bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3123: Targeting SHP2 and RAS MAPK pathway in neuroblastoma
Authors: Valencia-Sama Ivette , Adderley Teresa , Kee Lynn , Christopher Gabriella , Kano Yoshihito , Ohh Michael , Irwin Meredith 
Published: August 2019

Abstract
Introduction: Neuroblastoma (NB), the most common pediatric extra-cranial solid tumor, recurs in &gt;50% of patients who present with metastases. Strategies to treat relapsed NB, which is often fatal, include targeting relapse-specific signaling pathways. Recently, sequencing studies have revealed that 78% of mutations detected in relapse samples are predicted to activate the RAS-MAPK pathway, suggesting there may be opportunities to pharmacologically target this pathway to treat recurrent NB.
Experimental Design: Our lab previously reported that the PTPN11-encoded tyrosine phosphatase SHP2 is an activator of the RAS pathway, and pharmacologic inhibition of SHP2 inhibited glioblastoma growth in vivo. To determine whether inhibiting SHP2 in NB would impact tumor growth we treated a panel of NB cells with diverse genetic backgrounds, including mutations in NRAS, with different SHP2 inhibitors (SHP099 and II-B08) alone and in combination with additional drugs that target RAS-MAPK signaling.
Results: In comparison to NB cell lines harboring endogenous NRAS mutations (NRASmt), cells with NRAS wild-type (NRASwt) were more sensitive to SHP2 inhibitors. In addition, NRASwt cells engineered to overexpress NRASmt were more resistant to SHP099 than cells with endogenous or overexpressed NRASwt, as demonstrated by higher levels of proliferation, increased survival, and diminished apoptosis. Furthermore, SHP099 effectively inhibited SHP2 in both NRASwt and NRASmt cells, but only failed to inactivate the downstream RAS effector ERK1/2 in NRASmt cells, suggesting that SHP099 treatment alone is ineffective in cells harboring NRAS mutations. To determine whether SHP099 resistance in NRASmt cells could be overcome with combination strategies, sensitive and resistant NB cells were treated with SHP2 inhibitors alone or in combination with other RAS-MAPK pathway inhibitors (vemurafenib, trametinib and ulixertinib). Interestingly, in comparison to SHP099 or II-B08 alone, all three combinations significantly reduced survival and IC50 values in both NRASwt and NRASmt cells. Using the Bliss independence model we determined all three combinations were synergistic.
Conclusions: Our studies demonstrate that NRAS mutations are associated with resistance to SHP2 inhibitors, and that in certain tumors, based on the genetic status of RAS-MAPK-SHP2 signaling components, combinations of drugs targeting this pathway could be effective strategies for relapsed NB.
Citation Format: Ivette Valencia-Sama, Teresa Adderley, Lynn Kee, Gabriella Christopher, Yoshihito Kano, Michael Ohh, Meredith Irwin. Targeting SHP2 and RAS MAPK pathway in neuroblastoma [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 3123.
Abstract 3133: Leukocyte telomere length, cancer incidence and all-cause mortality among Chinese adults: Singapore Chinese health study
Authors: Samavat Hamed , Luu Hung N. , Wang Renwei , Jin Aizhen , Koh Woon-Puay , Yuan Jian-Min 
Published: August 2019

Abstract
Background: Telomeres play a key role in the chromosomal maintenance and stability. To date, very few studies have investigated the association between leukocyte telomere length with cancer incidence and all-cause mortality, particularly among Asian population.
Methods: Relative telomere lengths in genomic DNA from peripheral blood samples were quantified using a validated quantitative real-time PCR among 26,540 middle-aged or older Chinese adults. Hazard ratios (HRs) and 95% confidence intervals (CIs) of incident cancer and deaths by quintiles of telomere length were calculated using the Cox proportional hazards regression method with adjustment for potential confounders.
