bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2189: Evaluating efficacy of repurposed drugs in treatment of glioblastoma
Authors: Neal Tristan , Tang Nanyun , Reid George , Byron Sara , Dhruv Harshil , Berens Michael 
Published: August 2019

Abstract
Glioblastoma (GB) is the most aggressive adult brain tumor with a devastating median survival time of about fourteen months post-surgery and standard of care therapy with radiation and temozolomide. The low incidence of GB is a dis-incentive to develop novel therapies. To overcome that obstacle, we investigated the efficacy of repurposing four FDA approved drugs known to cross the BBB, minocycline, propranolol, chlorpromazine, and metformin, to inhibit signaling and metabolism in GB cells. Minocycline is a tetracycline class broad spectrum antibiotic commonly used to treat severe acne and other skin infections. Propranolol is a beta blocker type heart medication primarily used to treat high blood pressure and irregular heartbeat. Chlorpromazine is a phenothiazine antipsychotic usually used for schizophrenia. Metformin is the most widely used first-line oral treatment for type-2 diabetes. Based on a literature survey, minocycline is expected to prevent the phosphorylation of STAT3, a transcription factor downstream of EGFR; propranolol is expected to disrupt EGFR trafficking; chlorpromazine is expected to target the mTOR/AKT pathway; metformin is believed to exploit vulnerabilities in cancer cell metabolism. Efficacy of minocycline in inhibiting EGFR-driven STAT3 activation was investigated using western blot analysis. Our results demonstrate that Minocycline effectively inhibits activation of EGFR-driven STAT3 in U373 glioma cells at 100μM. The ability of chlorpromazine to inhibit the mTOR/AKT pathway was similarly tested via western blot, which showed inhibition of phosphorylated Akt and S6 at 10μM. Efficacy of propranolol in perturbing EGFR trafficking was evaluated using flow cytometry and immunofluorescence, which depicted altered membrane-associated EGFR abundance. Finally, concentration-dependent inhibition of colony formation was tested for all four drugs. Propranolol and minocycline showed potential stimulatory effects at 10μM, but all drugs inhibited cell growth at 50μM and higher. Efficacy of these drugs in treatment of GB is being further evaluated using in vitro neurosphere cultures from patients identified as having the cellular vulnerabilities potentially targeted by these drugs. Successful completion of this project will lead to in vivo efficacy testing of these four drugs in orthotopic GB PDX models.
Citation Format: Tristan Neal, Nanyun Tang, George Reid, Sara Byron, Harshil Dhruv, Michael Berens. Evaluating efficacy of repurposed drugs in treatment of glioblastoma [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 2189.
Abstract 2195: Real-world experience with afatinib as first-line treatment in advanced non-small cell lung cancer in a university hospital
Authors: Jang Taewon , Kim Jaehoon 
Published: August 2019

Abstract
Purpose: In patients with non-small cell lung cancer (NSCLC), mutations in the epidermal growth factor receptor (EGFR) have been associated with sensitivity to EFGR-Tyrosin Kinase Inhibitors (TKIs). The aim of this study was to analyze clinical efficacies of first line afatinib treatment.
Experimental Design: We collected patients with EGFR mutation positive NSCLC who started first-line afatinib treatment between Jan 2015 and Sep 2017. We reviewed clinical characteristics of the patients, laboratory finding, tumor response rate, side effects, progression free survival (PFS), 2nd biopsy result, and overall survival (OS), retrospectively.
