bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3090: In vivo characterization of AMG 510 - a potent and selective KRASG12Ccovalent small molecule inhibitor in preclinical KRASG12Ccancer models
Authors: Rex Karen , Saiki Anne Y. , Sun Ji-Rong , Holt Tyler , Koppada Neelima , Lanman Brian A. , Volak Laurie P. , Foti Robert S. , Cee Victor J. , Lipford J. Russell , Canon Jude 
Published: August 2019

Abstract
Somatic activating mutations of RAS family members are tumor driver mutations found in an estimated 21% of all cancers. Oncogenic KRAS mutations at residues G12, G13, and Q61 represent the most common RAS mutations found in solid malignancies. The prevalence of KRAS p.G12C tumors is ~13% of lung adenocarcinoma (including NSCLC), 3% of colorectal carcinoma (CRC), and 1% to 2% of numerous other solid tumors, representing an unmet medical need. We have developed AMG 510, an orally bioavailable, covalent inhibitor of KRASG12C with potent biochemical and cellular activity, and robust in vivo efficacy. AMG 510 inhibited SOS-catalyzed nucleotide exchange of recombinant mutant KRASG12C/C118A but had minimal effect on KRASC118A, which is wildtype at position 12. In cellular assays, AMG 510 covalently modified KRASG12C and inhibited KRASG12C signaling as measured by phosphorylation of ERK1/2 (p-ERK) in all KRAS p.G12C-mutant cell lines tested but did not inhibit p-ERK in cell lines with various other KRAS mutations. AMG 510 also selectively impaired viability of KRAS p.G12C mutant cell lines but did not affect cell lines with other KRAS mutations. In vivo pharmacodynamic assays demonstrated dose- and time-dependent inhibition of KRASG12Csignaling in human pancreatic and NSCLC tumor xenografts. Covalent modification of KRASG12C by AMG 510 was measured by mass spectrometry and correlated with p-ERK inhibition in tumors. AMG 510 significantly inhibited the growth of KRAS p.G12C xenografts and resulted in tumor regression. Combination treatment of AMG 510 with standard-of-care and targeted agents demonstrated enhanced tumor growth inhibition compared to either single agent. In a syngeneic model of KRAS p.G12C mutant cancer, AMG 510 treatment significantly inhibited tumor growth and caused regression. AMG 510 is currently in Phase 1, first-in-human clinical trials for patients with advanced solid tumors harboring a KRAS p.G12C mutation.
Citation Format: Karen Rex, Anne Y. Saiki, Ji-Rong Sun, Tyler Holt, Neelima Koppada, Brian A. Lanman, Laurie P. Volak, Robert S. Foti, Victor J. Cee, J. Russell Lipford, Jude Canon. In vivo characterization of AMG 510 - a potent and selective KRASG12Ccovalent small molecule inhibitor in preclinical KRASG12Ccancer 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 3090.
Abstract 3121: Osteopontin-c is overexpressed and mediates cell adhesion and proliferation in leukemia cell line with KMT2A-AFF1
Authors: Bastos Ana Clara Santos da Fonseca , Santoro Júlio César , Blunck Caroline Barbieri , Ferreira Luciana Bueno , Pombo-de-Oliveira Maria do Soccro , Emerenciano Mariana , Gimba Etel R. 
Published: August 2019