Results: During 13.2 years of follow-up, 4,353 individuals developed cancer and 2,660 participants died of cancer. Participants with the longest telomeres had significantly 16% higher risk of developing cancer compared to those with the shortest telomeres after controlling for established risk factors (95% CI: 1.06, 1.28; Ptrend= 0.0003). We found similar pattern of results for lung adenocarcinoma (HRQ5 vs. Q1=2.89; 95% CI: 1.95, 4.27), pancreatic cancer (HRQ5 vs. Q1=2.36; 95% CI: 1.29, 4.32), kidney cancer (HRQ5 vs. Q1=3.23; 95% CI: 1.47, 7.53), and genitourinary system cancers including kidney, renal pelvis, ureter, and bladder (HRQ5 vs. Q1=1.56; 95% CI: 1.02, 2.39). In contrast, longer telomeres were associated with lower risk of overall death (HRQ5 vs. Q1=0.93; 95% CI: 0.86, 1.00), and deaths due to ischemic heart disease (HRQ5 vs. Q1=0.85; 95% CI: 0.70, 1.02), respiratory disease (HRQ5 vs. Q1=0.76; 95% CI: 0.64, 0.91), non-cancer (HRQ5 vs. Q1=0.80; 95%: 0.73, 0.88) and other diseases (HRQ5 vs. Q1=0.77; 95% CI: 0.63, 0.94).
Conclusion: The findings of this cohort study support the hypothesis that longer telomere length may be a risk factor for cancer and cancer-related deaths, but might have opposing impact on overall survival.
Funding Sources: National Institutes of Health (NIH) (R01 CA144034 and UM1 CA182876); NIH/NCI T32CA186873; National Medical Research Council, Singapore (NMRC/CSA/0055/2013); NIH (P20CA210300).
Citation Format: Hamed Samavat, Hung N. Luu, Renwei Wang, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan. Leukocyte telomere length, cancer incidence and all-cause mortality among Chinese adults: Singapore Chinese health study [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 3133.
Abstract 3151: Quantitative measurement of Siglec-15 expression in non-small cell lung cancer and its association with PD-L1, B7-H4 and tumor infiltrating lymphocytes
Authors: Toki Maria , Zugazagoitia Jon , Altan Mehmet , Liu Linda , Mani Nikita , Liu Yuting , Syrigos Konstantinos , Chen Lieping , Langermann Solomon , Herbst Roy , Rimm David 
Published: August 2019

Abstract
Introduction: Siglecs are sialic acid-binding transmembrane receptors that regulate the functions of innate and adaptive immune system through the recognition of glycan ligands. Siglec-15 has been recently described as an immune suppressive molecule that shares molecular structure with PD-L1, but its role in NSCLC is still unknown. In this study, we determined Siglec-15 expression in three retrospective NSCLC cohorts and evaluated its association with mutation status, major clinicopathologic characteristics and survival.
Experimental procedures: We used multiplexed automated quantitative immunofluorescence (QIF) to develop a validated assay for Siglec-15 measurement and used it to assess Siglec-15 expression and its association to major clinicopathologic variables and survival in three NSCLC cohorts of over 600 patients. Additionally, we investigated the correlation of Siglec-15 expression with tumor-infiltrating lymphocytes, PD-L1, B7-H3 and B7-H4 tumor expression.
Results: In our study, Siglec-15 tumor positivity was found in 12.5%, 13.7% and 22.8% of NSCLC cohort patients. Siglec-15 expression was higher in EGFR mutant and EGFR/KRAS wild type tumors compared to KRAS mutants but was not associated with any other major clinicopathological characteristics. Siglec-15 followed a mutually exclusive pattern of expression with PD-L1, B7-H3 and B7-H4 (co-expression in 3.1%, 13.2% and 7.7% of the patients respectively), while high levels were not correlated with lymphocyte infiltration or T-cell activation, suggesting a different upregulation mechanism not mediated by IFN-gamma.
Conclusions: Siglec-15 is a protein expressed with high frequency in NSCLC. Co-expression of Siglec-15 with PD-L1, B7-H3 and B7-H4 is relatively rare, suggesting that Siglec-15 has distinct and non-redundant features compared to other B7 family members.
