenib and 3 different exploratory 2nd generation inhibitors. The system is based on rapid synthesis of the mutations and expression of the mutated protein together with fluorescently labeled reporters in a cell-based assay. Our results show that from the 151 different BRAF mutations, ~25% were found to activate the MAPK pathway. All of the class 1 and 2 mutations tested were found to be active, providing positive validation for the method. Additionally, many novel activating mutations were identified, some outside of the known domains. When testing the response of the active mutations to different classes of BRAF inhibitors, we show that while vemurafenib efficiently inhibited V600 mutations, other types of mutations and specifically BRAF fusions were not inhibited by this drug. Alternatively, the second-generation experimental inhibitors were effective against both V600 as well as non-V600 mutations. Using this large-scale approach to characterize BRAF mutations, we were able to functionally annotate the largest number of BRAF mutations to date. Our results show that the number of activating variants is large and that they possess differential sensitivity to different types of direct inhibitors. This data can serve as a basis for rational drug design as well as more accurate treatment options for patients.
Citation Format: Zohar Barbash, Dikla Haham, Liat Hafzadi, Ron Zipor, Shaul Barth, Arie Aizenman, Lior Zimmerman, Gabi Tarcic. A systematic analysis of BRAF mutations and their sensitivity to different BRAF inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1092.
Abstract 1107: Cell state diversity promotes metastasis through heterotypic cluster formation in melanoma
Authors: Campbell Nathaniel R. , Zhang Maomao , Baron Maayan , Heilmann Silja , Deforet Maxime , Ferretti Lorenza , Huang Ting-Hsiang , Levesque Mitchell P. , Yanai Itai , Xavier Joao B. , White Richard M. 
Published: September 2020

Abstract
Metastasis is the primary cause of cancer death, yet we know little about what determines its timing and aggressiveness. In melanoma, transcriptional profiling has revealed multiple co-existing cell states, including proliferative (PRO) versus invasive (INV) subpopulations that have been posited to represent a “go or grow” tradeoff in the etiology of metastasis. Although both of these populations are present in primary tumors and metastases, little is known about how they physically interact with each other in tumor dissemination. We use a combination of melanoma modeling in zebrafish and human validation to demonstrate that these subpopulations form spatially structured heterotypic clusters that cooperate in the seeding of metastasis. We unexpectedly found that INV cells were tightly adherent to each other and formed large tumor cell clusters. Mixing of PRO and INV cells generated heterotypic clusters, composed of a dense central core of INV cells surrounded by a rim of PRO cells. Using intravital imaging, we identified metastatic cooperation between these two subpopulations, in which the INV cells facilitated the earlier spread of the less metastatic PRO cells via collective extravasation. Mechanistically, we identified the TFAP2 family of neural crest transcription factors to be a master regulator of both clustering and the PRO/INV states. Knockout of TFAP2 from melanoma cells reduced proliferation but increased clustering and metastasis. TFAP2 loss resulted in increased expression of cell adhesion molecules, providing a mechanistic basis for cluster formation. Our data suggest a coherent framework for the co-existence of these two divergent cell populations in melanoma, in which differing cell states form heterotypic clusters that promote collective metastasis via cell-cell cooperation.
Citation Format: Nathaniel R. Campbell, Maomao Zhang, Maayan Baron, Silja Heilmann, Maxime Deforet, Lorenza Ferretti, Ting-Hsiang Huang, Mitchell P. Levesque, Itai Yanai, Joao B. Xavier, Richard M. White. Cell state diversity promotes metastasis through heterotypic cluster formation in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1107.
Abstract 112: Telomere proteins coordinate intracellular signaling to control telomere maintenance mechanism selection and metastatic recurrence
Authors: Robinson Nathaniel J. , Taylor Derek J. , Schiemann William P. 
Published: September 2020

