bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3158: Prediction of overall survival in urothelial cancer patients using tumor sizes and baseline risk factors: longitudinal modeling approach for durvalumab and durvalumab + tremelimumab
Authors: Tang Mei , Jiang Yu , Si Han , Zheng Yanan , Gao Chen , Gao Guozhi , Angra Natasha , Abdullah Shaad , Higgs Brandon , Roskos Lorin , Narwal Rajesh 
Published: August 2019

Abstract
Background: Durvalumab [D] is a human mAb that binds to PD-L1 and blocks its interaction with PD-1 and CD80. Tremelimumab [T] blocks the inhibitory effects of CTLA-4, and therefore enhances T-cell activation. The objectives of this analysis were to develop a model linking overall survival (OS) to baseline risk factors and changes in tumor size during treatment to identify key factors impacting response to D or D +T.
Methods: The analysis dataset included UC patients from two clinical trials: Study 1108 (D 10 mg/kg Q2W; n=201) and Study 10 (D 20 mg/kg Q4W + T 1 mg/kg Q4W for 4 doses, followed by D 20 mg/kg Q4W alone; n=168). Longitudinal tumor size data were analyzed using a nonlinear mixed effect model with key parameters describing tumor growth, tumor killing, and delay in immune response. Subsequently, a parametric survival model was developed to link baseline risk factors and predicted percent change in tumor size at week 8 to OS.
Results: Tumor kinetic model adequately described the longitudinal tumor size data from UC patients. Baseline tumor size (p&lt;0.01) and PD-L1 status (p&lt;0.01) were identified as significant covariates for tumor killing rate. The most influential factor associated with faster tumor growth was liver metastasis (p&lt;0.01), while higher hemoglobin levels (p&lt;0.01) were associated with decreased tumor growth rate. Based on parametric survival modeling, liver metastasis (~34% decrease in OS, p&lt;0.0001), albumin (~ 1-fold increase in OS per 1g/dL increase, p&lt;0.0001), and percent change in tumor size at week 8 (~52% increase in OS with 30% tumor shrinkage at week 8, p&lt;0.0001) were found to be significant and clinically relevant predictors of OS.
Conclusions: The parametric survival model coupled with tumor kinetic model adequately described clinical outcomes in UC patients treated with D or D+T and enabled identification of key factors potentially impacting response to immune therapy in UC. This approach can be a useful tool for guiding patient selection/enrichment strategies and optimizing trial designs for immuno-oncology (IO) therapies. Further validation and prospective evaluation of this model may be conducted in other IO trials.
Citation Format: Mei Tang, Yu Jiang, Han Si, Yanan Zheng, Chen Gao, Guozhi Gao, Natasha Angra, Shaad Abdullah, Brandon Higgs, Lorin Roskos, Rajesh Narwal. Prediction of overall survival in urothelial cancer patients using tumor sizes and baseline risk factors: longitudinal modeling approach for durvalumab and durvalumab + tremelimumab [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 3158.
Abstract 316: Parallel activation of MEK as a mechanism of resistance to ALK inhibitor therapy
Authors: Huang Vincent , Yan Yingjun , Qiao Huan , Zhang Yunkai , Lovly Christine M. 