Citation Format: Maria Toki, Jon Zugazagoitia, Mehmet Altan, Linda Liu, Nikita Mani, Yuting Liu, Konstantinos Syrigos, Lieping Chen, Solomon Langermann, Roy Herbst, David Rimm. Quantitative measurement of Siglec-15 expression in non-small cell lung cancer and its association with PD-L1, B7-H4 and tumor infiltrating lymphocytes [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 3151.
Abstract 3153: Prostatic acid phosphatase (PAP) predictive effect for prostate cancer in a population-based study: The renewal of PAP
Authors: Wang Fubo , Xu Huan , Sun Yinghao 
Published: August 2019

Abstract
Objective: Use prostatic specific acid phosphatase (PAP) to characterize the disease progression and median survivals of patients with prostate cancer (PCa) based on the analysis in a population-based study from Surveillance, Epidemiology, and End Results (SEER) database.
Materials and Methods: PCa patients with completed PAP results were selected from the SEER database of the National Cancer Institute. Mann-Whitney Sum test was utilized to compare the statistical significance for measurement data and ranked data, which were stratified by age, race, TNM Classification of Malignant Tumors (TNM), pathological grades, number of tumors, PAP and survival duration. Logistic analysis was performed to identify predictors of the presence of invasion and metastases. Cox regression was utilized to analyze the factors associated with all-cause mortality and prostate-cancer specific mortality. Moreover, survival curve was also present.
Results: In total, there are 5184 PAP+ patients and 3161 PAP- patients involved in this study. The Mann-Whitney Sum test showed that slightly greater tumor size(p=0.03), elevated lymphatic (p=0.005) and distant (p&lt;0.001) metastases rate, higher pathologic grade(p&lt;0.001), localized tumor number (p&lt;0.001), shortened survival months (p&lt;0.001) were observed in the PAP+ group compared with the PAP- group. In the Multivariable Logistic Regression, invasion and metastases Hazard Ratio (HR) were elevated significantly (p&lt;0.001) in the PAP+ individuals. In the survival analysis, PAP- patients experience the prolonged median survival. In the post-surgical patients, the survival months were still longer in PAP+ patients compared with the negative ones (p&lt;0.001), though surgery prolonged the survival months of both groups. Survival months stratified by localized, invasion and metastases situations were analyzed. In the three stratified sub-groups, survival duration is significantly decreased in the PAP+ individuals in the localized PCa group (P&lt;0.001**) and the metastases group (P=0.013).
Conclusions: The findings of this study provide population-based estimates of the PCa progress and prognosis for patients with different PAP results, which may suggest a renewed period for the PAP.
Citation Format: Fubo Wang, Huan Xu, Yinghao Sun. Prostatic acid phosphatase (PAP) predictive effect for prostate cancer in a population-based study: The renewal of PAP [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 3153.
Abstract 3154: Tumor expression of Activin A is associated with clinical outcomes in patients with colorectal cancer
Authors: Daitoku Nobuya , Miyamoto Yuji , Sakamoto Yuki , Etoh Kojiro , Hiyoshi Yukiharu , Nagai Yohei , Iwatsuki Masaaki , Ishimoto Takatsugu , Baba Yoshifumi , Iwagami Shiro , Yoshida Naoya , Baba Hideo 
Published: August 2019

Abstract
Background:
Activin A is a member of the transforming growth factor β (TGF-β) superfamily. Activin A shows an extensive variety of biological activities, including mesoderm induction, bone remodeling, muscle atrophy. Activin A is also related to Smad 2/3 mediated cancer development and metastasis. The overexpression of Activin A has been reported in several types of cancers and high expression of Activin A leads to poor prognosis. We examined the relationship between tumor expression of Activin A and clinical outcomes in patients with colorectal cancer.
Methods:
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We analyzed the association between tumor expression of Activin A and clinicopathological features and patient’s prognosis in 157 primary colorectal cancers, which were curatively resected between 2008 and 2012. The expression level of Activin A was measured in tumor tissue by quantitative RT-PCR. Patients were categorized into the high or low groups based on median expression value of Activin A and Kaplan-Meier survival analyses were performed to display difference in overall survival (OS) and relapse-free survival (RFS) between two groups. The between-group differences were assessed by the log-rank test and stepwise multivariate Cox regression analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for OS.