Results: Forty six patients were available for analysis among all 62 patients (1st to 8th line chemotherapy). At the time of data analysis in October 2018, nine patients were still on afatinib. Median age was 67.4 years-old. 20 (44%) patient had EGFR 19 deletion, 25 (54%) EGFR L858R mutation, 1 (2%) S768I. 10 patients (21.7%) had brain metastasis at baseline study. Tumor response was 58.7% with partial response, no change 19.6%, progressive disease 2%, and non-evaluable 19.6%. Mean follow-up time was 21.6 months (13.5 to 42.5 month) from start of afatinib treatment. Twenty-eight progression or death events were observed. Median PFS was 13.5 months (95% CI: 10.5 to 16.5 months). There were no differences in smoking, gender, EGFR types. 37 patients (80.4%) had dose reduction from initial dose. 6 patients (13.1%) discontinued due to afatinib toxicity. 6 patients (13%) had G3 toxicity, but usually manageable by dose reduction or supportive care. 1 case of doxycycline induced pneumonitis occurred. The PFS of dose reduction group due to adverse events was longer than standard group (14.9 months vs 10.1 months, p=0.023). In dose reduction group, body weight was low (53.1 kg vs 68.4 kg, p=0.002), the ratio of never smoker (87.9% vs 37.5%, p=0.001) and female (87.4% vs 47.4%, p=0.048) were higher than standard group. After progression, 2nd biopsy was done in 17 patients. T790M mutation was detected in 8 patients, so detection rate was 47.1%. 6 patients received oximertinib treatment. Median OS was 38.6 months.
Conclusions: Afatinib is one of appropriate first-line treatment option for patients with advanced EGFR positive NSCLC. The dose reduction due to adverse events was common in low-body weight female never smoking patients, but the PFS was increased. With use of new 3rd-gen EGFR TKIs in the first-line setting, optimal sequencing of EGFR TKIs needs to be validated in maximizes treatment outcomes.
Citation Format: Taewon Jang, Jaehoon Kim. Real-world experience with afatinib as first-line treatment in advanced non-small cell lung cancer in a university hospital [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 2195.
Abstract 2199: BOS172738: A novel highly potent and selective RET kinase inhibitor in Phase 1 clinical development
Authors: Keegan Mitchell , Wilcoxen Keith , Ho Peter T. 
Published: August 2019

Abstract
Background: RET gene alterations including point mutations and gene fusions have been detected in multiple cancers, including colorectal cancer, NSCLC and various thyroid cancers. RET fusion events involve the kinesin family member 5B (KIF5B-RET), as well as a number of other fusion partners such as CCDC6, TRIM33, and NCOA, and are considered to be the driver mutations in NSCLC and other tumors harboring RET fusions. Selective inhibitors of RET kinase recently has been associated with durable objective responses in patients with RET gene-altered NSCLC and papillary thyroid carcinoma. BOS172738 (formerly DS-5010) is an orally available small-molecule RET kinase inhibitor that has previously been shown to have potent in vitro RET inhibitor activity and in vivo potency against transfected allograft and xenograft models. In this study, we discuss additional in vitro characterization and in vivo efficacy in patient derived xenograft (PDX) models driven by RET fusions and emergent resistant mutations.
Results: An expanded kinase profile was conducted with BOS172738 against over 450 kinases, and demonstrated exquisite potency for RET and RET mutations with Kd values ≤ 1 nM for RETwt, RET(M918T), RET(V804L) and RET(V804M). BOS172738 also demonstrated high selectivity over KDR (&gt;300 fold). To confirm this selectivity in vitro, BOS172738 was compared to ponatinib, a multikinase inhibitor with potent activity against both KDR and RET. While BOS172738 demonstrated similar potency to ponatinib (IC50 0.5 µM vs. 0.3 µM) in inhibiting the in vitro proliferation of a NCO4-RET human CRC cell line (CR1520), it resulted in significantly less anti-proliferative activity in HUVEC normal endothelial cells (IC50 2.9 µM vs 0.2 µM). BOS172738 was also evaluated in a number of PDX models of RET fusion cancers, including three CRC PDX models (CR2518:CCDC6-RET, CR1520: NCOA4-RET and CR2545: CCDC6-RET with a V804M mutation) and one NSCLC PDX model (CTG-0838:KIF5B-RET). In all cases tested, BOS172738 demonstrated potent and durable tumor regression at doses of 30 mg/kg, with tumor growth inhibition at lower doses. BOS172738 also demonstrated potent tumor regression on larger, established tumors (&gt;1000 mm3).
Conclusion: These results support that BOS172738 is a potent and selective RET kinase inhibitor, with strong antitumor activity against a range of RET fusion proteins, as well as resistant RET active site mutations. BOS172738 is currently being evaluated in a Phase 1 clinical study.
