bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4843: TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models
Authors: Ghosh Arnab , Michel Judith , Dong Lauren , Suek Nathan , Zhong Hong , Budhu Sadna , Henau Olivier de , Wolchok Jedd , Merghoub Taha 
Published: August 2019

Abstract
An emerging body of literature suggests a role of TP53 pathway in antitumor immunity including antigen presentation and T cell proliferation. Stabilization of TP53 could therefore alter the immune tumor microenvironment, enabling the immune system to target tumor cells more effectively. APR-246 covalently modifies the core domain of cellular TP53 through the alkylation of thiol groups, leading to reactivation of endogenous TP53 activity. To further study the effect of APR-246 on antitumor immunity we used a B16 pre-clinical melanoma mouse model. In vitro treatment of B16 cells with APR-246 caused intracellular accumulation of TP53, leading to increased apoptosis. However, treatment of B16-melanoma bearing mice with APR-246 monotherapy did not result in a statistically significant change in tumor growth or survival. Analyses of the tumor immune microenvironment showed increased immune potentiating M1 polarized tumor-associated macrophages, and Granzyme B activity in CD8+ T cells, suggesting enhanced anti-tumor immunity. Concomitantly, there was increased PD-L1 expression in the macrophages, PD-1 expression on CD8+ T cells, and Foxp3+ Tregs in tumors from APR-246 treated animals. Therefore, we decided to combine anti-PD-1 antibody (RMP-1) to APR-246 treatment in tumor-bearing mice. The combination led to a significant delay in tumor growth (P &lt; 0.001) and improved survival of B16-bearing mice compared to anti-PD1 or APR-246 monotherapies (P &lt; 0.01). Improved responses were also seen in MC38 colorectal cancer-bearing mice (P &lt; 0.01). The anti-tumor effects of APR-246 and anti-PD1 were T cell dependent and abrogated in hosts lacking T cells. Analyses of the tumor immune microenvironment showed that the combination decreases proliferation but increases cytolytic activity of CD8+ T cells compared to anti-PD1 alone. We next studied the effect of combining APR-246 with anti-PD1+ anti-CTLA-4 (9B9). Combination of APR-246 with dual immune checkpoint blockade using anti-PD1 and anti-CTLA-4 showed further tumor growth inhibition in B16-melanoma compared to monotherapies (P &lt; 0.001). Our studies support a role for restoring TP53 in the tumor microenvironment and provide evidence that reactivation of TP53 by APR-246 can enhance anti-tumor immune responses and inhibit tumor growth in preclinical models.
Citation Format: Arnab Ghosh, Judith Michel, Lauren Dong, Nathan Suek, Hong Zhong, Sadna Budhu, Olivier de Henau, Jedd Wolchok, Taha Merghoub. TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models [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 4843.
Abstract 4844: A novel anti-TIGIT antibody (YH29143) enhances T cell activity and suppresses Treg cell activity and synergizes with anti-PD-L1 antibody
Authors: Lee Kwang-Hoon 
Published: August 2019

Abstract
TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a T cell coinhibitory receptor, highly expressed on regulatory and memory CD4+, CD8+ T cells and natural killer (NK) cells. TIGIT binding of PVR (poliovirus receptor) on the surface of antigen presenting cells leads to downregulation of CD8+ T cell and NK cell responses in tumors. In this study, we sought to determine the efficacy of TIGIT blockade in antitumor immunity and demonstrate the synergistic effect of treatment with other checkpoint blockade such as anti-PD-L1.
We generated anti-TIGIT monoclonal antibody that binds TIGIT with high affinity and blocks ligand binding. Anti-TIGIT antibody YH29143 was shown to increase T cell activities and suppress Treg cell activities from in vitro cell-based assays. We determined the crystal structure of YH29143 Fab fragment in complex with TIGIT and identified its epitope that overlaps with the PVR-binding interface. We also studied in vivo efficacy of YH29143 whether to inhibit the growth of tumor in two syngeneic colon tumor-bearing mouse models (CT26 and MC38). YH29143 reduced growth of both tumors compared to that of control IgG. In addition to these results, YH29143 showed synergistic efficacy for inhibition of tumor growth in combination with anti-PD-L1 antibody. From these tumor tissues, the ratio of CD8+ T cells to Treg cells was increased by treatment of anti-TIGIT antibody.
Taken together, we evaluated the efficacy of YH29143, a potent anti-TIGIT monoclonal antibody, which enhanced T cell activation and suppressd Treg cell function in vitro, and efficiently inhibited tumor growth in vivo having synergistic effect with anti-PD-L1 antibody. These data also provide the rationale for YH29143 as a potential combination candidate for cancer immunotherapy with other immune checkpoint blockades.
Citation Format: Kwang-Hoon Lee. A novel anti-TIGIT antibody (YH29143) enhances T cell activity and suppresses Treg cell activity and synergizes with anti-PD-L1 antibody [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 4844.
Abstract 4861: Chemotherapy improves overall survival in patients with T2N0M0 non-small cell lung cancer undergoing definitive radiation therapy: An analysis of the SEER database
Authors: Komiya Takefumi , Chaaya Gerard , Powell Emily 
Published: August 2019