Abstract
The relationship between telomere homeostasis and the development of cancer remains incompletely understood. In breast cancer (BC), these knowledge gaps are magnified by the fact that distinct telomere maintenance mechanisms (TMMs) are utilized across different disease subtypes and stages of progression. Accordingly, we have found that TMM identity in BC possesses an inherent plasticity that portends important prognostic and therapeutic insight, events regulated in part by SLX4-interacting protein (SLX4IP). To better understand how SLX4IP regulates TMM identity in BC, we employed proteomics of isolated chromatin segments (PICh) to capture the telomere proteomes of BC cells harboring differential SLX4IP expression. These analyzes revealed that SLX4IP blocks recruitment of the shelterin protein telomere repeat-binding factor 2-interacting protein (TERF2IP, also known as RAP1) to telomeres. Moreover, telomeres lacking RAP1 were able to be extended via the homologous recombination-based Alternative Lengthening of Telomeres (ALT) pathway. Mechanistically, SLX4IP disrupted the interaction between RAP1 and telomere repeat-binding factor 2 (TRF2), which facilitated the nuclear export of RAP1 and its binding to and activation of the NF-κB regulatory kinase, IKKβ. Activated IKKβ phosphorylated both NF-κB and β-catenin, thereby coordinating a transcriptional network of genes that are essential in promoting ALT. Conversely, loss of SLX4IP yielded telomeric retention of RAP1 with concomitant diminution of IKKβ activity, resulting in β-catenin-dependent stimulation of telomerase. Notably, telomerase was sufficient to drive the metastatic outgrowth of cells that were previously reliant upon ALT independent of its ability to extend telomere DNA. These findings shed new light on the functions of SLX4IP and the myriad roles of telomere proteins in influencing TMM plasticity and disease progression.
Citation Format: Nathaniel J. Robinson, Derek J. Taylor, William P. Schiemann. Telomere proteins coordinate intracellular signaling to control telomere maintenance mechanism selection and metastatic recurrence [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 112.
Abstract 1130: Cultural and socioeconomic factors affecting breast cancer screening in an Argentine city
Authors: Croce Maria Virginia , Cermignani Luciano , Rabassa Martin E. 
Published: September 2020

Abstract
In Argentina, there are no studies evaluating cultural and socioeconomic factors affecting breast cancer screening. Argentina presents social and economic disparities, and there is a mixture of features of both developed and developing societies. The goal of this research was to analyze cultural and social factors in advantaged and disadvantaged women of a metropolitan area in order to improve breast cancer screening by increasing the understanding of the complex society. A cross-sectional study was performed; a total of 739 women was included, being 379 of low economic power (ow group, LG) and 360 of middle economic power (MG); women were personally interviewed within three months. A structured previously validated questionnaire was employed considering socially shared values, beliefs, expectations, motivations, and emotions relevant to health behaviors, interactions with the health care system, educational level, occupation, and information about breast cancer and mammographic screening. Previous research in this area suggested that theoretical models and multivariate methods were needed in order to account for the complexity of relations among psychological, social structural, and cultural determinants of health behaviors. In this sense, an exhaustive statistical analysis was performed by multivariate analysis and logistic regression model. A Principal Component Analysis was performed employing previously selected variables; 3 factors were extracted which accounted for 35.8% of the total variance. Factor 1 was associated with fatalistic responses in association to attitudes to life and/or mammography screening while Factor 2 was related to concerns about cancer and exposition to radiation. These two factors and the covariates age, social group, education, health system, and primary doctor were use in a logistic regression model to assess mammographic adherence. Low score Factor 2 (p=0.003), MG (p=0.024) and the availability of a primary doctor (p=0.000) were associated with high mammographic adherence. Conclusions: This study highlights that mammographic screening is highly influenced by socioeconomic power, health system, and access to primary doctor. It appears that, some psychological factors related to concerns about cancer and exposition to radiation are also important. These data would be important to plan specific prevention and early diagnosis programs to be implemented by governmental entities.
Citation Format: Maria Virginia Croce, Luciano Cermignani, Martin E. Rabassa. Cultural and socioeconomic factors affecting breast cancer screening in an Argentine city [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1130.