bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3354: Patterns of care for patients with non-operable T1-4 N+ M0 non-small cell lung cancer in the US and outcomes with radiation or chemotherapy monotherapies
Authors: Kim Ellen , Daly Megan E. , Westover Kenneth , Murphy James , Mitin Timur
Published: August 2019

Background Standard management of unresectable N+ M0 non-small cell lung cancer (NSCLC) is concurrent chemoradiation (CRT). However, some patients may receive only radiation therapy (RTmono) or chemotherapy (CTmono) as monotherapies. The primary aim of this study was to investigate the patterns of care in the US and analyze the outcomes achieved with monotherapies.

Methods Patients in the National Cancer Database (NCDB) diagnosed in 2004-2013 with N+ M0 NSCLC who did not undergo surgery and received monotherapy with either high dose radiation alone (RTmono) or chemotherapy alone (CTmono) were studied. Patient characteristics and overall survival (OS) were compared with descriptive statistics (chi-square, Kruskal-Wallis, logistic regression), Kaplan-Meier and stratified Cox models, and restricted mean survival times (RMST); all used alpha of 0.05.

Findings 74,867 patients received CRT (10,915, 15%), CTmono alone (34,978, 47%), RTmono (2,396, 3%), or no treatment (26,578, 36%). In a multivariable model, RTmono was associated with non-Medicare insurance, academic or research facility, Western geography, lower T and N stages, and older age. CTmono had better RMST compared to RTmono: at 3 years, average survival was 17.9 vs 16.1 months (difference 1.8, 95% CI 1.3-2.3); at 5 years, average survival was 21.6 vs 18.7 months (difference 2.9, 95% CI 2.2-3.6). In stratified Cox models, improved survival was associated with female gender, White race, private insurance, metropolitan location, lower Charlson comorbidity score, lower T and N stage, smaller tumor, younger age, and later year of diagnosis.

Interpretation Despite the established benefits of CRT, only 15% of non-operable N+ M0 NSCLC US patients received definitive CRT. Future clinical studies should focus on patients not receiving concurrent CRT, as outcomes with monotherapies (RTmono or CTmono) are suboptimal.

Note: This abstract was not presented at the meeting.

Citation Format: Ellen Kim, Megan E. Daly, Kenneth Westover, James Murphy, Timur Mitin. Patterns of care for patients with non-operable T1-4 N+ M0 non-small cell lung cancer in the US and outcomes with radiation or chemotherapy monotherapies [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 3354.
Abstract 3357: The fibrolamellar registry: A model for the study of rare diseases
Authors: Desmond Michelle , Latone Julie , Lett Siobhan , Migler Rachael D. , Simon Elana P. , Simon Sanford M.
Published: August 2019

Advances in genomics and proteomics have enabled more precise characterizations of tumors with the consequence that many cancers are being segregated into smaller categories. With this larger number of categories, more cancers are being categorized as rare. The downside to such categorizations is that the reduced numbers of patients in each category makes it difficult to gather enough information about each cancer. We are a group of patients and caregivers who have joined together to form a repository for patient-shared data and reports in an IRB-approved, non-profit medical registry for the rare and usually lethal childhood liver cancer, fibrolamellar hepatocellular carcinoma (FLC). Since the Fibrolamellar Registry is patient-run and patient-owned, we have the trust of the patient community that the records will not be sold for profit. This has enabled us, in our first two years, to gather detailed medical records, scans and tests from over 140 patients. With input from scientists and clinicians who study FLC, we have written 600 questions of specific interest to this disease. Most of our patients have also opted to allow these medical records to be shared with a tissue FLC repository that already has samples from 110 patients. We have initiated two different collaborations with the clinical-research community to explore the records and our patients have been answering additional questions when pertinent to a particular study. Our ability to gather so many records for what is a rare cancer comes from our ability to involve patients from across institutions and across the globe. We are working with other patient groups and we feel that the Fibrolamellar Registry could be a model for gathering and organizing data for many rare diseases.

Citation Format: Michelle Desmond, Julie Latone, Siobhan Lett, Rachael D. Migler, Elana P. Simon, Sanford M. Simon. The fibrolamellar registry: A model for the study of rare diseases [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 3357.
Abstract 3368: Prevalence and significance of drug-drug interactions among patients with lung cancer
Authors: Rashdan Sawsan , Yang Hui , Le Tri , Hsieh David , Alvarez Carlos A. , Gerber David
Published: August 2019

IMPORTANCE: Significant drug-drug interactions may exclude patients from clinical trials and complicate routine clinical care. Prevalence and significance of drug-drug interaction (DDI) among cancer populations is unknown.

OBJECTIVE: To determine the rate of all potential drug interactions as well as the rate of major DDIs among individuals newly diagnosed with lung cancer in a national cohort.

DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cross-sectional study of adult patients in the United States Veterans’ Affairs (VA) medical system diagnosed with lung cancer between 2003 and 2016. Data were obtained from the VA Corporate Data Warehouse. Lists and categorization of potential DDIs were obtained from the Flockhart table provided by Indiana University School of Medicine. A list of commonly prohibited medications that are associated with major DDI, was determined after 11 clinical trials protocols of tyrosine kinase inhibitors in lung cancer treatment were reviewed.

