bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4410: Predictive model of palbociclib response reveals indications in which CDK4/6 inhibitor can be a potential combination partner
Authors: Hafner Marc , Dompe Nicholas , Zhou Wei , Lin Eva , Durrbaum Milena , Daemen Anneleen , Junttila Melissa R. , Metcalfe Ciara , Merrick Karl 
Published: August 2019

Abstract
CDK4/6 inhibitors are a promising class of targeted therapies, with three molecules (palbociclib, ribociclib, and abemaciclib) approved for advanced hormone-receptor positive (HR+) breast cancers. With hope of building on this success, clinical trials across multiple oncology indications have been initiated. The determinants of response to CDK4/6 inhibitors, beyond pRb-deficiency and Cyclin-E amplification, remain unclear as limited clinical data have been published in indications other than HR+ breast cancers. Here, we measured the response to palbociclib across a panel of tumor cell lines from multiple indications and were able to build a computational model predictive of drug response using the expression of a handful of transcripts. This model revealed cellular states that are related to palbociclib resistance, such as G1-S entry deregulation, or sensitivity, such as competent p53 pathway and high KRAS signaling.
As validation of our model, we compared its predictions with dependency scores from Project Achilles and found good correlations between predicted sensitivity and dependence on CDK4 and CCND1. By applying the predictive model on TCGA data, our analysis uncovered indications, disease subtypes, and genomic alterations that are related to the predicted response to palbociclib in addition to Rb-deficiency and Cyclin-E amplification. As expected, HR+ breast cancer was predicted to be among the most sensitive diseases, along with prostate, thyroid, and some renal cancers. Among non-small cell lung cancers, squamous-cell tumors are predicted to be more resistant than adenocarcinomas. In adenocarcinomas, BRAF and KRAS mutations are predicted to be associated with increased responsiveness. Combining these results with published biomarkers of resistance to standard of care therapies reveals indications in which CDK4/6 inhibitors can be potential combination partners. These results may guide the design of new trials for CDK4/6 therapies and the evaluation of better stratification biomarkers.
Citation Format: Marc Hafner, Nicholas Dompe, Wei Zhou, Eva Lin, Milena Durrbaum, Anneleen Daemen, Melissa R. Junttila, Ciara Metcalfe, Karl Merrick. Predictive model of palbociclib response reveals indications in which CDK4/6 inhibitor can be a potential combination partner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4410.
Abstract 4411: Identification of novel natural compounds as potential inhibitors of cyclin dependent kinases
Authors: Sankaranarayanan Ranjini , Dachineni Rakesh , Kesharwani Siddharth , Dhandapani Ramesh Kumar , Tummala Hemachand , Gunaje Jayarama B. 
Published: August 2019

Abstract
Colorectal cancer (CRC) is the second highest cause of cancer deaths in the United States according to CDC (2017). Lifestyle factors including, but not limited to, elevated Body Mass Index (BMI), obesity and diet are proposed to lead to the development of CRC with an estimated annual incidence of 95,520 cases. Increasing evidences suggest that a diet rich in fruits and vegetables will reduce incidences of colorectal adenomas. We hypothesize that the natural compounds present in fruits and vegetables, along with their metabolites generated by the gut microbiota, could be responsible for cancer prevention by targeting the cell cycle proteins. In this study, we investigated the ability of polyphenols [Epigallocatechin Gallate (EGCG), Catechin, Catechin Gallate (CG), and Epigallocatechin (EGC)] and their degradation products [Phloroglucinol; 2,4,6 Trihydroxybenzoic acid (2,4,6 THBA); 3,4 Dihydroxyhydrocinnamic acid (3,4-DHHCA); etc.] to inhibit the CDKs (that regulate cell cycle) activity. Our pilot studies show that the different catechin compounds and their degradation products are capable of inhibiting different CDKs, suggesting their potential role in cancer prevention. We are currently investigating the mechanism of inhibition of CDKs by these compounds utilizing biochemical and molecular docking studies. Elucidation of this pathway will suggest the role of polyphenols in the prevention of CRC as well as assist in the identification of novel compounds that can be used for both cancer prevention and therapy.
Citation Format: Ranjini Sankaranarayanan, Rakesh Dachineni, Siddharth Kesharwani, Ramesh Kumar Dhandapani, Hemachand Tummala, Jayarama B. Gunaje. Identification of novel natural compounds as potential inhibitors of cyclin dependent kinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4411.
Abstract 4436: Ubiquitin-specific peptidase 24 decreases c-Myc expression to inhibit lung cancer formation
Authors: Hung Jan-Jong , Chang Wen-Chang 
Published: August 2019