Published: August 2019

Abstract
Chromosomal rearrangements of ALK can result in a fusion protein that serves as an oncogenic driver in non-small cell lung cancer (NSCLC). Although patients with ALK-positive (ALK+) lung cancer have significant response rates when treated with tyrosine kinase inhibitors (TKIs), resistance against ALK targeted therapy consistently develops. Here, we modeled acquired resistance to ALK TKI therapy using 5 different FDA-approved ALK TKIs, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib, using two distinct ALK+ lung cancer cell lines, H3122 and STE-1 (10 resistant cell lines total). Both of these cell lines harbor an EML4-ALK E13;A20 fusion and were derived from patients prior to ALK directed therapy. An ALK kinase domain mutation (F1174L) was detected in the H3122 ceritinib resistant cells, but none of the other resistant cell lines harbored mutations in the ALK kinase domain known to confer TKI resistance. For each of the cell lines tested, we found that ALK TKI treatment in TKI-resistant cells failed to inhibit MAP kinase pathway activity. We hypothesized that inhibition of the MAP kinase pathway, via MEK inhibition, could restore drug sensitivity. The allosteric MEK inhibitors, trametinib and binimetinib, did not effectively reduce cell viability as single agents. However, ALK TKI co-treatment with a MEK inhibitor resensitized these cells by reducing cell viability in a synergistic manner across all ALK TKI-resistant cell lines tested. Whole transcriptomic analysis of ALK TKI-resistant cell lines also revealed an upregulation in EGFR and HER2 mRNA levels. These results provide rationale for combined ALK+MEK inhibitor therapy in patients who have relapsed on first line ALK TKI therapy.
Citation Format: Vincent Huang, Yingjun Yan, Huan Qiao, Yunkai Zhang, Christine M. Lovly. Parallel activation of MEK as a mechanism of resistance to ALK inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 316.
Abstract 3160: Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer
Authors: Alcaraz Jordi , Carrasco Josep-Lluís , Millares Laura , Benchea Iuliana-Cristiana , Fernández Francisco-Javier , Martínez Anabel , Pajares María José , Cos Julio Sánchez de , Rami-Porta Ramon , Seijo Luis , Ramírez Josep , Reguart Noemí , Barreiro Esther , Monsó Eduard 
Published: August 2019

Abstract
Tumor associated fibroblasts (TAFs) are essential contributors of the progression of non-small cell lung cancer (NSCLC). Most lung TAFs exhibit an activated phenotype characterized by the expression of α-SMA and fibrillar collagens. However, the prognostic value of these activation markers in NSCLC remains unclear. To address this question we conducted a retrospective multicentric study of the prognostic value of the standard markers of activated fibroblasts. For this purpose, we conducted a quantitative image analysis of α-SMA immunostaining and picrosirius red staining of fibrillar collagens imaged by bright-field and polarized microscopy, respectively, using tissue microarrays with samples from 220 surgical patients, which elicited a percentage of positive staining area for each marker and patient. Kaplan-Meier curves showed that all TAF activation markers were significantly associated with poor survival, and their prognostic value was independent of TNM staging as revealed by multivariate analysis, which elicited an adjusted increased risk of death after 3 years of 129% and 94% for fibrillar collagens imaged with bright-field (p = 0.004) and polarized light (p = 0.003), respectively, and of 89% for α-SMA (p = 0.009). We also found a significant association between all TAF activation markers and tumor necrosis, which is often indicative of hypoxia, supporting a pathologic link between tumor desmoplasia and necrosis/hypoxia. Our findings identify patients with large histologic coverage of fibrillar collagens and α-SMA+ TAFs to be at higher risk of recurrence and death, supporting that they could be considered for adjuvant therapy. Moreover it supports that antifibrotic drugs aiming to target tumor fibrosis may be an effective therapeutic approach to improve survival in NSCLC.
Citation Format: Jordi Alcaraz, Josep-Lluís Carrasco, Laura Millares, Iuliana-Cristiana Benchea, Francisco-Javier Fernández, Anabel Martínez, María José Pajares, Julio Sánchez de Cos, Ramon Rami-Porta, Luis Seijo, Josep Ramírez, Noemí Reguart, Esther Barreiro, Eduard Monsó. Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell 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 3160.
Abstract 3170: BRAF expression is associated with poor survival in colorectal cancers independent of BRAF (V600E) mutation
Authors: Yang Mingli , Schell Michael J. , Yeatman Timothy J. 