Abstract
Objectives: Despite relatively routine practice and recommendations by clinical guidelines, an advantage of adding systemic chemotherapy to definitive radiation in patients with early stage non-small cell lung cancer (NSCLC) has never been demonstrated by randomized or large-scale studies. This study evaluates the role of chemotherapy in addition to thoracic radiation in T2N0M0 NSCLC patients who did not undergo surgical resection.
Materials and Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we screened for patients with T2N0M0 NSCLC who received radiation therapy without surgical resection from 2004 to 2015. T-staging was defined according to the American Joint Committee on Cancer (AJCC) 6th (Year 2004+) and 7th(Year 2010+) versions. Kaplan-Meier curves and estimated overall survival according to chemotherapy status were determined by Log-rank test. Both univariate and multivariate analyses were conducted for the AJCC 6th (T2), 7th T2a, and 7th T2b groups. All the statistical analyses were performed using JMP software version 13 (SAS Institute, Cary, NC), and significance was achieved when P-value is below 0.05.
Results: A total of 6,075 and 3,138 patients were identified for AJCC 6th (T2; 3cm -7cm) and 7th (T2a; 3 - 5cm, T2b; 5-7 cm) version, respectively. Administration of chemotherapy was associated with younger age, male sex, non-adenocarcinoma, and high pathologic grade. Kaplan-Meier estimates demonstrated that the chemotherapy group had a statistically significant longer five-year overall survival than the non-chemotherapy group in patients with AJCC 6th T2 (19.9% vs 15.8%, p=0.0023) and AJCC 7th T2b (5-7cm, 20.9% vs 13.6%, p=0.0046) but not those with AJCC 7th T2a (3-5cm, 24.3% vs 21.1%, p=0.4369). Multivariate analyses also revealed that the use of chemotherapy was an independent prognostic factor in AJCC 6th T2 and AJCC 7th T2b.
Conclusions: This study strongly suggests that chemotherapy may benefit non-adenocarcinoma patients with primary tumor larger than 5cm (AJCC 8th T3) undergoing chest radiation.
Citation Format: Takefumi Komiya, Gerard Chaaya, Emily Powell. Chemotherapy improves overall survival in patients with T2N0M0 non-small cell lung cancer undergoing definitive radiation therapy: An analysis of the SEER 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 4861.
Abstract 4869: Chromosomal and telomeric biomarkers of normal tissue injury to evaluate risk of secondary malignancy following IMRT for prostate cancer
Authors: Luxton Jared J. , McKenna Miles J. , Taylor Lynn , Swanson Gregory P. , Bailey Susan M. 
Published: August 2019

Abstract
An overall intent of radiotherapy is to precisely target tumor cells, while minimizing exposures to surrounding normal tissue. Despite successes, there is growing concern that an unacceptably large volume of normal tissue is unavoidably exposed. Chromosome aberrations provide a direct measure of ionizing radiation (IR)-induced DNA damage, as well as an indirect measure of future risk since they are associated with virtually all known cancers. Such structural variants (SVs) include translocations (rearrangements between chromosomes) and inversions (rearrangements within chromosomes), the latter being recently identified as part of a distinctive mutational signature associated with radiation therapy-induced second malignancies. Directional Genomic Hybridization (dGH), is a strand-specific cytogenomics-based methodology for cell-by-cell, high-resolution detection of all SVs, particularly inversions, which when combined with compatible subtelomere probes (Telo-dGH), can be used to distinguish inversions from recombination events (sister chromatid exchange) involving chromosomal termini. Telomeres are critical structural elements that serve to protect the physical ends of chromosomes. Dysfunctional telomeres are associated with instability and carcinogenesis, as well as with a variety of other age-related pathologies (e.g., cardiovascular disease). We are validating Telo-dGH as a prospective “personalized” approach of evaluating normal tissue injury, and therefore future risk, associated with radiation therapy - regardless of tumor type or treatment modality. Here, we report results of monitoring prostate cancer patients before and after intensity-modulated radiation therapy (IMRT) to assess radiosensitivity (toxicity), as well as risk of secondary malignancy and other degenerative late effects. Such a strategy has the potential to better inform patient treatment and management decisions based on predicted individual risk.
Citation Format: Jared J. Luxton, Miles J. McKenna, Lynn Taylor, Gregory P. Swanson, Susan M. Bailey. Chromosomal and telomeric biomarkers of normal tissue injury to evaluate risk of secondary malignancy following IMRT for prostate 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 4869.
Abstract 4899: The impact of the EGFR-T790M mutation detection by re-biopsy in EGFR mutant NSCLC patients in the retrospective analysis
Authors: Yoshimura Akihiro , Yamada Tadaaki , Okura Naoko , Uchino Junji , Takayama Koichi 
Published: August 2019