MAIN OUTCOMES AND MEASURES: The primary endpoint was the prevalence of exposure to all potential DDI during the three months leading up to and including the date of lung cancer diagnosis. The secondary endpoint was the prevalence of exposure to major DDIs (prohibited medications).

RESULTS: Overall, 280 068 patients were included in the study. Mean age was 70 years, 98% were male, and 72% were white. Overall, 55.9% of patients were prescribed medications associated with potential DDI, and 5.1% of patients were prescribed medications with major DDIs that would be prohibited in

certain clinical trials. Among the 20 most commonly prescribed drugs associated with potential DDI, only two (gemfibrozil and phenytoin) were associated with major DDI.

CONCLUSIONS AND RELEVANCE: Medications with potential DDI are commonly prescribed to patients with lung cancer. However, only about 5% of patients are prescribed medications with major DDIs that would be prohibited in certain clinical trials. Further studies to determine the true clinical risk of all potential DDIs are warranted.

Note: This abstract was not presented at the meeting.

Citation Format: Sawsan Rashdan, Hui Yang, Tri Le, David Hsieh, Carlos A. Alvarez, David Gerber. Prevalence and significance of drug-drug interactions among patients with lung cancer [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 3368.
Abstract 3374: Assessing the impact of neoantigen load on checkpoint blockade efficacy
Authors: Kosaloglu-Yalcin Zeynep , Frentzen Angela , Premlal Ashmitaa Logandha Ramamoorthy , Greenbaum Jason , Sette Alessandro , Peters Bjoern
Published: August 2019

Mutations acquired during oncogenesis can result in so-called neoantigens, i.e. mutation-bearing peptides that have the potential to be bound by HLA molecules and recognized by T cells. Neoantigens were suggested to be crucial for the outcome of immune checkpoint therapies and accordingly, the neoantigen load of a tumor is often being used to predict therapy outcome. Current approaches utilize HLA binding predictions to rank peptides, assuming that neoepitopes are ranked towards the top. The neoantigen load of a given tumor is then usually defined as the number of peptides binding above a certain threshold. Using this approach some reports found a very strong correlation of neoantigen load and response to checkpoint blockade therapy while others found a better correlation when mutational load was used instead. However, comparing results between studies is hard because they used different tools and thresholds to identify mutations, and applied different criteria to prioritize their set of mutated peptides. We sought to overcome this lack of uniformity in re-analyzing data from several published checkpoint blockade therapy studies to consistently define the mutational burden and neoantigen load, and correlate them with therapy outcomes

We obtained sequencing data from checkpoint blockade studies deposited in NCBI dbGaP and run all datasets through our in-house mapping and variant calling pipelines. Neoepitope candidates were predicted and scored using our previously published pipeline. We applied different scoring schemes to define the neoantigen load which were based on HLA binding predictions with varying thresholds and different metrics used (i.e. predicted IC50 vs. percentile rank). We found that the exact definition of neoantigen load has a major impact on how well this metric performs in predicting checkpoint blockade therapy outcome. Furthermore, we implemented a likelihood score which is based on data of known immunogenic neoantigens and describes the likelihood of a predicted neoantigen to be immunogenic. Based on our preliminary analysis to date, we found that the cumulative likelihood score of a patient is a good predictor of checkpoint blockade therapy outcome, outperforming tumor mutational burden and predicted neoantigen load in several cohorts.

Citation Format: Zeynep Kosaloglu-Yalcin, Angela Frentzen, Ashmitaa Logandha Ramamoorthy Premlal, Jason Greenbaum, Alessandro Sette, Bjoern Peters. Assessing the impact of neoantigen load on checkpoint blockade efficacy [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 3374.
Abstract 3375: leveraging protein dynamics to identify mutational hotspot communities in cancer driver genes
Authors: Kumar Sushant , Clarke Declan , Gerstein Mark
Published: August 2019

Large-scale exome sequencing of tumor genomes has enabled the identification of cancer driver genes using recurrence analysis and clustering-based approaches. Some of these methods also employ 3D protein structural data to identify missense mutational hotspots in many cancer-associated genes. However, in determining such mutational clusters in protein structures, a majority of these approaches overlook the role of protein dynamics. In this work, we present a novel framework to identify cancer driver genes using a more sensitive search of mutational hotspot communities on protein structures by incorporating models of protein dynamics. We applied our method to the TCGA pan-cancer atlas missense mutation catalog to identify cancer genes with hotspot mutational clusters within their associated PDB structures. Overall, our analysis predicts one or more mutational hotspot within the resolved structures of known as well as novel cancer driver genes. Ontological enrichment analysis implicates the roles of genes with predicted hotspots in vital biological processes, including cell differentiation, cell proliferation, signal transduction, kinase activity, and nucleotide binding. Furthermore, a comparison between our approach with previous 3D structure-based cancer hotspot detection methods suggests that the including protein dynamics significantly improves the identification of additional putative driver genes. In summary, our proposed framework predicts novel cancer driver genes and provides mechanistic insight into cancer progression through the lens mutational hotspots.