Published: August 2019

Abstract
The RAS pathway is known to be commonly activated and a key determinant of colorectal cancer (CRC) biology, with mutational activation of RAS/RAF genes observed in ~50% of CRC patients. The relationship between gene mutation and expression is, however, poorly understood. We analyzed how the expression of RAS/RAF genes vs. their respective mutations impacted outcomes. The relationship to other rarely mutated RAS/RAF genes (HRAS, ARAF, RAF1 (i.e. c-RAF)) was also examined in these tumors. While KRAS expression was positively associated with KRAS mutations (r=0.26, p&lt;0.0001), BRAF expression was, unexpectedly, negativelycorrelated with BRAF (V600E) mutation (r= -0.18, p=0.0001). Thus, a substantial number of patients express relatively high levels of BRAF absent of BRAF mutations. Additional analysis indicates that lower BRAF expression was significantly correlated with MSI or the CMS1 subtype that is strongly associated with BRAF (V600E). Intriguingly, despite negative association with mutant BRAF (V600E) that is well-established to be associated with poor prognosis, higher BRAF expression was also associated with poor overall survival, as indicated by Kaplan-Meier survival analysis of BRAF expression by quartiles in either 458 CRCs (Logrank test for trend p=0.0262) in 406 WT BRAF CRCs (p=0.0102). Note that the expression of all other five RAS/RAF genes (HRAS, KRAS, NRAS, ARAF and RAF1) was not associated with survival. Further analysis with the gene expression signatures measuring RAS pathway activation reveals that unlike BRAF (V600E) (or KRAS mutations or KRASexpression), BRAF expression appeared to be negatively correlated with RAS pathway activation signature scores. Taken together, these data suggest that higher BRAF expression in CRC patients may activate an “alternative” pathway to the canonical pathway directed by mutant BRAF (V600E) as yet another means to deliver tumor progression.
Citation Format: Mingli Yang, Michael J. Schell, Timothy J. Yeatman. BRAF expression is associated with poor survival in colorectal cancers independent of BRAF (V600E) mutation [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 3170.
Abstract 3174: A novel prognostic model for tongue squamous cell carcinoma based on the characteristics of tumor and its microenvironment: iBD score
Authors: Liu Xiqiang 
Published: August 2019

Abstract
Aims: Tumor budding and invasive depth can predict survival of patients with tongue squamous cell carcinoma (TSCC), while the prognostic value of tumor microenvironment (TME) remains unknown. Here, both characteristics of tumor and its microenvironment were examined and a novel prognostic model has been proposed.
Methods: A total of 246 patients with TSCC were included. Using H&E stained sections, pathological parameters of tumor and the TME were assessed. Inflammatory response (i), tumor budding (B), and invasive depth (D) were combined as iBD score. The association between these variables and the patient survival was determined.
Results: Both tumor budding and inflammatory status were independent variables for predicting overall survival (OS) and disease-free survival (DFS) of TSCC patients. Invasive depth was correlated with differentiation, T classification, lymph node metastasis, clinical stage, and recurrence (P&lt; 0.05). The novel iBD model was strongly correlated with T classification, lymph node metastasis, clinical stage, and recurrence, and showed clear distinction of score 0, 1 and 2. High iBD score had a strong association with reduced OS and DFS (P&lt; 0.01).
Conclusions: iBD scoring model is strongly associated with lymph node metastasis and recurrence in TSCC and could be a promising survival predictor for TSCC patients.
Note: This abstract was not presented at the meeting.
Citation Format: Xiqiang Liu. A novel prognostic model for tongue squamous cell carcinoma based on the characteristics of tumor and its microenvironment: iBD score [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 3174.