Citation Format: Mitchell Keegan, Keith Wilcoxen, Peter T. Ho. BOS172738: A novel highly potent and selective RET kinase inhibitor in Phase 1 clinical development [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 2199.
Abstract 2205: CBT-102, an oral small molecule multi-kinase inhibitor, demonstrates favorable CSF-1R activity, offering means of controlling tumor associated macrophages
Authors: Liu Elaine , Yang Lan , Choy Gavin , Zhang Xiaoling , Pearce Tillman , Reddy Mamatha , Redkar Sanjeev , Shi Qian 
Published: August 2019

Abstract
Background: The role of the tumor microenvironment (TME) in fostering the development of malignancies is prompting the pursuit of anticancer therapies that target its components as to opposed to the tumor itself. As part of their immune surveillance duties, immune cells form part of this microenvironment, and yet, cancer cells have devised means to downplay their tumoricidal capabilities. Colony stimulating factor 1 receptor (CSF-1R) may offer such a means of controlling tumor associated macrophages in the tumor microenvironment.
Methods: The IC50 of CBT-102 against CSF1R was evaluated in both cell free system and cell based assays, where enzyme activity was evaluated with radiometric assay format, and cell growth inhibition was evaluated in the Ba/F3 hCSF1R cell line by the CellTiter-Glo (CTG) method. Further evaluation of CBT-102 IC50 was undertaken in M-NFS-60 syngeneic cell lines and human monocytes. In vivo studies of CBT-102 in combination with anti-PD1 antibody were performed in H22 and MC38 syngeneic models.
Results: CBT-102 demonstrated a reproducible activity against CSF1R in a radiometric enzyme activity assay. Using engineered BaF3 hCSF1R cell lines, we demonstrated the IC50 value of CBT-102 was 0.588 µM compared to 1.333 µM of sulfatinib, a similar multi-kinase inhibitor, and 0.279 µM of GW2580, a more specific CSF1R kinase inhibitor. Similar studies conducted in M-NFS-60 cell lines and human monocyte also showed sub-micromolar activities of CBT-102. In vivo study combining CBT-102 with anti-PD1 antibody in syngeneic models demonstrated a favorable combination effect compared to each of the single agents.
Conclusions: We demonstrated previously that CBT-102 effectively inhibits VEGFR and angiogenesis. The newly revealed mechanism of CBT-102, inhibiting CSF1R and macrophages, offers a promising dual mechanism of action in addition to targeting VEGFR and angiogenesis. Rational combination with check-point inhibitors (CPIs) may improve the efficacy of CBT-102 and broaden the impact of CPIs. Further studies may be needed to delineate the interplay among CBT-102’s different mechanisms and its impact in combination with CPIs.
Citation Format: Elaine Liu, Lan Yang, Gavin Choy, Xiaoling Zhang, Tillman Pearce, Mamatha Reddy, Sanjeev Redkar, Qian Shi. CBT-102, an oral small molecule multi-kinase inhibitor, demonstrates favorable CSF-1R activity, offering means of controlling 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 2205.
Abstract 2210: Discovery of a novel third generation EGFR TKI and identification of its potential mechanism of resistance
Authors: Zhang Tao , Qu Rong , Chen Chengbin , Tong Linjiang , Feng Fang , Chen Yi , Geng Meiyu , Ding Ke , Xie Hua , Ding Jian 
Published: August 2019

Abstract
Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first generation EGFR inhibitors (such as gefitinib and elortinib), however, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR T790M mutation. In this work, we identified a pyrimidine-backbone compound D7 as a novel irreversible inhibitor of EGFR T790M mutation and sensitizing mutation, with selectivity over the wild type EGFR (WT EGFR). D7 exhibited potent in vitro anti-proliferation activity in tumor cells harboring EGFR T790M (NCI-H1975 cells) and sensitizing mutations (PC-9 and HCC827 cells), whereas it showed moderate or weak inhibition in cells expressing WT EGFR. Oral administration of D7 induced dramatic tumor regression in EGFR mutated NSCLC tumor xenograft models as well as in patient-derived xenograft (PDX) model harboring EGFR T790M mutation. To further explore potential mechanisms mediating drug resistance, we constructed D7-resistant cells by prolonged exposure of parental NCI-H1975 cells to gradually increasing concentration of this compound. Resistant cells exhibited signs of apoptosis-resistance to D7 treatment and demonstrated increased sensitivity when combined with Src kinase inhibitors both in vitro and in vivo. Mechanistic investigation revealed that hyperphosphorylation of Src and subsequent activation of anti-apoptotic signaling via Akt pathway contributed to D7 resistance. These results support D7 as a promising third generation EGFR inhibitor deserving further development, and identify potential combination strategies with potential biomarkers for NSCLC tumors that is resistant to this compound.