Citation Format: Sushant Kumar, Declan Clarke, Mark Gerstein. leveraging protein dynamics to identify mutational hotspot communities in cancer driver genes [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 3375.
Abstract 3384: Genome-wide epigenetic and transcriptional comparison of CD8 T cell functional states between mouse models of cancer and chronic viral infection
Authors: Pritykin Yuri , Leslie Christina
Published: August 2019

Recent studies in mouse models of cancer and chronic viral infection applied genomic assays to profile various states of impaired T cell function and demonstrated that T cell dysfunction is epigenetically imprinted. However, comprehensive characterization of T cell dysfunction across models based on their epigenetic and transcriptional profiles is lacking. We reanalyzed a large collection of recently published chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) data sets. After batch effect correction, we observed that epigenetic profiles of dysfunctional tumor-infiltrating T cells and exhausted T cells in chronic viral infection were surprisingly extremely similar. Furthermore, we observed that temporal progression towards dysfunction in chronic infection resembles that in tumorigenesis, and found that T cells committed to becoming dysfunctional early after activation. Motif analysis using generalized linear modeling allowed us to find candidate transcription factors associated with development of dysfunction in both immune settings. This analysis provides a better systematic understanding of cell-intrinsic mechanisms driving different functional states of CD8 T cells and demonstrates the power of systems biology approaches in cancer immunology.

Citation Format: Yuri Pritykin, Christina Leslie. Genome-wide epigenetic and transcriptional comparison of CD8 T cell functional states between mouse models of cancer and chronic viral infection [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 3384.
Abstract 3389: Analysis of the hepatocellular carcinoma transcriptome reveals dysregulation in pathways implicated in immunotherapy efficacy
Authors: Li Wei Tse , Honda Christine O. , Qu Yuanhao , Honda Thomas K. , Saad Omar A. , Wang-Rodriguez Jessica , Ongkeko Weg M.
Published: August 2019

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality in the world, but current treatment options are very limited in efficacy for patients who are diagnosed late, which often occurs because of limitations in current screening methods. Immunotherapy has emerged in recent years as arguably the most effective treatment for advanced HCC, but the failure of a large percentage of patients to respond to immunotherapy remains the ultimate obstacle to successful treatment. A phase I clinical trial with CTLA-4 checkpoint blockade has only achieved a 17.6% partial response rate in patients with advanced HCC, while another clinical trial using the PD-1 checkpoint inhibitor nivolumab has reported 18% partial response. Etiology-associated dysregulation of immune-associated (IA) genes may be able to explain the development of this differential clinical response. Using large-scale RNA-sequencing data from The Cancer Genome Atlas (TCGA), we identified immune-associated genes potentially dysregulated by alcohol or viral hepatitis B in HCC. Thirty-four dysregulated IA genes exhibiting significant correlation of gene expression to survival data and clinical variables were identified. To investigate the molecular mechanism for their dysregulation and explore the possibility of genome-based patient stratification, we profiled the correlation of all genomic alterations in HCC patients to IA gene expression using the information theory-based algorithm REVEALER. We also studied gene expression regulators and identified multiple microRNAs implicated in HCC pathogenesis that can potentially regulate these IA genes’ expression. Finally, we validated the dysregulation of several genes by alcohol, including the downregulation of NDRG2 and SOCS2, in vitro using HCC cell lines. Our study identified several potentially key pathways, including the IL-7 pathway, TNFRSF4 (OX40)- NF-κB pathway, and IL-10 pathway, that may be targeted in HCC immunotherapy treatments as well as possible sources of dysregulation for pathways known to be implicated in HCC immunotherapy efficacy. Lastly, we present microRNAs as promising therapeutic targets for dysregulated IA genes because of their extensive regulatory roles in the cancer immune landscape.

Citation Format: Wei Tse Li, Christine O. Honda, Yuanhao Qu, Thomas K. Honda, Omar A. Saad, Jessica Wang-Rodriguez, Weg M. Ongkeko. Analysis of the hepatocellular carcinoma transcriptome reveals dysregulation in pathways implicated in immunotherapy efficacy [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 3389.
Abstract 3391: Dissecting intratumoral cell-cell interactions in myeloid reprogramming by single cell RNA-seq
Authors: Song Qianqian , Hawkins Gregory A. , Wudel Leonard , Chou Ping-Chieh , Forbes Elizabeth , Pullikuth Ashok K. , Liu Liang , Jin Guangxu , Craddock Lou , Topaloglu Umit , Kucera Gregory , O’Neill Stacey , Levine Edward A. , Sun Peiqing , Watabe Kounosuke , Lu Yong , Alexander-Miller Martha A. , Pasche Boris , Miller Lance D. , Zhang Wei
Published: August 2019