Abstract
Lung cancer is a malignant lung tumor characterized by high incidence and motility. c-Myc is a transcription factor that plays an important role in oncogenic activation to influence cellular metabolism and proliferation. Ubiquitin-specific peptidase 24 (USP24) is one of the members of USPs family to regulate protein ubiquitination. However, it is lack of evidence to uncover the role of USP24 in cancer formation. In this study, we found that cell proliferation was significantly increased by USP24 knockdown in A549 cells as accompanied by the increase of c-Myc protein. In particular, the RNA level and protein stability of c-Myc were not affected by USP24 knockdown, suggesting that USP24 affects c-Myc through regulating the translational pathway. Furthermore, c-Myc participated in USP24-knocked down-induced proliferation, not migration. To further clarify the mechanism underlying the regulation of c-Myc by USP24, we investigated whether mTOR pathway is involved in c-Myc upregulation by USP24 knockdown. Herein rapamycin, the mTOR inhibitor, prevented c-Myc upregulation caused by USP24 knockdown, suggesting that USP24 affect the protein level of c-Myc by regulating mTOR-mediated translation. We found that the downstream signaling of mTOR is activated by USP24 knockdown, including S6K and RPS6 phosphorylation. In addition, USP24 knockdown induced the binding of activated PRS6 to 5′-UTR of c-Myc, indicating that USP24 regulates c-Myc through mTOR-mediated translation. However, USP24 did not affect the phosphorylation of mTOR at Ser-2448, implying that other phosphorylation residue(s) within mTOR might be regulated by USP24. Since mTOR pathway is critical for many cancers formation, understanding the role of USP24 in regulating mTOR pathway will contribute to develop strategies to fight lung cancer.
Citation Format: Jan-Jong Hung, Wen-Chang Chang. Ubiquitin-specific peptidase 24 decreases c-Myc expression to inhibit lung cancer formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4436.
Abstract 4439: MLN4924, a protein neddylation inhibitor, elicits antitumor effect via suppression of angiogenesis
Authors: Kuo Kuan-Lin , Yang Shao-Ping , Liao Shih-Ming , Pu Yeong-Shiau , Huang Kuo-How 
Published: August 2019

Abstract
In the process of tumorigenesis, angiogenesis provide oxygen and nutrients for tumor progression. Anti-angiogenesis has become a promising target of cancer therapy. Cullin-RING ligases (CRLs) are a cullin scaffold RING-finger domain containing E3 and are involved in the ubiquitination of specific substrates which regulate important biological processes. The holoenzyme E3 activity of CRLs is controlled by NEDD8. A novel NEDD8-activating enzyme inhibitor, MLN4924, is reported to block the neddylation of cullins and elicits antitumor effect. MLN4924 has been reported to be assoiciated with antiangiogenesis. In this study, we aim to investigate the role of anti-angiogensis in the antitumor effect of MLN4924. Our results showed that MLN4924 induces the cell cycle arrest, apoptosis and suppresses the cell viability and migration in human umbilical vein endothelial cells (HUVECs). Moreover, MLN4924 inhibits angiogenesis in Matrigel plug assay in vivo and tube-formation assay in vitro. Anti-angiogesis was involved in the antitumor effect on human urothelial carcinoma cells (T24) and colon cancer cells in vivo xenograft model. MLN4924 suppressed the VEGF-mediated VEGFR2 downstream activation.
Note: This abstract was not presented at the meeting.
Citation Format: Kuan-Lin Kuo, Shao-Ping Yang, Shih-Ming Liao, Yeong-Shiau Pu, Kuo-How Huang. MLN4924, a protein neddylation inhibitor, elicits antitumor effect via suppression of angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4439.
Abstract 4442: CUL7 promotes cancer cell survival through promoting Caspase-8 ubiquitination
Authors: Kong Yanjie , Wang Zehua , Zhou Zhongmei , Mao Xiaoyu , Chen Ceshi 
Published: August 2019

Abstract
The Cullin 7 (CUL7) gene encodes a member of the cullin family of E3 ubiquitin ligases. Accumulated evidence suggests that CUL7 is oncogenic. However, the mechanism by which CUL7 improves cancer cell survival has not been fully elucidated. Here, we reported that CUL7 confers anti-apoptotic functions by interacting with Caspase-8. CUL7 prevents Caspase-8 activation by promoting Caspase-8 modification with non-degradative polyubiquitin chains at K215. CUL7 knockdown sensitized cancer cells to TRAIL-induced apoptosis in vitro and in nude mice. These results suggest that CUL7 limits extrinsic apoptotic signaling by promoting Caspase-8 ubiquitination.
Citation Format: Yanjie Kong, Zehua Wang, Zhongmei Zhou, Xiaoyu Mao, Ceshi Chen. CUL7 promotes cancer cell survival through promoting Caspase-8 ubiquitination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4442.
Abstract 4444: Deep learning of the immune synapse
Authors: Sidhom John-William , Pardoll Drew M. , Baras Alexander S. 
Published: August 2019