Keywords: EGFR inhibitor, lung cancer, drug resistance, combination therapy
Citation Format: Tao Zhang, Rong Qu, Chengbin Chen, Linjiang Tong, Fang Feng, Yi Chen, Meiyu Geng, Ke Ding, Hua Xie, Jian Ding. Discovery of a novel third generation EGFR TKI and identification of its potential mechanism of resistance [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 2210.
Abstract 2211: Discovery of orally available and potent MPS1(TTK) kinase inhibitors for anti-cancer drugs
Authors: Lee Younho , Kang Juhee , Kang Sein , Kim Hyunkyung , Seo Kyung-ah , Choi Jieun , Ahn Jaeyoung , Son Jung Beom , Kim Nam Doo 
Published: August 2019

Abstract
There are many cell cycle regulating kinases such as CDKs, Polo, Aurora, Bub, NEK/NimA, etc. Dual specificity protein kinase, MPS1(TTK) is one of them. The role of MPS1 is to regulate spindle assembly checkpoint(SAC) during cell mitosis. The inhibition of MPS1 activity causes cell death by premature mitotic exit. Some of MPS1 inhibitors (NMS-P153, BOS-172722, CFI-402257, BAY-1217389, and BAY-1161909) are in clinical trials. These compounds are treated for solid tumors with or without Paclitaxel. We discovered new orally available and potent inhibitors of MPS1 kinase (MPS1 enzyme IC50 &lt; 10nM / MDA-MB-231 GI50 &lt; 50nM, MDA-MB-468 GI50 &lt; 50nM / HCT116 GI50 &lt; 50nM, F% &gt; 30%). The compounds selectively inhibit MPS1 based on kinase profiling and decrease phosphorylation of MPS1 and Phospho-HH3 signaling, effectively. Some of compounds were selected for further preclinical studies.
Citation Format: Younho Lee, Juhee Kang, Sein Kang, Hyunkyung Kim, Kyung-ah Seo, Jieun Choi, Jaeyoung Ahn, Jung Beom Son, Nam Doo Kim. Discovery of orally available and potent MPS1(TTK) kinase inhibitors for anti-cancer drugs [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 2211.
Abstract 2215: SLFN11 and EZH2 protein expression and localization in circulating tumor cells to predict response or resistance to DNA damaging therapies in small cell lung cancer
Authors: Byers Lauren Averett , Stewart Allison , Gay Carl , Heymach John , Fernandez Luisa , Lu David , Rich Robin , Chu Lincy , Wang Yipeng , Dittamore Ryan 
Published: August 2019

Abstract
Background: A recent phase II trial in recurrent small cell lung cancer (SCLC) demonstrated that patients with high SLFN11 expression in tissue biopsies had improved survival when treated with PARP inhibition (PARPi). EZH2 is also highly expressed in SCLC tissue and is associated with chemo-resistance through epigenetic silencing of SLFN11. Here we developed a liquid biopsy test to explore the clinical feasibility of utilizing SLFN11 and EZH2 expression on circulating tumor cells (CTCs) to aid in the prediction of drug response/resistance of DNA damaging chemotherapy or PARPi in SCLC.