Tumor-infiltrating myeloid cells are the most abundant leukocyte population within tumors. Molecular cues from the tumor microenvironment promote the differentiation of immature myeloid cells toward an immunosuppressive phenotype. However, the in situ dynamics of the transcriptional reprogramming underlying this process are poorly understood. Therefore, we applied single cell RNA-seq (scRNAseq) to computationally investigate the cellular composition and transcriptional dynamics of tumor and adjacent normal tissues from 4 early-stage non-small cell lung cancer (NSCLC) patients. Our scRNA-seq analyses identified 11,485 cells that varied in identity and gene expression traits between normal and tumor tissues. Among these, myeloid cell populations exhibited the most diverse changes between tumor and normal tissues, consistent with tumor-mediated reprogramming. Through trajectory analysis, we identified a differentiation path from CD14+ monocytes to M2 macrophages (monocyte-to-M2). This differentiation path was reproducible across patients, accompanied by increased expression of genes (e.g. MRC1/CD206, MSR1/CD204, PPARG, TREM2) with significantly enriched functions (Oxidative phosphorylation and P53 pathway) and decreased expression of genes (e.g. CXCL2, IL1B) with significantly enriched functions (TNFa signaling via NF-kB and inflammatory response). Our analysis further identified a co-regulatory network implicating upstream transcription factors (JUN, NFKBIA) in monocyte-to-M2 differentiation, and activated ligand-receptor interactions (e.g. SFTPA1-TLR2, ICAM1-ITGAM) suggesting intratumoral mechanisms whereby epithelial cells stimulate monocyte-to-M2 differentiation. Overall, our analysis identified the prevalent monocyte-to-M2 differentiation in NSCLC, accompanied by an intricate transcriptional reprogramming mediated by specific transcriptional activators and intercellular crosstalk involving ligand-receptor interactions.

Citation Format: Qianqian Song, Gregory A. Hawkins, Leonard Wudel, Ping-Chieh Chou, Elizabeth Forbes, Ashok K. Pullikuth, Liang Liu, Guangxu Jin, Lou Craddock, Umit Topaloglu, Gregory Kucera, Stacey O’Neill, Edward A. Levine, Peiqing Sun, Kounosuke Watabe, Yong Lu, Martha A. Alexander-Miller, Boris Pasche, Lance D. Miller, Wei Zhang. Dissecting intratumoral cell-cell interactions in myeloid reprogramming by single cell RNA-seq [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 3391.
Abstract 3398: Interaction of STAT proteins with genistein: A computational analysis
Authors: Govardhanagiri Sneha , Bethi Shipra Reddy , Saddala Madhu Sudhana , El-Rayes Bassel F. , Nagaraju Ganji Purnachandra
Published: August 2019

Background: Signal transducer and activator of transcription (STAT) proteins are a seven-member family of cytoplasmic proteins. A conserved SH2 domain facilitates STAT initiation by allowing binding to phosphotyrosine motifs for STAT-receptor interactions and STAT dimerization. STAT proteins (STAT1, STAT2 and STAT3) are promising targets for anti-cancer drugs, because irregular facilitation of STAT initiation may result in cancer, inflammation and auto-immunity.

Methods: The crystal structure of the phosphotyrosine STAT1 and STAT3 dimers bound to DNA was obtained from a protein data bank (PDB), while STAT2 was modelled through Swiss-Model workspace by using 1YVL as a template. The stereochemical quality and integrity of STAT2 was tested by RAMPAGE server, ERRAT, ProSA, and Verify3D programs. The active sites were predicted using CASTp 3.0 with a new algorithm, which identifies and measures surface accessible pockets and interior inaccessible cavities on STAT1, STAT2, and STAT3. MD (molecular dynamics) simulation was conducted with STAT2 protein. Molecular Docking was used to predict the binding modes and approximate binding free energies of genistein to STAT1, STAT2 and STAT3 SH2 dimerization sites. Genistein was docked into the active site with AutoDock Vina in PyRx Virtual Screening tool.

Results: Genistein showed best binding energies. The most successful binding energies were -5.6 (STAT1), -6.7 (STAT2), -6.3 (STAT3) kcal/mol respectively. The binding interactions of this compound with the active site of STAT proteins suggested that amino acid residues (Tyr631, Leu639, Tyr640, Glu643, His647, Met648, Gln649, Ile659, Met660 and LYS16) play a crucial role in anti-cancer activity.

Conclusion: These observations increase the understanding of the functional role of STAT proteins in cancer and allow better development for additional druggable STAT inhibitors with high potency, specificity and outstanding bioavailability.

Citation Format: Sneha Govardhanagiri, Shipra Reddy Bethi, Madhu Sudhana Saddala, Bassel F. El-Rayes, Ganji Purnachandra Nagaraju. Interaction of STAT proteins with genistein: A computational analysis [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 3398.
Abstract 340: Development of high affinity anti-CLDN18.2 antibody to treat gastric cancers
Authors: Zhou Zhenhao
Published: August 2019

Claudins are tight junction proteins that regulate epithelial-cell barrier function and polarity. Gastric lineage-specific isoform 2 of CLDN18 (CLDN18.2) has been proposed as therapy target in primary/metastatic gastric cancers and CLDN18.2-ectopically-activated cancers, such as pancreatic, esophageal and lung adenocarcinomas. As demonstrated by Zolbetuximab, a monoclonal chimeric antibody directing CLDN18.2, the median overall survival was prolonged to 16.7 months when treated with Zolbetuximab+EOX (OS of EOX group: 9.0 months) in pre-screened CLDN18.2 highly expressing patients (2+/3+ staining in ≥70% tumor cells). Expression of CLDN18.2 in gastric tumors in Chinese population, however, showed diverse levels of frequency with low-frequency expression in a significant portion of tumor cells. Antibody of high affinity is expected to have advantage in targeting antigen of low-frequency, thus clearing tiny lesions clinically. We developed a high affinity anti-CLDN18.2 antibody, GB7004-09. GB7004-09 binded to human/mouse CLDN18.2 while sparing CLDN18.1. It displayed significantly better binding/ADCC/CDC potency against CLDN18.2 expressing tumor cells comparing to leading clinical drug entity. And its in vitro superiority translated to greater in vivo efficacy. Humanization version of GB7004-09, GB7004-09hu15, has been put into preliminary toxicity and PK study. As we are observing safety, stability and activity of GB7004-09hu15, GB7004-09hu15 is a promising agent for extended clinical exploration in cancer indications mention above