Abstract
Background: EGFR-TKIs show a good anticancer effect in to most of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. However, it ultimately acquires resistance to EGFR-TKIs. We currently attempt to detect EGFR-T790M mutation by re-biopsy after disease progression, because the third generation EGFR-TKI osimertinib was effective against the refractory tumors with EGFR-T790M mutation. However, the re-biopsy from tumors is relatively invasive and some cases are impossible to biopsy. Therefore, it is a beneficial if we predict the EGFR-T790M mutation before re-biopsy. In this study, we analyzed the patients with disease progression after initial EGFR-TKIs to address the issues.
Methods: 78 advanced NSCLC patients with EGFR mutations were enrolled from five institutions in Japan. In all patients, re-biopsy samples were obtained successfully after the resistance to initial EGFR-TKI treatment We analyzed the relationship between the emergence of EGFR-T790M mutation and clinical parameters including clinical outcomes with EGFR-TKI treatment and EGFR activating mutation status.
Results: Of 78 advanced NSCLC patients with EGFR mutations, 39 patients were EGFR-T790M positive and 39 were negative based on the re-biopsy samples. Of 39 EGFR-T790M positive patients, 2 patients achieved complete response (CR), 33 partial response (PR), and 4 stable disease (SD) by initial EGFR-TKI treatment. In contrast, 1 patient experienced a CR, 19 a PR, 18 SD, and 1 progressive disease (PD) in 39 T790M negative patients. The objective response rate was higher in patients with T790M positive mutations than those with T790M negative mutations (89.7% versus 51.2%, p&lt; 0.01). There was no statistically significant difference in progression free survival and time to failure treated with initial EGFR-TKIs between both groups.
Conclusion: The response to initial EGFR-TKIs treatment might be one of good predictors for emerging of refractory tumors with EGFR-T790M mutation.
Citation Format: Akihiro Yoshimura, Tadaaki Yamada, Naoko Okura, Junji Uchino, Koichi Takayama. The impact of the EGFR-T790M mutation detection by re-biopsy in EGFR mutant NSCLC patients in the retrospective 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 4899.
Abstract 4900: Dynamic metabolic response of prostate cancer patients treated with ADT and low carb diet
Authors: Freedland Stephen , Lin Pao-Hwa , Chen Emily Y. , Tolstikov Vladimir , Chi Jen-Tsan , Sarangarajan Rangaprasad , Narain Niven R. , Kiebish Michael A. 
Published: August 2019

