bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1075: Conditionally active de novo IL-2 cytokine mimetics for targeted immunotherapy: de novo split technology
Authors: Quijano-Rubio Alfredo , Ali Lestat R. , Bhuiyan Md A. , Lajoie Marc J. , Dougan Michael , Baker David , Silva Daniel-Adriano 
Published: September 2020

Abstract
IL-2 is a highly potent, pleiomorphic cytokine approved for the treatment of melanoma and renal cell carcinoma. The therapeutic potential of this cytokine has been restricted by dose-limiting toxicities and off-tumor effects associated with systemic IL-2 administration. Scientists have long-pursued the development of targeted IL-2 variants to control biodistribution and improve the therapeutic index, e.g. IL-2-antibody fusions or immunocytokines. However, the potential benefit of targeting IL-2 is limited by the high affinity of the cytokine for its cellular receptor, which dominates biodistribution and results in activation of cells outside the tumor microenvironment. To address this challenge, we took advantage of the remarkable stability of Neoleukin-2/15 (Neo-2/15), a fully de novo cytokine mimetic that potently activates the beta and gamma subunits shared by the IL-2 and IL-15 receptors. We demonstrate that Neo-2/15 can be divided into two pieces that cannot signal individually, but that can recover their binding and cell-signaling potential when co-localized. Fusing the split molecules to independent targeting domains creates a modular and highly specific implementation of conditional activation. We demonstrate that if one split fragment is targeted to one tumor-associated antigen, and the complementary fragment is targeted to a second tumor-associated antigen, the ability to bind the IL-2 receptor and trigger signaling is only restored when these split fragments bind to the surface of cells expressing both targets. The split Neo-2/15 molecules have anti-tumor activity in syngeneic cancer models and have the potential to enhance the therapeutic index of cytokine mimetics in immunotherapy. To our knowledge, these are the first designed examples of strictly conditionally-active, targeted, cytokine-like molecules for immunotherapy.
*Current affiliation for D-A.S.: Neoleukin Therapeutics Inc, Seattle, WA, USA.
Citation Format: Alfredo Quijano-Rubio, Lestat R. Ali, Md A. Bhuiyan, Marc J. Lajoie, Michael Dougan, David Baker, Daniel-Adriano Silva. Conditionally active de novo IL-2 cytokine mimetics for targeted immunotherapy: de novo split technology [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 1075.
Abstract 1081: DNA methylation at the intersect of chromatin structure and transcriptome diversity
Authors: Ting Angela H. , Nanavaty Vishal , Abrash Elizabeth , Lee Byron , Fink Emily , Hwang Tae Hyun , Hong Changjin 
Published: September 2020

Abstract
Dysregulation of DNA methylation and mRNA alternative cleavage and polyadenylation (APA) are both prevalent in cancer, but they have been studied as independent processes. We discovered a DNA methylation regulated APA mechanism when we compared genome-wide DNA methylation and polyadenylation site usage between DNA methylation-competent and DNA methylation-deficient cells. Here we show that removal of DNA methylation enables CTCF binding and recruitment of the cohesin complex, which in turn, promotes proximal polyadenylation site usage. In this DNA de-methylated context, depletion of the RAD21 cohesin complex component can recover distal polyadenylation site usage. We also confirmed, using chromosomal conformation capture (3C), that CTCF and the cohesin complex mediate chromatin loops in the absence of DNA methylation to modulate polyadenylation site usage. Leveraging data from The Cancer Genome Atlas, we authenticated the relationship between DNA methylation and mRNA polyadenylation isoform expression in vivo. This DNA methylation regulated APA mechanism demonstrates how aberrant DNA methylation impacts transcriptome diversity and highlights the potential sequelae of global DNA methylation inhibition as a cancer treatment.
Citation Format: Angela H. Ting, Vishal Nanavaty, Elizabeth Abrash, Byron Lee, Emily Fink, Tae Hyun Hwang, Changjin Hong. DNA methylation at the intersect of chromatin structure and transcriptome diversity [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 1081.
Abstract 1082: Arid1a deletion results in enhanced osteosarcomagenesis and altered chromosome structure
Authors: Fatema Kaniz , Plyler Shawn , Pavek Adriene , Nartker Chris , Wang Yanliang , Jones Kevin , Barrott Jared 
Published: September 2020