Abstract
Osteopontin (OPN) primary transcript suffers alternative splicing generating at least five OPN splicing isoforms (OPN-SI) named OPNa, OPNb, OPNc, OPN4 and OPN5. In solid tumors, total OPN (tOPN) expression has been correlated to several cancer features. However, OPN-SI roles in hematological malignancies are still under investigation. A hallmark of B-cell acute lymphoblastic leukemia (B-ALL) is the recurrence of specific gene rearrangements associated with prognostic risk stratification. Patients harbouring the KMT2A-AFF1 fusion gene are included into poor prognostic subgroup, with an overall survival rate of 50% and increased risk of extramedullary sites involvement. In B-ALL, it has been reported that tOPN support tumor dormancy and cell survival in response to chemotherapeutic drugs. However, the specific roles of OPN-SI have not been addressed. The aim of this study was to analyze the expression of OPN-SI in B-ALL samples and then investigate the role of the most overexpressed OPN-SI on modulating cellular and molecular aspects of B-ALL presenting KMT2A-AFF1. We found that OPNc is overexpressed in relation to OPNa and OPNb in patients with KMT2A-AFF1. In addition, OPNc transcript levels were associated with poor prognostic features, such as central nervous system infiltration, white blood cell counting and the high-risk group at diagnosis. In response to OPNc silencing in B-ALL cell lines, we found increased proliferation rates, as opposed to decreased cell adhesion properties over matrigel matrix. Our data evidenced that overexpressed OPNc in B-ALL with KMT2A-AFF1 is correlated to poor prognostic features and may modulate the leukemic phenotype by the decrease of cell proliferation while promoting cell adhesion. Further work should be conducted in order to evaluate OPNc putative application as an additional risk-stratification and prognostic marker for B-ALL and how OPNc could control leukemia development and progression.
Note: This abstract was not presented at the meeting.
Citation Format: Ana Clara Santos da Fonseca Bastos, Júlio César Santoro, Caroline Barbieri Blunck, Luciana Bueno Ferreira, Maria do Soccro Pombo-de-Oliveira, Mariana Emerenciano, Etel R. Gimba. Osteopontin-c is overexpressed and mediates cell adhesion and proliferation in leukemia cell line with KMT2A-AFF1 [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 3121.
Abstract 313: AXL confers intrinsic resistance to osimertinib and the emergence of tolerant cells
Authors: Taniguchi Hirokazu , Yamada Tadaaki , Wang Rong , Tanimura Keiko , Nishiyama Akihiro , Tanimoto Azusa , Adachi Yuta , Takeuchi Shinji , Yamaguchi Hiroyuki , Fukuda Minoru , Takayama Koichi , Mukae Hiroshi , Yano Seiji 
Published: August 2019

Abstract
A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib adversely stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.
Citation Format: Hirokazu Taniguchi, Tadaaki Yamada, Rong Wang, Keiko Tanimura, Akihiro Nishiyama, Azusa Tanimoto, Yuta Adachi, Shinji Takeuchi, Hiroyuki Yamaguchi, Minoru Fukuda, Koichi Takayama, Hiroshi Mukae, Seiji Yano. AXL confers intrinsic resistance to osimertinib and the emergence of tolerant cells [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 313.
Abstract 3136: Discovery of low abundance colorectal cancer related biomarkers by the ADAPT Biotargeting System
Authors: Hornung Tassilo , Zarkovic Jelena , Kassner Michelle , Rosenow Matthew , Miglarese Mark R. , Mayer Günter , Famulok Michael , Spetzler David B. 
Published: August 2019

Abstract
Disease biomarkers play an essential role in disease-diagnostics and in monitoring their responses to therapies. Identification of low to medium abundance biomarkers is one of the biggest challenges in the field. We have developed Adaptive Dynamic Artificial Poly-ligand Targeting (ADAPT), a method in which libraries of single-stranded oligodeoxynucleotides (ssODNs) are enriched for sequences that bind to targets existing in samples in various amounts. Pull-downs with enriched libraries followed by LC-MS/MS allows for the enrichment and identification of low abundance biomarkers that cannot be identified by conventional proteomics.
A highly diverse library of 1011 ssODNs was subjected to multiple rounds of positive selection against formalin-fixed paraffin-embedded (FFPE) colorectal cancer tissue with negative selection against adjacent non-cancer tissue of the same specimen. An enriched library of ~3x106 ssODNs that bound preferentially to cancer tissue was obtained and used in combination with LC-MS/MS to identify biomarkers related to colorectal cancer. Using this approach, a total of 14 proteins were identified in cancer but not in non-cancer tissue lysates. Their identification was only possible due to their enrichment by binding of the immobilized ssODN library to the cancer sample since the same proteins were undetectable by conventional proteomics. Immunohistochemical staining (IHC) of multiple colorectal cancer cases verified that several of the identified target proteins, including nucleophosmin (NPM1) and synaptotagmin-like protein 2 (SYTL2), showed higher expression in cancer tissue compared to adjacent non-cancer tissue.
Our data indicate the potential of the ADAPT platform to profile small differences between cancer affected and unaffected tissue and provide a novel approach for cancer biomarker discovery.
Citation Format: Tassilo Hornung, Jelena Zarkovic, Michelle Kassner, Matthew Rosenow, Mark R. Miglarese, Günter Mayer, Michael Famulok, David B. Spetzler. Discovery of low abundance colorectal cancer related biomarkers by the ADAPT Biotargeting System [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 3136.
Abstract 3172: Prognostic and therapeutic implication of programmed death ligand 1 (PD-L1), microsatellite instability, and PIK3CA gene in lipoarcoma
Authors: Kim Hyo Song , Jeon Hyae Min , Lee Jae Seok , Kim Soo Hee , Lee Young Han , Hur Hyuk , Kim Sung Hoon , Kim Seung Hyun , Jeung Hei-Cheul 
Published: August 2019