Abstract 3264: A novel TLR8 agonist induces immune responses and tumor regression
Authors: Wang Yuxun , Yang Heping , Li Huanping , Zhao Shuda , Zhang Yin , Huang Renjie , Wu Jinmiao , Zeng Yikun , Zhang Panpan , Zhang Xingzhong , Wang Longsheng , Fu Guangliang , Wu Zhiheng , Zhu Panhu , Xu Hui , Gao Yaqiao , Wang Pei , Gao Daxin 
Published: August 2019

Abstract
Toll like receptors (TLRs) have been a recent focus of drug discovery for cancer immunotherapy. TLRs play a crucial role in bridging innate and adaptive immunity. TLR8 is distinguished from other TLRs by its functions in reversing regulatory T (Treg) cell and myeloid derived suppressor cell (MDSC)’s immune suppression effects. Treg and MDSCs induce an immunosuppressive microenvironment that is a major cause of failed tumor immunotherapy. Therefore, activation of TLR8 can exert potent immune-mediated anticancer activity. We discovered a novel TLR8 selective agonist DN052 and demonstrated that DN052 clearly differentiated from motolimod, the only TLR8 agonist drug candidate in clinical development. DN052 was more potent than motolimod and exhibited better PK profiles and more strongly induced immune responses in the in vivo monkey and ex vivo human PBMC studies. However, it has been challenging to characterize TLR8 agonists in vivo partially due to the phylogenetic specificity of TLR8 and its diminished activity in rodents. We developed two new in vivo approaches using mouse syngeneic and mouse xenograft tumor models. Our in vivo studies showed that DN052 strongly suppressed tumor growth in a dose-dependent manner as a single agent and combination with the chemotherapeutic agent or PD-1 monoclonal antibody further enhanced the efficacy of the single agents in several tumor models. Remarkably, DN052 caused complete tumor regression as a single agent or in combination in some of the immune-competent tumor-bearing mice. GLP toxicity studies in rats and monkeys showed that DN052 had favorable safety profiles. Taken together, DN052 is a novel Best-in-Class TLR8 selective agonist for immunotherapy as a single agent or in combination with other immuno-oncology agents or chemotherapeutics for broad cancer indications. DN052 warrants further clinical development.
Citation Format: Yuxun Wang, Heping Yang, Huanping Li, Shuda Zhao, Yin Zhang, Renjie Huang, Jinmiao Wu, Yikun Zeng, Panpan Zhang, Xingzhong Zhang, Longsheng Wang, Guangliang Fu, Zhiheng Wu, Panhu Zhu, Hui Xu, Yaqiao Gao, Pei Wang, Daxin Gao. A novel TLR8 agonist induces immune responses and tumor regression [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 3264.
Abstract 327: The impact of PIK3CA/PTEN/AKT1 genes in advanced NSCLC patients with acquired EGFR-TKI resistance and clinical response to EGFR-TKI plus everolimus combination therapy
Authors: Fang Wenfeng , Huang Yihua , Gan Jiadi , Yang Yunpeng , Wu Yifen , Huang Jingbin , Xu Zhiyong , Wang Wenjing , Zhang Li 
Published: August 2019

Abstract
Background EGFR-TKIs have shown remarkable effect in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. Nevertheless, several mechanisms including activation of PI3K/AKT/mTOR pathway have been proved to generate acquired assistance to EGFR-TKIs. In this study, we investigated the genomic characteristics of PI3K pathway in NSCLC patients with acquired resistance to EGFR-TKIs and whether both targeting EGFR and mTOR could reverse resistance.
Methods A total of 605 NSCLC cases who received prior TKI treatment were reviewed, in which 328 patients harboring EGFR-mutants were confirmed to have progressed on one or more TKI and finally enrolled. FFPE tumor or blood samples were collected at the onset of TKI resistance for NGS based panel assay (PIK3CA/PTEN/AKT1 genes and NSCLC driver genes are included). Six patients with co-mutations in EGFR and PI3K pathway who had been heavily treated and progressed on EGFR-TKI received EGFR-TKI plus mTOR inhibitor everolimus combination therapy.