Abstract
Osteosarcoma (OS) is a primary malignant bone tumor mainly affecting children and young adults. Early metastasis, chemoresistance and stagnation in the treatment options for the last 4 decades result in a less than 20% chance of long-term survival in metastatic OS. Investigating the molecular mechanisms underlying a more aggressive phenotype in osteosarcoma will certainly help develop novel treatment alternatives.
Through a transposon-mediated forward genetic screen, we were able to increase osteosarcomagenesis by random mutagenesis. Among the possible candidate genes on our list, we discovered a loss-of-function mutation in ARID1A. ARID1A is a member of the SWI/SNF chromatin-remodeling protein complex and has been implicated as a tumor suppressor in other cancers. We hypothesized that loss of ARID1A in osteosarcoma would increase the rate of tumor progression and metastasis by impacting the epigenetic configuration of the chromatin.
In-vitro (CRISPR/Cas9) deletion in human OS cell lines and cell behavioral studies validated that ARID1A loss contributes to faster tumorigenesis. To understand its effect in-vivo, we have developed mice cohorts with or without ARID1A with a Cre-mediated, Osteoblast specific (Osx) conditional knockout system. We observed that Arid1a-mutant mice develop tumors and die on an average 13 weeks earlier than that of the wildtype cohort. By 3D micro CT scanning, we further confirmed a relatively higher number of primary and metastatic tumors in the Arid1a mutant mice, albeit the histology and morphology of the tumors did not change. The analysis of genome-wide chromatin accessibility by ATAC-seq confirmed an open chromatin organization in Arid1a mutant mouse samples.
We conclude that, acting as an epigenetic regulator, ARID1A plays a significant role in osteosarcoma progression and metastasis. Further investigation to strengthen this link would present the opportunity for alternatively targeting genetically unstable cancers with epigenetic drugs.
Citation Format: Kaniz Fatema, Shawn Plyler, Adriene Pavek, Chris Nartker, Yanliang Wang, Kevin Jones, Jared Barrott. Arid1a deletion results in enhanced osteosarcomagenesis and altered chromosome structure [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 1082.
Abstract 1086: Downstream kinase signaling is dictated by specific KRAS mutations
Authors: Budagyan Konstantin , Chernoff Jonathan 
Published: September 2020

Abstract
Oncogenic KRAS mutations are common in colorectal cancer (CRC), found in ~50% of tumors, and are associated with poor prognosis and resistance to therapy. There is substantial diversity of KRAS alleles observed in CRC. Importantly, emerging clinical and experimental analysis of relatively common KRAS mutations at amino acids G12, G13, A146, and Q61 suggest that each mutation differently influences the clinical properties of a disease and response to therapy. For example, KRAS G12 mutations confer resistance to EGFR-targeted therapy, while G13D mutations do not. Although there is clinical evidence to suggest biological differences between mutant KRAS alleles, it is not yet known what drives these differences and whether they can be exploited for allele-specific therapy. We hypothesized that different KRAS mutants elicit variable alterations in downstream signaling pathways. To investigate this hypothesis, we created a novel system by which we can model KRAS mutants in isogenic mouse colon epithelial cell lines. To generate the cell lines, we developed an assay using fluorescent co-selection for CRISPR-driven genome editing. This assay involves simultaneous introduction of single-guide RNAs (sgRNAs) to two different endogenous loci resulting in double-editing events. We first introduced Cas9 and blue fluorescent protein (BFP) into mouse colon epithelial cell line containing heterozygous KRAS G12D mutation. We then used sgRNAs targeting BFP and the mutant G12D KRAS allele along with homology-directed repair (HDR) templates for a GFP gene and a KRAS mutant allele of our choice. Cells that successfully undergo HDR are GFP-positive and contain the desired KRAS mutation. Therefore, selection for GFP-positive cells allows us to identify those with phenotypically silent KRAS edits. Ultimately, this method allows us to toggle between different mutant alleles while preserving the wild-type allele, all in an isogenic background. Using this method, we have generated cell lines with endogenous heterozygous KRAS mutations commonly seen in CRC (G12D, G12V, G12C, G12R, G13D). In order to elucidate cellular signaling pathway differences between the KRAS mutants, we screened the mutated cell lines using a small-molecule library of ~160 protein kinase inhibitors. We found that there are mutation-specific differences in drug sensitivity profiles. These observations suggest that KRAS mutants drive specific cellular signaling pathways, and that further exploration of these pathways may prove to be valuable for identification of novel therapeutic opportunities in CRC.
Citation Format: Konstantin Budagyan, Jonathan Chernoff. Downstream kinase signaling is dictated by specific KRAS mutations [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 1086.
Abstract 1090: Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis
Authors: Mukherjee Radha , Vanaja Kiran Gireesan , Boyer Jacob A. , Qiu Juan , Chen Xiaoping , de Stanchina Elisa , Chandarlapaty Sarat , Levchenko Andre , Rosen Neal 
Published: September 2020