Citation Format: Zhenhao Zhou. Development of high affinity anti-CLDN18.2 antibody to treat gastric cancers [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 340.
Abstract 3413: CRIPAK genomic alterations are associated with indolent lung adenocarcinoma and predicts longer survival
Authors: Qian Jun , Chen Heidi , Zou Yong , Massion Pierre
Published: August 2019

Background: Multiple lung screening studies have shown a beneficial reduction in cancers specific mortality with annual low-dose computed tomography (LDCT) screening in high risk patients and resulted in a much improved probability of early stage disease at diagnosis. Nonetheless, still ~30% of such patients have a recurrence within 5 years following surgical resection. This begs the question what are the molecular determinants of cancer behavior between indolent and aggressive tumors.

Methods: A targeted deep sequencing was performed on the DNA samples of 21 adenocarcinoma in situ (AIS), 27 minimally invasive adenocarcinoma (MIA) and 54 fully invasive adenocarcinoma. These cancers were classified based on the tumor size (1.5 cm) as indolent (n=42) and aggressive (n=60) tumors. We analyzed the association between tumor aggressiveness and genomic alterations of these targeted genes including frequency of gene mutations, copy number changes, mutation signatures, tumor clonality as well as overall survival.

Results: Copy number loss of CRIPAK (chr4p16) and copy number gain of NOTCH1 were enriched in indolent tumors and chromosome 19q13 deletion was enriched in aggressive tumors. CRIPAK alterations including both mutations and copy number loss together were further significantly enriched in a subset of indolent tumors (16/25) that only consists of AIS/MIA. CRIPAK alterations were associated with longer survival in all population, after adjusting for histology and age (P=0.02). Interestingly, we found higher CRIPAK mRNA level was also significantly associated with better survival in a combined seven public lung adcarcinoma datasets (n=673, HR=0.37, P=1.1e-05), after adjusting for stage, gender and smoking history. In addition, both APOBEC and MMR mutation signatures were correlated with indolent tumors. Known driver genes such as KRAS, EGFR or TP53 mutations were not distinct between indolent and aggressive tumors, indicating an early role for these genes in the development of lung adenocarcinoma. Finally, we found that mutations of NCOR1, USP9X and NF1 were enriched in indolent tumors while mutations in GNAS and ATM were enriched in aggressive tumors.

Conclusion: Our study suggests the genomic alterations of the chromosome 4p16 harboring a novel cancer gene CRIPAK’s deletions and mutations are predictive of indolent behavior, a finding that warrants further validation. This work was supported by UO1CA196405.

Citation Format: Jun Qian, Heidi Chen, Yong Zou, Pierre Massion. CRIPAK genomic alterations are associated with indolent lung adenocarcinoma and predicts longer survival [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 3413.
Abstract 3419: Sex, mutations, and mortality in early stage melanoma
Authors: Schwartz Matthew R. , Luo Li , Berwick Marianne
Published: August 2019

Our goal is to investigate the relationship between sex, tumor mutation burden (TMB) and survival in untreated primary melanoma tumors, using data collected in an ongoing large P01 study on the Integration of Clinical and Molecular Biomarkers for Melanoma Survival (InterMEL). Here we present preliminary findings on sex, survival, and somatic TMB from 60 Stage II and Stage III primary melanoma tumors, none of which have received immunotherapy using the MSK IMPACT™ next generation sequencing assay. Our preliminary analysis includes 30 patients who died within 5 years (median survival of 31 months) and 30 patients who lived for more than 5 years since diagnosis (median follow-up of 86 months). We found the expected relationship between TMB and better survival in a univariate Cox regression analysis (HR=0.43, 95% CI=0.19 to 0.97, P=0.04), but no evidence of association between TMB and sex (Wilcoxon rank-sum test P=0.7) or any relationship between sex and survival (logrank test P=0.42).

Our study is the first to investigate the relationship between sex, tumor mutational burden, and mortality in an early stage primary cohort that has not received immunotherapy. In our small sample, we observed the expected protective effect of TMB on survival, but no evidence of gender differences in TMB or survival. This is surprising given the robust, consistent, and well-documented female survival advantage (Roh et al., 2015; de Vries et al., 2008), and merits further investigation. Our results are an important first step to increasing our understanding of the relationship between mutational burden, survival, and biological sex.

References

Roh, M.R., Eliades, P., Gupta, S., Grant-Kels, J.M., and Tsao, H. (2015). Cutaneous melanoma in women. Int. J. Womens Dermatol. 1, 21–25.

de Vries, E., Nijsten, T.E.C., Visser, O., Bastiaannet, E., van Hattem, S., Janssen-Heijnen, M.L., and Coebergh, J.-W.W. (2008). Superior survival of females among 10

538 Dutch melanoma patients is independent of Breslow thickness, histologic type and tumor site. Ann. Oncol. 19, 583–589.