Material and methods: 26 blood samples (19 baseline and 7 on-therapy) from SCLC patients treated at MDACC were sent to Epic Sciences for CTC enumeration (intact DAPI, CK+, cancer cell morphology) and characterization with SLFN11 and EZH2 immunoassays. Nuclear localization and expression of SLFN11 and EZH2 were quantified.
Results: 17/19 (89%) of baseline and 5/7 (71%) post-therapy samples had detectable CTCs. 19/26 (73%) samples had SLFN11+ CTCs and 8/26 (31%) samples had nuclear localized SLFN11. For samples with SLFN11+ CTCs detected, the percentage of SLFN11+ cells ranged from 2.4 to 100%. 10/26 (38%) samples had EZH2+ CTCs and 9/26 (35%) samples had nuclear localized EZH2. For samples with EZH2+ CTCs, the percentage of EZH2+ cells ranged from 19 to 83%. 6 samples had both nuclear localized SLFN11 and EZH2 CTCs detected.
Conclusions: Inter- and intra-sample heterogenous SLFN11 and EZH2 protein expression was observed in SCLC patients. Use of these assays is underway in SCLC patient samples to assess correlation with PARPi and platinum agent response.
Citation Format: Lauren Averett Byers, Allison Stewart, Carl Gay, John Heymach, Luisa Fernandez, David Lu, Robin Rich, Lincy Chu, Yipeng Wang, Ryan Dittamore. SLFN11 and EZH2 protein expression and localization in circulating tumor cells to predict response or resistance to DNA damaging therapies in 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 2215.
Abstract 2224: A panel of autoantibodies against multiple tumor-associated antigens in the early immunodiagnosis of lung cancer
Authors: Jiang Di , Wang Tingting , Pei Lu , Wang Peng , Ye Hua , Song Chunhua , Wang Kaijuan , Zhang Jianying , Dai Liping 
Published: August 2019

Abstract
Lung cancer is the most common cancers worldwide and with very low 5-year survival rate due to lack of effective early diagnostic methods. In our previous study, nine autoantibodies against tumor-associated antigens (TAAs) were identified to be potential biomarkers in detection of lung cancer and this study aimed to find the optimal panel of TAAs to detect lung cancer in the early stage.
Methods A total of 1,130 serum samples were included in this study, including patients with lung cancer, normal control and benign lung diseases patients. Autoantibodies against PSIP1,TOP2A,ACTR3,RPS6KA5,HMGB3,MMP12,GREM1,ZWINT and NUSAP1 were detected by enzyme-linked immunosorbent assay. Logistic regression models were generated from the training set and further validated in another independent set. We also evaluated the ability of the model to detecting benign lung diseases and early-stage lung cancer.
Results Two greater models were selected. One model including 5 autoantibodies panel (GREM1,HMGB3,ZWINT,TOP2A and PSIP1) and another model including 3 autoantibodies panel (GREM1,HMGB3 and PSIP1). Finally, the panel of 3 autoantibodies showed high diagnostic accuracy with areas under the curve (AUC) of 0.711(95 % CI 0.674-0.746) in training cohort and 0.891(95% CI 0.845-0.927) in validation cohort, respectively. The AUC of the model of 3 autoantibodies panel was 0.948(95% CI 0.912-0.972) in discriminate lung cancer and benign pulmonary disease. This model could discriminate early-stage lung cancer patients from normal controls, with AUC of 0.686(95 % CI 0.633-0.735) in training cohort and AUC of 0.911(95 % CI 0.849-0.954) in validation cohort, and the overall AUC for early-stage lung cancer was 0.779(95 % CI 0.738-0.816) when the two cohorts were combined.
Conclusions In summary, it would be more cost-effective and more efficient to use the model with 3 autoantibodies panel which has a high diagnostic performance for lung cancer detection, especially for early-stage lung cancer. And the model may apply a new help for the discrimination for benign pulmonary disease and lung cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Di Jiang, Tingting Wang, Lu Pei, Peng Wang, Hua Ye, Chunhua Song, Kaijuan Wang, Jianying Zhang, Liping Dai. A panel of autoantibodies against multiple tumor-associated antigens in the early immunodiagnosis of 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 2224.