Results In a total of 328 patients, 294 (89.6%) of the patients were adenocarcinomas, 4(12.2%) were small cell lung cancer, while the rest were squamous carcinoma or NSCLC not otherwise specified (30, 9.2%). Forty nine (14.9%) patients with TKI resistant have genomic alterations in PI3K pathway. PIK3CA, PTEN and AKT1variations were detected in 31(9.5%), 18(5.5%) and 3(0.9%) of patients respectively. Three patients had both PIK3CA and PTEN mutations and one patient had co-mutation of PIK3CA/PTEN/AKT1. PIK3CA hotspot mutations of E545, H1047 and E542 accounted for 60.5% of PIK3CA mutations. Six patients were treated with everolimus (5mg) plus EGFR-TKI (2 patients with gefitinib, 250mg; 1 patient with afatinib, 30mg; 3 patients with osimertinib 80mg, daily) combination therapy. One (1/6, 16.7%) patient achieved partial response and the rest (5/6, 83.3%) achieved stable disease. The most common adverse events were dental ulcer (6/6), rash (2/6), pruritis (1/6) and diarrhea (1/6). One patient withdrew combination treatment due to grade 3 dental ulcer.
Conclusions Our study revealed that PI3K pathway was activated in approximately 15% of EGFR-TKI resistant patients. Combination therapy of EGFR-TKIs and everolimus revealed limited antitumor activity in EGFR-TKI resistant NSCLC patients with dysregulation of PI3K pathway.
Citation Format: Wenfeng Fang, Yihua Huang, Jiadi Gan, Yunpeng Yang, Yifen Wu, Jingbin Huang, Zhiyong Xu, Wenjing Wang, Li Zhang. The impact of PIK3CA/PTEN/AKT1 genes in advanced NSCLC patients with acquired EGFR-TKI resistance and clinical response to EGFR-TKI plus everolimus combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 327.
Abstract 3274: LTX-401 as a novel antitumor and immunotherapeutic agent in an experimental liver cancer model
Authors: Mauseth Brynjar , Camilio Ketil , Shi Ji-Hua , Rekdal Øystein , Sveinbjørnsson Baldur , Line Pål-Dag 
Published: August 2019

Abstract
Liver cancer is estimated to be the third most common cause of cancer-related mortality worldwide in both sexes. Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer in which potential curative surgical options are limited and overall survival poor. Hence, there is an unmet need for new and improved therapies. LTX-401 is a novel oncolytic compound with potent antitumor properties. Owing to its amphiphatic nature, LTX-401 may affect the integrity of cancer cell membranes and induce rapid cell death. Transmission electron microscopy indeed revealed a necrotic cell death phenotype accompanied by massive vacuolization of the cytoplasm and dilated mitochondria. Additionally, LTX-401 induces features of immunogenic cell death (ICD) as seen by the extracellular release of ATP and HMGB1, as well as the mitochondrial DAMP cytochrome C. The antitumor effects of LTX-401 has been explored in an experimental model of hepatocellular carcinoma (JM1 model) using immunocompetent rats. When injected into subcutaneously established lesions, the majority of animals went into remission followed by systemic protective immune responses. Additionally, LTX-401 could affect the growth of distal tumor deposits simulating metastases, hence indicating immune-mediated abscopal responses. Intratumoral treatment of orthotopic liver tumors resulted in cure of approximately half of the animals treated, which later displayed protection against subcutaneous tumor (re)challenge. Splenocytes harvested from immunized animals produced significantly larger amounts of IFN-y when stimulated with tumor cells ex vivo, indicating the presence of tumor-specific (memory) T cells. Histological examinations revealed that LTX-401 caused massive hemorrhagic tumor necrosis, both in subcutaneous and intrahepatic compartments, followed by increased infiltration of T cells. Taken together these results indicate that oncolytic compounds generate an immunogenic tumor environment and may be therapeutically exploited as a novel antitumor and immunotherapeutic approach in HCC.
Citation Format: Brynjar Mauseth, Ketil Camilio, Ji-Hua Shi, Øystein Rekdal, Baldur Sveinbjørnsson, Pål-Dag Line. LTX-401 as a novel antitumor and immunotherapeutic agent in an experimental liver cancer model [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 3274.