Citation Format: Matthew R. Schwartz, Li Luo, Marianne Berwick. Sex, mutations, and mortality in early stage melanoma [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 3419.
Abstract 3423: HER2 amplification and microsatellite status distribution in Chinese gastric cancer patients
Authors: Guo Jun , Jiang Da , Zhang Wei , Deng Ting , Niu Zhaojian , Chen Wenting , Shi Junping , Zhang Shuirong , Zhang Lin
Published: August 2019

Background:Amplification and/or overexpression of human epidermal growth factor receptor-2 (HER2, also known as ERBB2) were present in 6.1-23.0% of gastric cancer. In breast cancer, amplification and overexpression of the HER2 are associated with poor prognosis. Meanwhile, MSI-H patients have an improved prognosis in gastric cancer. However, little is known about the association of these two indicators in gastric cancer.

Method:260 tumor tissues and matched normal from gastric cancer patients were included in this study to reveal HER2 amplification and microsatellite status distribution of Chinese patients with gastric cancer using deep next generation sequencing (NGS) targeting 450 cancer genes. Microsatellite status (MSS or MSI-H) were evaluated according to NGS algorithms.

Result:Male to female ratio was about 2:1 with a mean age of 60 years old. 241 tumors were primary tumors and 19 were metastases. MSI-H was detected in 16 samples (6.2%) and HER2 amplification was detected in 18 samples (6.9%), which were consistent with the previously reported incidences. The proportion of MSI-H in metastatic lesions was higher than that in primary lesions, but the difference was not statistically significant (10.5% vs. 5.8%, P=0.33). The detection of HER2 amplification in metastatic foci and primary tumors had a similar trend as that in MSI-H (15.8% for metastatic foci vs. 6.2% for primary tumors, P=0.13). Interestingly, our study revealed that HER2 amplification was mutually exclusive with MSI-H in both primary and metastatic lesions. MSI-H/HER2amp-, MSS/HER2amp+, and MSS/HER2amp- subgroups accounted for 5.8%, 6.2%, and 88% in primary cancers, while MSI-H/HER2amp-, MSS/HER2amp+ and MSS/HER2amp- subgroups accounted for 10.5%, 15.8% and 73.7% in metastasis, respectively.

Conclusion:We analyzed the distribution of HER2 amplifications and microsatellite status in Chinese patients with gastric cancer. The detection rate of HER2 amplifications and MSI-H was consistent with previous reports. Interestingly, our data showed that both HER2 amplifications and MSI-H have higher detection rate in metastases than that in primary lesions, and the two biomarkers were mutual exclusive in our cohort.

Citation Format: Jun Guo, Da Jiang, Wei Zhang, Ting Deng, Zhaojian Niu, Wenting Chen, Junping Shi, Shuirong Zhang, Lin Zhang. HER2 amplification and microsatellite status distribution in Chinese gastric cancer patients [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 3423.
Abstract 3424: Consensus molecular subtype of triple negative breast cancer to implicate in chemotherapy response
Authors: Kim Jihyun , Yu Doyeong , Noh Jiyoon , Jang Wooyeong , Yang Hanna , Kwon Youngmee , Lee Keun Seok , Sim Sung Hoon , Kong Sun-Young , Park In Hae , Park Charny
Published: August 2019

Objective: The heterogeneity of triple negative breast cancer (TNBC) confers the difficulties in chemotherapy and induces poor outcome. Subtype classification of TNBC using gene expression profile could achieve to identify molecular markers to suggest therapeutic guidance.

Methods: In this study, we collected gene expression profiles of 957 TNBC patients from GEO and integrated into one meta-data using meta analysis. We identified subtypes using nonnegative matrix factorization (NMF) and explored for comprehensive characteristics of consensus molecular subtype (CMS) by investigating key pathway activity, tumor microenvironment, stemness and so on. In addition, we computed the drug response score (DRscore) from MSigDB chemical perturbation signature gene set and examined drug associations with key pathways of CMS. Drug candidates were validated from independent two data sets; our patients’ expression profile (n = 38) and biobank TNBC organoids (n=64).

Results: We classified four different TNBC subtypes displaying gene expression patterns including mesenchymal-like (MSL), luminal-AR (LAR), immunomodulatory (IM), and stem-like (SL). MSL were activated pathways with epithelial-to-mesenchymal (EMT) and TGF-beta signaling whereas SL was up-regulation of cell cycle and WNT signaling pathway. The LAR subtype was activated of androgen and estrogen receptor pathway. Although metastatic TNBC generally shared equal activity of key pathways with primary, coagulation, toll-like receptors, TNF, and Jak-STAT signaling pathways were dysregulated in metastasis. Especially, SPP1 gene expression to induce metastasis was associated with poor prognosis. DRscores were discriminative in CMS of meta-data and biobank expression profile. We found subtype-specific 18 drugs as therapeutic candidates and these drugs were also correlated with key pathways. In a case of cisplatin, DRscores appear resistant in MSL while response in SL. Our patients’ expression profiles were shown to consistent result as well as biobank.

Conclusion: These finding might facilitate understanding heterogeneity of TNBC. Our novel approach to explore drug response suggested functional intervention landscape of drug

response without in-vivo experiment. Taken together, we propose biomarkers for diagnosis and also suggest therapeutic strategy depending on CMS.