Abstract
The PI3K pathway is a key regulator of metabolism, cell proliferation and migration and some of its components (e.g. PIK3CA and PTEN) are frequently altered in cancer by genetic events that deregulate its output. However, PI3K signaling is not usually the primary driver of these tumors and inhibitors of components of the pathway have only modest antitumor effects. We now show that both physiologic and oncogenic activation of the PI3K signaling by growth factors and an activating hotspot PIK3CA mutation respectively, cause an increase in the expression of the lipid phosphatase PTEN, thus limiting the duration of the signal and the output of the pathway in tumors. Pharmacologic and physiologic inhibition of the pathway by HER2/PI3K/AKT/mTOR inhibitors and nutrient starvation respectively reduce PTEN, thus buffering the effects of inhibition and contributing to the rebound in pathway activity that occurs in tumors. This regulation is found to be a feature of multiple types of cancer, non-cancer cell line and PDX models thereby highlighting its role as a key conserved feedback loop within the PI3K signaling network, both in vitro and in vivo. Regulation of expression is due to mTOR/4EBP1 dependent control of PTEN translation and is lost when 4EBP1 is knocked out. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the output of oncogenic mutants that deregulate the pathway and the antitumor activity of PI3K pathway inhibitors.
Citation Format: Radha Mukherjee, Kiran Gireesan Vanaja, Jacob A. Boyer, Juan Qiu, Xiaoping Chen, Elisa de Stanchina, Sarat Chandarlapaty, Andre Levchenko, Neal Rosen. Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis [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 1090.
Abstract 1131: Preventive effect of Celecoxib in Sorafenib-related hand-foot syndrome in hepatocellular carcinoma patients, a single-center, open-label, randomized, controlled clinical phase III trial
Authors: CHEN JIANCONG 
Published: September 2020