Result:
RT-PCR analysis showed that expression of Activin A was significantly higher in tumor areas compared with that in normal (p&lt;0.001). Activin A was highly expressed in the rectal cancer (p=0.015). Other clinicopathological factors were not significantly correlated with Activin A expression. Patients with Activin A high-expressed colorectal cancers showed a significantly shorter OS and RFS than those with activin A low-expressed tumor (5-year OS: Low 79.2% vs High 63.8%, p=0.037). High expression of Activin A is an independent predictor of poor prognosis in patients with colorectal cancers after curative surgery (Low vs High, HR=5.558, 95%CIs=2.229-15.17,
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p=0.003).
Conclusion:
We concluded that high Activin A expression in tumor is associated with poor prognosis in colorectal patients.
Citation Format: Nobuya Daitoku, Yuji Miyamoto, Yuki Sakamoto, Kojiro Etoh, Yukiharu Hiyoshi, Yohei Nagai, Masaaki Iwatsuki, Takatsugu Ishimoto, Yoshifumi Baba, Shiro Iwagami, Naoya Yoshida, Hideo Baba. Tumor expression of Activin A is associated with clinical outcomes in patients with colorectal 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 3154.
Abstract 3180: Targeting peptide-loaded-DC CIK cells induce a specific antitumor response
Authors: Zhu Yimin , Cui Xueyuan , Liu Cuijuan 
Published: August 2019

Abstract
Currently, immunotherapy has become an effective alternative therapeutic approach for cancers. Cytokine-induced killer (CIK) cells have a higher proliferation rate, increased efficacy with few side-effects, and non- MHC-restricted killing after co-culturing with dendritic cells (DCs). However, the specificity and efficacy of DC-CIK treatment still need to be improved. In our study, the antitumor effects of CIK cells co-culturing with DCs pulsed with non-cell derived targeting peptides, which could specifically bind to certain tumor cells, were evaluated. Our results indicated that targeting peptide-loaded DCs could enhance the differentiation and cytotoxicity of CIK cells. CIK cells, which were treated with specific targeting peptide-loaded DCs, could effectively and specifically kill tumor cells in vitro and in vivo, as long as tumor cells were pre-treated with these targeting peptides. Moreover, the CIK cytotoxic effect of this type acquired a certain properties of memory and resistance to the tolerance. In conclusion, targeting peptides could guide DC-CIK more effectively and specifically kill tumor cells and this non-cell derived targeting peptide-loaded-DC CIK may work as a novel means for cancer therapy.
Citation Format: Yimin Zhu, Xueyuan Cui, Cuijuan Liu. Targeting peptide-loaded-DC CIK cells induce a specific antitumor 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 3180.
Abstract 3198: Therapeutic potential of MET inhibitor combined with immune checkpoint blockade in pancreatic cancer
Authors: Gao Mei , Lin Miranda , Yang Yachao , Kim Joseph 
Published: August 2019

Abstract
Novel Combination Therapeutic Targeting of the Immune Checkpoint PD-1 and c-MET in Pancreatic Cancer
Introduction: Therapeutic regimens incorporating immune checkpoint inhibitors (ICIs) have improved survival in many cancers, but have had little impact in pancreatic ductal adenocarcinoma (PDAC). We previously discovered that these ICIs directly target autonomously expressed and functional PD-1 on PDAC cells. We sought to investigate downstream effectors of PD-1 signaling in PDAC cells as potential novel therapeutic targets.
Methods: We performed a Phospho Explorer Array, which measures the levels of over 200 phospho-specific antibodies and their corresponding total proteins, to determine activated signaling pathways following exposure of PDAC cells to PD-L1 (the ligand for PD-1). Upon detecting upregulation of PD-1 mediated MET signaling, we verified MET pathway activation by exposing PDAC cells (MIAPaCa-2 and PANC-1) to PD-L1 and measuring levels of phosphorylated MET by immunoblotting. Then, we tested whether the MET small molecule inhibitor blocked PD-1 mediated MET signaling. Finally, PDAC patient-derived organoids (PDOs) were utilized to test the cytotoxicity of ICIs alone or in combination with cabozantinib.