Citation Format: Jihyun Kim, Doyeong Yu, Jiyoon Noh, Wooyeong Jang, Hanna Yang, Youngmee Kwon, Keun Seok Lee, Sung Hoon Sim, Sun-Young Kong, In Hae Park, Charny Park. Consensus molecular subtype of triple negative breast cancer to implicate in chemotherapy response [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 3424.
Abstract 343: A potent and selective cfms inhibitor EI-1071 inhibits CSF1R signaling and regulates the tumor-associated macrophages
Authors: Chen Hung-Kai , Hsiao Huey-Wen , Lu Li-Ming , Hsiao Chih-Lun , Wang Yin-Ping , Huang Jing-Yi , Liao Chu-Bin , Peng Shao-Zheng , Shih Daw-Tsun
Published: August 2019

We have found that tumor-associated macrophages (TAMs) isolated from metastatic tumors displayed a predominant M2 phenotype. Preclinical studies show that M2-polarized TAMs forge an immunosuppressive microenvironment at metastatic niches to facilitate colonization. Colony-stimulating factor 1 receptor (CSF-1R) signaling is known to regulate the survival and maintenance of M2 TAMs, suggesting targeting CSF-1R might have therapeutic potential in halting cancer progression. To this end, we developed an orally active and selective small-molecule CSF-1R inhibitor EI-1071.

Experimental procedures: EI-1071 was evaluated in kinase and cell-based bioassays, including macrophage proliferation and osteoclast differentiation. In vivo activity was verified using murine syngeneic models of colorectal cancer and breast cancer. EI-1071 was administered individually or in combination with an anti-PD1 antibody. Tumor infiltrating leucocytes were profiled using flow cytometric analysis.

Results: EI-1071 exhibited nanomolar potency for inhibition of CSF-1R but not other 453 kinases tested. In cell-based bioassays, EI-1071 inhibited CSF-1R activity in human monocytes/macrophages, AML-5 leukemia, MNFS-60 leukemia, and human osteoclasts. In preclinical studies, EI-1071 displayed a favorable ADME properties, including hepatocyte stability, high Caco-2 permeability, and pharmacokinetic profiles. Oral administration of EI-1071 reduced TAM infiltration in the MC38 colorectal cancer and EMT6 breast cancer models. Moreover, EI-1071 dosed with an anti-PD-1 antibody showed further enhanced antitumor activity in vivo .

Conclusions: Preclinical characterization of EI-1071 demonstrated that it is a potent and selective CSF-1R inhibitor and has a favorable drug like properties for further clinical evaluation. Therefore, EI-1071 is undergoing IND-enabling activities for the First-In-Human (FIH) Phase 1 study.

Citation Format: Hung-Kai Chen, Huey-Wen Hsiao, Li-Ming Lu, Chih-Lun Hsiao, Yin-Ping Wang, Jing-Yi Huang, Chu-Bin Liao, Shao-Zheng Peng, Daw-Tsun Shih. A potent and selective cfms inhibitor EI-1071 inhibits CSF1R signaling and regulates the tumor-associated macrophages [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 343.
Abstract 3430: TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling
Authors: Nyati Shyam , Gregg Brandon , Xu Jiaqi , Young Grant , Kimmel Lauren , Mukesh Nyati , Ray Dipankar , Yu Hongtao , Rehemtulla Alnawaz
Published: August 2019

The Ser/Thr kinase BUB1 (budding uninhibited by benzimidazoles-1) is required for efficient signaling by the TGF-β receptor. Recruitment of BUB1 to the activated heteromeric TGF-β-receptor complex including SMAD2 and SMAD3, is required for ligand mediated canonical and non-canonical downstream cascades (Nyati et. al. 2015). In an effort to delineate the structure-function basis for this, we utilized in vitro kinase reactions followed by mass spectrometry to demonstrate that TGFBR2 phosphorylates BUB1 at Serine 318. To elucidate the functional significance of TGFBR2 mediated phosphorylation of BUB1, S318 was substituted with alanine (S318A) or aspartic acid (S318D). Co-immunoprecipitation studies of these phospho-deficient or phospho-mimicking BUB1 mutants with TGFBR1, and SMAD2 revealed that the S318A mutant interacted more efficiently to TGFBR1 and SMAD2 compared to the S318D BUB1. To investigate if the Ser318 residue was involved in mediating BUB1 interaction with TGF-β signaling components, we utilized deletion mutants of BUB1. Our findings reveal that the N-terminal (1-241) and C-terminal (482-723) domains of BUB1 independently interact with SMAD2, SMAD3, TGFBR1, or TGFBR2. The middle domain (241-482) having a S318A mutation interacted efficiently with TGFBR2 while the S318D mutant did not. Additionally, the 241-482 S318D mutant exhibited an increased interaction with SMAD2. Over-expression of 241-482 S318D resulted in a decrease in TGFBR1-TGFBR2 interaction as well as TGFBR1-SMAD2 interaction, suggesting that TGFBR2 mediated BUB1 phosphorylation at S318 maybe the trigger for the dissociation of the activated receptor complex, and therefore a key regulator of TGF-β signaling. Taken together, we show that TGFBR2 phosphorylates BUB1 at Ser318 and propose a model with the following steps: (i) BUB1 is recruited to TGFBR1-TGFBR2 complex in response to ligand, (ii) BUB1 participates in the recruitment of SMAD2/3 to the receptor, (iii) TGFBR2 phosphorylates BUB1 at S318, which triggers the disassembly of the activated complex.