Abstract
Background: Skin toxicity, especially hand-foot syndrome (HFS), is one of the most common sorafenib-induced adverse events (AEs) in hepatocellular carcinoma (HCC) patients, leading to treatment interruption and failure. Mucocutaneous inflammation may cause HFS; therefore, we investigated whether celecoxib can alleviate HFS, improve patients' quality of life and increase survival when administered in conjunction with active therapy.
Methods: Our randomized, open-label study prospectively enrolled 116 advanced HCC patients receiving sorafenib as targeted therapy from July 2015 to July 2016. All patients were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib with or without celecoxib. Sorafenib-related AEs were recorded, Survival was compared between the two groups.
Results: Compared to the Sorafenib group, the SoraCele group had lower incidence rates of ≥ grade 2 and grade 3 HFS (63.8% vs 29.3%, P &lt; 0.001; 19.0% vs 3.4%, P = 0.008, respectively), hair loss, rash and abdominal pain. Kaplan-Meier analysis revealed a lower risk of ≥ grade 2 HFS (HR, 0.384; P = 0.002) and a lower dose reduction/interruption rate (46.6% to 15.5%, P &lt; 0.001) in the SoraCele group. Cox proportional hazards regression analysis demonstrated that celecoxib was the only independent predictive factor of developing ≥ grade 2 HFS (HR, 0.414; P = 0.004). Longer progression-free survival (PFS) was also observed in the SoraCele group (P = 0.039), although overall survival was not prolonged (P = 0.305).
Conclusions: Sorafenib+Celecoxib administration alleviated sorafenib-related skin toxicity. Longer PFS was achieved in clinical practice, although overall survival was not prolonged (ClinicalTrials.gov: NCT02961998).
Keywords: hand-foot syndrome; celecoxib; sorafenib; hepatocellular carcinoma
Citation Format: JIANCONG CHEN. Preventive effect of Celecoxib in Sorafenib-related hand-foot syndrome in hepatocellular carcinoma patients, a single-center, open-label, randomized, controlled clinical phase III trial [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 1131.
Abstract 1133: Risk effect of primary prevention strategy with aspirin on lung cancer incidence depends on high-level use, bodyweight and age: A U.S. adults evidence
Authors: Dong Xuesi 
Published: September 2020

Abstract
Chemoprevention of cancer with aspirin is of particular interest as a primary prevention strategy, which was still in controversial. Using 101,462 individual participants' data from a U.S. adult's cohort, Cox regression model was used to detect the aspirin dosage effect on lung cancer risk. We calculated the effects of irregular use, low-dose use, and high-dose use of aspirin on lung cancer risk in population stratified by bodyweight and age. High-dose use of aspirin raised up 28% risk of lung cancer compared to no use (HR = 1.28, 95%CI = [1.14-1.45], P = 3.37×10-5). Meanwhile, the risk effect of high-dose aspirin significantly decreased with bodyweight increasing, indicating an antagonistic interaction (HRinteraction = 0.96, 95%CI = [0.94-0.99], P = 1.26×10-2). Furthermore, for these participants prone to lung cancer with bodyweight less than 80 kg, high-dose aspirin usage showed an elevated risk if their age less than 76 (HRage≤76 = 1.47, 95%CI = [1.25-1.73], P = 3.81×10-6), but did not exhibit risk effect in elders (HRage&gt;76 = 1.13, 95%CI = [0.46-2.69], P = 0.80). The three-way interaction among dose of aspirin, bodyweight and age indicated that these vulnerable people (age ≤76 years and bodyweight &lt;80 kg) with high lung cancer risk should be cautious to use high-dose aspirin for lung cancer chemoprevention.
Citation Format: Xuesi Dong. Risk effect of primary prevention strategy with aspirin on lung cancer incidence depends on high-level use, bodyweight and age: A U.S. adults evidence [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 1133.
Abstract 1150: Targeting PI3K inhibits ER-mammary tumor initiation and early dissemination
Authors: Zhang Yuan , Wang Jingyang , Xiao Yi , Seewaldt Victoria , Yu Dihua 
Published: September 2020