Abstract
Artificial intelligence is poised to revolutionize every aspect of human life, finding applications in everything from self-driving cars to diagnosing cancer. In fact, almost any task that involves pattern recognition can be formulated in a way that modern AI algorithms can be used to achieve super-human performance. The immune synapse is a highly complex interaction between several proteins and peptides that allows for a constant surveillance of foreign invaders. However, modeling these interactions is extremely difficult as the combinations of interactions is simply intractable. In immuno-oncology, the study of this interaction is crucial as anti-tumor responses rely on sensitive and specific recognition of tumor-specific antigens. Implications of accurately predicting and modeling these interactions in immune-oncology range from improved and potent vaccine design to biomarkers for predicting response to immunotherapy. Our group has developed a variety of deep learning models to model the signal transmission within the immune synapse. At the core of all architectures designed, convolutional layers, similar to ones used to learn features in images, are used to learn motifs within the sequencing data for a predictive or descriptive purpose.We first present AI-MHC, an applied deep convolutional neural network for class-specific MHC binding algorithm that achieves state-of-the-art performance in both Class and Class II predictions. By incorporating ‘meaning’ of the allele within the network, we are able to model the interaction of allele and peptide within the context of a neural network. We take these concepts further in the development of DeepMANA, a deep learning framework which combines sequence-specific information about an allele/peptide pairing to not only predict binding affinity for any allele with a known protein sequence but also provide an antigen ‘quality’ score, based on the “non-self/foreign-ness” of a neoantigen. We observe in three previously published immunotherapy clinical trials, these quality neoantigens are enriched in long-term survivors or responders. Finally, we present DeepTCR, a collection of unsupervised and supervised deep learning algorithms capable of revealing structure in T-cell receptor repertoire. We demonstrate that DeepTCR achieves state-of-the-art performance in clustering antigen-specific TCR’s and is capable of learning a predictive signature in TIL repertoire of mice treated with various immunotherapies.These types of AI technologies could yield an entire new area of biomarker discovery as well as improve our understanding of the complex interaction occurring at the immune synapse that is ultimately required for a successful anti-tumor response.
Citation Format: John-William Sidhom, Drew M. Pardoll, Alexander S. Baras. Deep learning of the immune synapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4444.
Abstract 446: Plasma genome sequencing identifies prostate cancer patients that are sensitive to platinum-based therapy
Authors: Ramesh Naveen , Sei Emi , Tsai Pei Ching , Logothetis Christopher , Corn Paul , Aparicio Ana , Zurita Amado J. , Navin Nicholas E. 
Published: August 2019

Abstract
Castration-resistant prostate cancer (CRPC) is a lethal disease. A subset of these patients present with atypical clinical characteristics and aggressive disease behavior. These patients, classified as Aggressive Variant Prostate Cancer (AVPC), may derive benefit from platinum-based chemotherapy. However, the identification of AVPC patients is often challenging due to heterogeneity in clinical presentations and potentially in biological drivers, which may not be fully reflected in a biopsy obtained from a single tumor site. To address these challenges, we developed an unbiased genome sequencing method called PEGASUS (Plasma Exome and Genome Analysis by Size-Selection and Unbiased Sequencing) that enables the simultaneous detection of copy number aberrations and exome mutations from circulating-tumor DNA (ctDNA). We applied this method to plasma specimens obtained from 160 CRPC patients with and without AVPC participating in a randomized trial of cabazitaxel alone or in combination with carboplatin. We were able to successfully isolate ctDNA (&gt;2 ng) for genomic profiling using PEGASUS in 91/160 (57%) CRPC patients. Among these 91 CRPC patients, we detected common prostate cancer mutations as well as genomic copy number changes in genes such as RB1, PTEN and TP53 and several other genes associated with DNA repair. One of the most salient features that distinguished the patients’ outcomes was whether they had diploid or aneuploid genomes detected by whole genome profiling of the ctDNA. Patients with aneuploid ctDNA had worse progression-free and overall survival. Overall, our data shows the feasibility of performing whole-genome and exome profiling of ctDNA in CRPC patients to characterize the molecular features associated with distinct clinical presentations. Candidate markers associated to benefit from platinum-based chemotherapy are being evaluated. These results pave the way for future clinical applications in biomarker discovery to assist treatment decisions in prostate cancer patients.
Citation Format: Naveen Ramesh, Emi Sei, Pei Ching Tsai, Christopher Logothetis, Paul Corn, Ana Aparicio, Amado J. Zurita, Nicholas E. Navin. Plasma genome sequencing identifies prostate cancer patients that are sensitive to platinum-based therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 446.
Abstract 4462: Sensitivity and reproducibility of onco-panel sequencing across multiple laboratories and technologies
Authors: Xu Joshua , Gong Binsheng , Jones Wendell , Johann Don ,   Onco-panel Working Group of the Sequencing QualityControl Phase 2 (SEQC2) Consortium
Published: August 2019