Citation Format: Shyam Nyati, Brandon Gregg, Jiaqi Xu, Grant Young, Lauren Kimmel, Nyati Mukesh, Dipankar Ray, Hongtao Yu, Alnawaz Rehemtulla. TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling [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 3430.
Abstract 3433: IL11 promotes the PhIP/DSS-induced colon carcinogenesis
Authors: Wang Hong , Wang David , Sun Yuhai , Yang Xu , Yang Chung S.
Published: August 2019

Inflammation of the large intestine, such as colitis, is known to increase the risk of colorectal cancer in human. The colitis induced by dextran sodium sulfite (DSS) has been shown to promote carcinogen- and genetic-induced colon tumorigenesis in rodent models. In a CYP1A-humanized (hCYP1A) mouse colon cancer model that we developed to study dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), DSS-induced colitis was required for colon tumor development after the PhIP treatment. Nevertheless, the mechanism for DSS-induced colitis to promote carcinogenesis is not clear. To uncover the key cancer promotion factor induced by colitis is important in understanding the mechanism of colon cancer development. By investigating the gene expression profiles of PhIP/DSS-induced colon tumors and normal colon epithelium, we found that cytokine IL11 was significantly upregulated in all tumors. The elevated levels of IL11 are also found in the human colon cancer genomic data available in The Cancer Genome Atlas (TCGA), suggesting an important role of IL11 in human colon cancer. Consistently, the activation/phosphorylation of STAT3, a key downstream factor of IL11 signaling, was also positively identified in tumors but not the normal adjacent tissues. To investigate the role of IL11 signaling, we generated hCYP1A:IL11Rα1-/- mice for investigating the role of IL11 signaling in PhIP/DSS-induced carcinogenesis by crossing the IL11Rα1-/- mice with hCYP1A mice. These mice are infertile as the phenotype reported previously for the IL11Rα1 knockout mice, and need to be maintained through the breeding by the heterozygous. The experimental mice were maintained on the AIN93M diet. We found that the tumor incidence was reduced by 51.0% in hCYP1A:IL11Rα1+/- mice and 80.0% in hCYP1A:IL11Rα1-/- mice, suggesting that IL11 signaling plays critical roles in PhIP/DSS-induced colon carcinogenesis. By immunohistochemical staining for pSTAT3, we found the pSTAT3 staining in the colitis epithelial tissues induced by the DSS treatment in both heterozygous and homozygous mice were significantly reduced; whereas the tissues from the wildtype mice displayed strong positive staining in the nucleus. IL11 signaling could be a potential therapeutic target for colon cancer prevention. (supported by the John L. Colaizzi Chair Endowment Fund and GI Pilot Study from Rutgers Cancer Institute of New Jersey Cancer Center Support Grant P30CA072720)

Citation Format: Hong Wang, David Wang, Yuhai Sun, Xu Yang, Chung S. Yang. IL11 promotes the PhIP/DSS-induced colon carcinogenesis [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 3433.
Abstract 3434: Selective inhibition of mTORC2 by disruption of mLST8 scaffolding function
Authors: Kim Laura C. , Hwang Yoonha , Song Wenqiang , Cook Rebecca S. , Chen Jin
Published: August 2019

Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that acts in two distinct complexes, mTORC1 and mTORC2, and is dysregulated in many diseases including cancer. mLST8 is a shared component of both mTORC1 and mTORC2, yet little is known regarding how mLST8 contributes to assembly and activity of the mTOR complexes. We assessed mLST8 loss in a panel of normal and cancer cells, finding little to no impact on mTORC1 activity, nor on assembly of mTOR with the mTORC1 co-factor Raptor. However, mLST8 loss blocked mTOR association with the mTORC2 co-factors Rictor and Sin1, and impaired mTORC2 kinase activity, including its phosphorylation of AKT at S473. We identified two sites within mLST8 governing its interaction with mTOR, finding that simultaneous mutation of these sites together, but not individually, disrupted not only mTOR-mLST8 interactions, but also blocked mTOR assembly with Rictor and Sin1, thus disrupting mTORC2 activity. Similary, a single mutation on mLST8 with a corresponding mutation on mTOR interfered with mTORC2 assembly, without affecting mTORC1 assembly or activity. We further discovered a direct interaction between mLST8 and the NH2-terminal domain of the mTORC2 cofactor Sin1. Using PTEN-null prostate cancer xenografts, we found that mLST8 mutations disrupting the mTOR interaction motif inhibited AKT S473 phosphorylation, decreased tumor cell proliferation, and increased tumor cell death in vivo. Together, these data suggest that the scaffolding function of mLST8 is critical for assembly and activity of mTORC2, but not mTORC1, an observation which could enable therapeutic mTORC2-selective inhibition, while sparing the activity of mTORC1.

Citation Format: Laura C. Kim, Yoonha Hwang, Wenqiang Song, Rebecca S. Cook, Jin Chen. Selective inhibition of mTORC2 by disruption of mLST8 scaffolding function [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 3434.