Abstract
Background: Prostate cancer (PrCa) is one of the most common cancers among men and managed through surgery, hormonal therapy, chemotherapy, radiation, and cryotherapy. Depending on the stage of PrCa, androgen deprivation therapy (ADT) is commonly utilized as an intervention. ADT has proven effective in intervening in PrCa progression, although there are several side effects. Recently, the use of low carb diets has been shown to alter patients’ metabolic phenotype and as such may reduce the side effects of ADT.
Methods: In this study 35 men, who were beginning ADT, were randomized to low carb diet intervention with recommended exercise or control (no lifestyle change) for 6 months. Primary results have been reported showing significant weight loss at both 3-month (17lb, p&lt;0.01) and 6-month (23 lbs, p&lt;0.01) and improved insulin control at 3-month (HOMA=-19 as compared to baseline, p=0.02) but not at 6-month (HOMA=-4 as compared to baseline, p=0.13). For this exploratory analysis, sera collected at baseline, 3, and 6 months was used for metabolomics analysis utilizing GC/MS TOF, QqQ LC-HILIC-MS/MS, and TripleTOF 6600 LC-RP-MS and lipidomics analysis using TripleTOF 5600+ MS/MSALL workflows to quantify the chemical diversity of the metabolome and lipidome.
Results: Over 450 metabolites and 1000 lipid species were quantified. Metabolomics analysis of sera from the control patients (ADT alone) demonstrated alterations in steroid biosynthesis, androgen/estrogen metabolism, fatty acid metabolism, and lysine degradation. Lipidomics analysis of the control patients demonstrated changes in selective long chain polyunsaturated phosphatidylcholine species. Analysis of the ADT plus low carb patients revealed a change in pyruvate, glucose-alanine cycle, selenoamino acid, phenylalanine/tyrosine, and taurine metabolism. Further, lipidomic analysis revealed changes in several triglycerides, plasmalenylethanolamine, and phosphatidic acid species.
Conclusion: In summary, integration of metabolomic and lipidomic analysis in hormonal and metabolic interventions of PrCa patients revealed dynamic changes providing novel insight for tailoring therapeutic intervention and monitoring.
Citation Format: Stephen Freedland, Pao-Hwa Lin, Emily Y. Chen, Vladimir Tolstikov, Jen-Tsan Chi, Rangaprasad Sarangarajan, Niven R. Narain, Michael A. Kiebish. Dynamic metabolic response of prostate cancer patients treated with ADT and low carb diet [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 4900.
Abstract 4925: Development of a novel PTK7 immunohistochemistry (IHC) assay and analytical validation in epithelial malignancies of lung, breast and ovary
Authors: Whalen Pamela M. , Jackson-Fisher Amy , Vizcarra Pamela , Painter Cory , Pirie-Shepherd Steven , Fernandez Diane R. , Lee Joseph , Powell Eric L. 
Published: August 2019

Abstract
An immunohistochemistry (IHC) assay was developed to detect protein tyrosine kinase 7 (PTK7) membrane staining in formalin-fixed paraffin embedded (FFPE) human tumors with the intention of selecting non-small cell lung carcinoma (NSCLC) patients, breast cancer (BrCa) patients, or ovarian cancer (OVCA) patients for enrollment in an early stage clinical trial for a PTK7-ADC (antibody drug conjugate) experimental therapeutic. The IHC assay was developed using an anti-PTK7 specific antibody and a panel of five cancer cell lines with a range of constitutive PTK7 expression as characterized by gene transcript and protein based assays. PTK7 messenger RNA (mRNA) and protein levels were highly correlative in the control cell lines in vitro and the corresponding cell line xenografts. A pre-analytic variables study (PAV) using these characterized control cell line xenografts demonstrated that the PTK7 IHC assay was robust to the pre-analytic variables of under-fixation and ischemia. This IHC assay was used to profile PTK7 levels in human lung cancers, breast cancers, and ovarian cancers, and a dynamic range of PTK7 H-scores was detected (see Table 1). The resulting PTK7 H-scores correlated with orthogonal methods for measuring PTK7 protein and gene transcript levels in the human tumors.
Table 1.PTK7 H-scoresNumber of SamplesMinimum H-scoreMaximum H-scoreMean H-scoreMedian H-scoreNSCLC3034230117.4117OvCa2424240151151
Citation Format: Pamela M. Whalen, Amy Jackson-Fisher, Pamela Vizcarra, Cory Painter, Steven Pirie-Shepherd, Diane R. Fernandez, Joseph Lee, Eric L. Powell. Development of a novel PTK7 immunohistochemistry (IHC) assay and analytical validation in epithelial malignancies of lung, breast and ovary [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 4925.
Abstract 493: The landscape of adenosine signaling in cancer
Authors: Sidders Ben , Zhang Pei , Goodwin Kelly , O'Connor Greg , Borodovsky Alexandra , Dry Jonathan , Woessner Richard , Sachsenmeier Kris 
Published: August 2019