Abstract
Onco-panel sequencing targets sequencing reads to few small regions of the genome and thus is better enabled to detect of rare but clinically relevant sub-clonal mutations. Accurate diagnosis and subsequent tailoring of therapy depends on thorough characterization of tumor mutational spectra. The lack of tumor reference samples, comprehensive approaches to assessing reproducibility and detection sensitivity, and standard practice guidelines is hindering the development of onco-panel sequencing and the realization of its benefits in cancer diagnosis and treatment. As a component of the FDA-led SEQC project phase 2 (SEQC2), the Onco-panel Working Group has designed and characterized a set of reference materials. These materials were created using cell line gDNA pooling and dilution to enable such comprehensive assessments of targeted mutation detection approaches. To this end, a cross-lab evaluation of eight Pan-Cancer panels and five ctDNA liquid biopsy assays is currently underway. Each panel was tested in three independent laboratories. To further evaluate methods to boost reproducibility, synthetic spike-in controls and synthetic plasma were also incorporated into the testing samples. Contrived samples for liquid biopsy testing were prepared through enzymatic fragmentation and size selection to mimic cell-free DNA. The onco-panels tested represent two target enrichment approaches (amplicon based and capture based) and sequencing technologies (multiple Illumina platforms and Ion Torrent). Of note, the liquid biopsy assays employ various molecular barcoding techniques to improve their detection sensitivity of rare mutations. Extensive lab QC data has been collected along with sequencing data. Performance measures have been devised to evaluate reproducibility and sensitivity of the variant/mutation calling results that are produced by the panel providers. Meta-analysis of performance measures will then be conducted for cross panel comparison. This comprehensive study will yield insights into factors underpinning sensitivity and reproducibility of onco-panel sequencing. Quantitative performance metrics and actionable data analysis recommendations will be presented to the targeted sequencing panel community.
Citation Format: Joshua Xu, Binsheng Gong, Wendell Jones, Don Johann, Onco-panel Working Group of the Sequencing QualityControl Phase 2 (SEQC2) Consortium. Sensitivity and reproducibility of onco-panel sequencing across multiple laboratories and technologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4462.
Abstract 4465: The effect of insurance status on childhood and adolescent cancer survival using data from the National Cancer Database
Authors: Wang Xiaoyan , Ojha Rohit P. , Johnson Kimberly J. 
Published: August 2019

Abstract
Background
Differences in access, delivery or utilization of health care may impact childhood and adolescent cancer survival. In this study, we evaluated the impact of insurance coverage on survival among children and adolescents diagnosed with cancer, and explored potential mechanisms.
Methods
We obtained data from 58,421 individuals diagnosed with any cancer type at ≤ 19 years old from 2004-2010 from the National Cancer Database. We examined associations between insurance status at diagnosis or initial treatment and stage at diagnosis, treatment received (any vs. none), and all-cause mortality using logistic regression, Cox proportional hazards regression, restricted mean survival time and mediation analyses for all cancers combined and by cancer type. We evaluated the moderation effect of age on cancer death in association with insurance status using the likelihood-ratio test.
Results
Children and adolescents with Medicaid, unknown insurance, and those who were uninsured were more likely to be non-White, from lower income counties, be diagnosed at an advanced stage, and less likely to receive any treatment than those with private insurance. Those with Medicaid, unknown insurance, and who were uninsured had a 27% (95%CI, 1.22 to 1.33), 39% (95%CI, 1.26 to 1.53), and 32% (95%CI, 1.20 to 1.46) higher hazard of death during 5 years of follow-up versus those with private insurance. Survival at 60 months was modestly lower for these groups than those who were privately insured at 1.73 months (95%CI, -2.07 to -1.38), 2.48 months (95%CI, -3.29 to -1.68), and 2.13 months (95%CI, -2.91 to -1.34). The higher mortality risk and lower survival months in non-privately insured cases were observed for most cancer types. In mediation analyses, for Medicaid and uninsured patients, earlier diagnosis for staged cancers was estimated to reduce the survival deficit by approximately one fourth and one half. Treatment did not account for the insurance associated survival difference.
Conclusion
Enhancing existing insurance coverage and ensuring equal and early diagnosis may help to improve survival overall for children and adolescents diagnosed with cancer. Future qualitative studies are needed to understand institutional and family level barriers to diagnosis and care of children with cancer and to further explain the underlying mechanisms for differences in childhood survival by insurance status.
Citation Format: Xiaoyan Wang, Rohit P. Ojha, Kimberly J. Johnson. The effect of insurance status on childhood and adolescent cancer survival using data from the National Cancer Database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4465.