Results: The phospho-protein array revealed 10-fold upregulation of MET activity followed exposure of PDAC cells to PD-L1. Western blot assay verified increased levels of MET phosphorylation that varied in a time-dependent manner following PD-L1 treatment in both PANC-1 and MIAPaCa-2 cell lines. Pre-treatment of PDAC cells with cabozantinib completely blocked PD-1/PD-L1 mediated MET phosphorylation. By CellTiter-Glo assay the IC50 of cabozantinib was calculated in MIAPaCa-2 and PANC-1 cells as 9.5 µM and 8.6 µM, respectively. Combining cabozantinib with clinical grade anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab revealed synergistic cytotoxicity in PDAC cells and PDOs.
Conclusion: In these preliminary studies, we report PD-1 activation of the MET pathway and synergy killing of PDAC cancer models with novel combination therapy of cabozantinib and ICIs in PDAC. This positive data warrants further exploration of the interaction of MET with the PD-1/PD-L1 axis and its role in PDAC progression.
Note: This abstract was not presented at the meeting.
Citation Format: Mei Gao, Miranda Lin, Yachao Yang, Joseph Kim. Therapeutic potential of MET inhibitor combined with immune checkpoint blockade in pancreatic 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 3198.
Abstract 3218: Anti-PD1 and -CTLA-4 combination in vivo enhances DC-based tumor-associated mitochondria antigen immunotherapy efficacy
Authors: Perales-Linares Renzo F. , Pierini Stefano , Uribe Mireia , Pustylnikov Sergei , Costabile Francesca , Beghi Silvia , Facciabene Andrea 
Published: August 2019

Abstract
Somatic mitochondria DNA (mtDNA) abnormalities have been identified in various types of human cancers. Previously, we generated tumor protective immunity under prophylactic and therapeutic approaches employing a murine kidney tumor model system and dendritic cell (DC)-based vaccination containing RENCA-derived mitochondria enriched lysates. Our results shown that tumor-associated mitochondria antigens (TAMAs) are targetable antigens for cancer immunotherapy (PMID: 26378078). Preliminary data also revealed increased endogenous PD-L1 mRNA expression levels in RENCA tumors of treated mice versus healthy kidney tissue. To investigate the impact of PD1/PD-L1 axis antagonism, Balb/C mice were challenged with RENCA cells at day 0 followed by TAMA-vaccination at day 3 and concurrent administration of anti-PD1 (aPD1) 5 times every 3 days. Interestingly, the aPD1-TAMA treatment resulted in reduced tumor growth, greater T CD4+ and T CD8+ cell infiltration, and lower intratumoral-MDSC as compared to the TAMA vaccine alone. In addition, we observed higher T cell activation from the aPD1-TAMA group upon co-culture with bone marrow-derived dendritic cells exposed to RENCA mitochondria lysate, suggesting that the inhibition of PD1 also enhanced the immunogenicity of the TAMA vaccine. Further analysis of the tumor environment revealed that the PD1-PD-L1 axis antagonism correlated with an increment of intratumoral CTLA4 expression and recruitment of T regulatory (Treg) cells. We introduced a third arm of treatment including a CTLA4 antagonist antibody in combination with aPD1 and TAMA vaccine in vivo. Strikingly, the tumor progression was greatly impacted causing tumor rejection in the majority of tumor-bearing animals, sustained tumor volume reduction in the others, a decrease in Treg cell recruitment, and concomitant increment of T CD8+ cell infiltration and activation. Altogether, the combination of check point inhibitors in vivo significantly improved the efficacy of the TAMA immunotherapy by remodeling the tumor microenvironment, reducing the immunosuppressive potential, and facilitating the infiltration of effector T cells into the tumor.
Citation Format: Renzo F. Perales-Linares, Stefano Pierini, Mireia Uribe, Sergei Pustylnikov, Francesca Costabile, Silvia Beghi, Andrea Facciabene. Anti-PD1 and -CTLA-4 combination in vivo enhances DC-based tumor-associated mitochondria antigen 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 3218.