Abstract
Adenosine is a key suppressor of immune cell function. CD73 and other nucleotidases/phosphatases dephosphorylate and convert extracellular AMP into adenosine, which binds the A2A adenosine receptor (A2aR). There are several agents in early clinical trials targeting components of the adenosine pathway including A2AR and CD73. The identification of cancers with a significant adenosine drive is therefore critical to our understanding of the potential for these molecules. However, it is challenging to measure tumour adenosine levels on a pan-cancer scale. Here we describe the generation & validation of a gene expression signature that we use to characterise the pan-cancer landscape of adenosine signalling and its role within the tumour microenvironment.
Natural Language Processing (NLP) was used to define a network of regulatory interactions between the A2aR receptor and downstream entities. 14 genes were identified as being positively regulated by A2aR and robustly expressed in tumours and so constitute the signature, which we demonstrate accurately recapitulates adenosine drive in mouse syngeneic models. We therefore applied the signature to a pan-cancer analysis of tumour transcriptomes from TCGA and found a significant negative impact on both overall survival (HR = 0.6, Cox PH p=0) and progression free survival (HR = 0.77, Cox PH p=0.0000006) in adenosine high tumours. An adenosine related survival deficit was also seen in CD8+ T-cell infiltrated tumours (OS HR = 0.47, Cox PH p=0; PFS HR = 0.65, Cox PH p=0.0000002). Studying adenosine signalling in the context of tumour genetics identified highly significant associations with TGFB super-family members including TGFBR2 (p=0.0000000013). These data support the adenosine pathway as a key mediator of a successful anti-tumour immune response, demonstrate the prognostic potential of the gene expression signature and could inform patient selection strategies for adenosine pathway modulators.
Citation Format: Ben Sidders, Pei Zhang, Kelly Goodwin, Greg O'Connor, Alexandra Borodovsky, Jonathan Dry, Richard Woessner, Kris Sachsenmeier. The landscape of adenosine signaling in 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 493.
Abstract 4939: Alteration of TGFB signaling pathway predicts worse prognosis in pancreatic ductal adenocarcinoma
Authors: Li Mao , Li Ang , Zhao Xiaochen , Hou Shengzhong , Lu Shan , Mou Yu , Liu Xubao , Cao Dan , Cai Shangli , Tian Bole 
Published: August 2019

Abstract
Background: For pancreatic ductal adenocarcinoma (PDAC), a reliable and practical prognostic biomarker is still in unmet needs. Transforming growth factor beta (TGFB) signaling pathway is one of the core pathways involved in tumor initiation and progression via canonical and non-canonical pathway. The prognostic value of TGFB pathway genes as a functionally related group in PDAC is rarely studied.Methods: 72 PDAC patients who underwent surgery between November 30, 2015 and September 13, 2017 in West China Hospital, Sichuan University were identified and included in this study. Whole-exome sequencing (WES) or targeted next-generation sequencing was performed with tumor tissue from primary tumors. Clinical data was retrospectively collected. Clinicopathologic characteristics and overall survival were analyzed.Results: Genetic alterations were detected in 70 patients (97.2%). While 1 patient (1.4%) had only one genetic alteration, 28 patients (38.9%) had 2-4 genetic alterations and 43 patients (59.7%) had ≥5 genetic alterations. Overall, 25 patients (34.7%) with alteration of TGFB pathway and 47 patients (65.3%) with wild type of TGFB pathway were identified as TGFBm+ group and TGFBm- group respectively. TGFBm+ group had worse overall survival (HR, 1.875, 95% CI: 1.06-4.72; P = 0.04), especially in patients who had radical surgery (HR, 3.11, 95% CI: 1.11-20.3; P = 0.04). While in the subgroup of patients who underwent palliative surgery, OS was not statistically different (HR, 0.93, 95% CI: 0.42-2.04; P = 0.85). Subgroup analysis showed that overall survival hazard ratio favored participants with wild type of TGFB pathway in patients with ECOG performance score &gt;1, abnormal CA199, without metastasis, stage I to II and patients who accepted radical surgery.Conclusion: Alteration of TGFB pathway genes is prevalent in PDAC. Inferior prognosis was observed in PDACs with mutations of TGFB pathway. TGFB signaling might play different role in different tumor stages, which is consistent with previous report about paradoxical effect of TGFB pathway. Genomic sequencing could help screen out patients at risk after surgery and adjuvant therapy might benefit this subgroup of PDACs.
Note: This abstract was not presented at the meeting.
Citation Format: Mao Li, Ang Li, Xiaochen Zhao, Shengzhong Hou, Shan Lu, Yu Mou, Xubao Liu, Dan Cao, Shangli Cai, Bole Tian. Alteration of TGFB signaling pathway predicts worse prognosis in pancreatic ductal adenocarcinoma [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 4939.