Abstract
Despite recent advances in cancer treatment, including targeted therapies and immunotherapies, many women still die of breast cancer. To ultimately reduce breast cancer death, it is of urgent need to develop more effective prevention and early intervention strategies. Although tamoxifen and aromatase inhibitors decrease incidences of estrogen receptor positive (ER+) breast cancer, there is no effective agent for prevention of ER negative (ER-) breast cancer. In this study, we identified that PI3K pathway is significantly activated in premalignant ER- breast lesions compared to paired normal tissue from breast cancer patients. We therefore tested whether blocking PI3K pathway by genetic knockdown or using a clinically applicable PI3K inhibitor (GDC0941) can inhibit ER- tumor initiation and progression. Indeed, both genetic knockdown of PI3K and low dose GDC0941 intervention reversed the disorganized three-dimensional growth of semi-transformed human ER- mammary epithelial cells in vitro. More importantly, low dose GDC0941 treatment significantly delayed the tumor initiation in MMTV-neu mouse model which develops ER-HER2+ mammary tumors. Notably, low dose GDC0941 treatment did not show discernable adverse effects, including no significant changes in body weight and liver functions, no immuno-toxicity. Since PI3K activation is crucial for early disseminated tumor cells, we collected bone marrow from treated mice versus vehicle control group, and examined the impact of GDC0941 treatment on early dissemination of tumor cells into the bone marrow. Excitingly, we found that administration of low dose GDC0941 significantly decreased CD45-ErBb2+/CK8/18+ early disseminated mammary tumor cells into the bone marrow, indicating that low dose PI3K inhibitor not only delayed primary tumor initiation but also prevented tumor cell early dissemination in the bone marrow. Taken together, these data support the notion that using low dose targeting drug to block PI3K pathway is safe and promising for ER- breast cancer prevention.
Citation Format: Yuan Zhang, Jingyang Wang, Yi Xiao, Victoria Seewaldt, Dihua Yu. Targeting PI3K inhibits ER-mammary tumor initiation and early dissemination [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 1150.
Abstract 1170: Socioeconomic disparities in patients with esophageal cancer at time of diagnosis: A national cancer data base analysis
Authors: Sadaps Meena , Mehta Neal , Wei Wei , Tullio Katherine , Bhatt Amit , Khorana Alok 
Published: September 2020

Abstract
Introduction: There have been noted to be significant gender and socioeconomic disparities in the incidence, prognosis, and clinical outcomes of patients with esophageal cancer. The purpose of this study was to characterize disparities amongst patients with esophageal cancer at time of diagnosis, as stratified by their stage, as there is a paucity of published data in this realm.
Methods: We identified patients in the National Cancer Data Base diagnosed with esophageal cancer, from 2004 to 2016 and grouped them by stage: early stage (stage I-III) and advanced stage (stage IV). These groupings were then compared based on various patient demographics and socioeconomic factors, including age, gender, insurance status, education, and income. p-values were determined by chi-square test.
Results: 102,540 patients (79.5% male; 84.0% Caucasian) were included in our analysis. There was a statistically significant increase in the diagnosis of de novo metastatic disease seen with younger age (⇐59 years), male gender, lack of insurance coverage, residential communities with lower education, and lower income (&lt;$38,000 annual income) as shown in Table 1.
Summary Table of Stage at Diagnosis by Patient CharacteristicsTotal NTotal %Stage 0-IIINStage 0-III%Stage IVNStage IV %p-valueAge⇐59298301001840361.691142738.31&lt;0.000160-74475031003244668.31505731.7&gt;=75252071001789971.01730828.99GenderFemale210701001510671.69596428.31&lt;0.0001Male814701005364265.842782834.16InsuranceUnknown2902100194967.1695332.84Government612231004204368.671918031.33&lt;0.0001Not Insured3450100184053.33161046.67Private349651002291665.541204934.46Community Median IncomeUnknown52610035567.4917132.51&lt;38K185611001221065.78635134.22&lt;0.000138-63K526941003531767.021737732.98&gt;=63K307591002086667.84989332.16Percent No High School Degree Quartiles 2012-2016Unknown142710091664.1951135.81&gt;=17.6%197021001290265.49680034.51&lt;0.000110.9-17.5%274621001845067.18901232.826.3-10.8%300291002013867.06989132.94&lt;6.3%239201001634267.053379232.95
Conclusion: Data from the National Cancer Data Base supports the association of younger age and lower socioeconomic status with higher stage at diagnosis in patients with esophageal cancer, highlighting the need for increased awareness and education in these at-risk subgroups.
Citation Format: Meena Sadaps, Neal Mehta, Wei Wei, Katherine Tullio, Amit Bhatt, Alok Khorana. Socioeconomic disparities in patients with esophageal cancer at time of diagnosis: A national cancer data base analysis [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 1170.