Abstract
Background: With the promising efficacies with personalized approach, we tested clinically relevant molecular target programmed death ligand 1 (PD-L1), microsatellite Instability (MSI), and PIK3CA molecules in liposarcoma to provide practical guide.
Methods: A consecutive series of 74 liposarcoma patients who underwent curative resection between 2005 and 2016 were assessed using immuno-molecular panels: PD-L1 (22C3 pharmDx assay) and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry (IHC), MSI using PCR, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization.
Results: For all the cases, PD-L1 was positive only in tumor infiltrating lymphocytes (TILs), while no PD-L1 expression was found on tumor cell and 23% were tumors with PD-L1+ TILs. PD-L1+ TILs was significantly predominant in abdominal site (P=0.004) and had significantly longer overall survival than PD-L1- TILs (5 year OS 84.4% vs 60.8%, P=0.007). Regarding the MSI status, 2 well differentiated liposarcoma showed MSI [MSI-H (n=1) and MSI-L (n=1)]. For concordance with mismatch repair protein using IHC, only 1 out of 8 with concurrent loss of MLH1, MSH6, and PMS2 showed MSI-H (D2S123, D17S250). Activating PIK3CA mutation was detected in 7 patients [9.5%, exon 9 (n=4) and exon 20 (n=3) mutation] and 6 cases were PD-L1-TIL group. PIK3CA copy number gain were detected in 18 (24.3%) cases and significantly associated with PD-L1+TIL tumors (P=0.045).
Conclusions: With our comprehensive immuno-moleuclar panel, liposarcoma need to be categorized based on the molecular genomic subtype and this may facilitate the development of successful future clinical trials using molecular agents.
Citation Format: Hyo Song Kim, Hyae Min Jeon, Jae Seok Lee, Soo Hee Kim, Young Han Lee, Hyuk Hur, Sung Hoon Kim, Seung Hyun Kim, Hei-Cheul Jeung. Prognostic and therapeutic implication of programmed death ligand 1 (PD-L1), microsatellite instability, and PIK3CA gene in lipoarcoma [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 3172.
Abstract 3186: A novel combination therapy for treating advanced drug resistant acute lymphoblastic leukemia
Authors: Vicioso Yorleny M. , Beck Rose , Gram Herman , Asthana Abhishek , Zhang keman , Wong Derek , Letterio John , Parameswaran Reshmi 
Published: August 2019

Abstract
Purpose: Drug resistance and relapse are two major problems in Acute Lymphoblastic Leukemia (ALL) as these patients do not respond to chemotherapy. We observed BAFF-R expression on drug resistant and relapse B-ALL patient cells. We wanted to explore the in vivo therapeutic efficacy of a BAFF-R antibody, optimized for antibody dependent cellular cytotoxicity (ADCC), against drug resistant ALL cells.
Experimental design: ADCC assay was performed using primary human natural killer (NK) cells isolated from normal donors or ALL patients. NK cell mediated cytotoxicity was measured using Calcein-AM assay. Immunocompromised NSG mice were used for in vivo xenograft model of ALL.
Results: We found that anti-BAFF-R antibody enhanced NK cell mediated killing of drug resistant ALL cells in vitro. Early treatment with anti-BAFF-R antibody and NK cells significantly reduced disease burden in xenograft ALL models and increased overall mice survival. However, in advanced disease, the efficacy of NK cells to mediate ADCC is reduced. ALL cells are known to produce TGF beta, that causes NK cell dysfunction. We found that ALL cells produce TGF-β and co-culturing ALL cells with NK cells lead to a decrease in CD16 expression on NK cells, which is reversible by addition of EW-7197, a potent TGF-beta receptor I inhibitor. We found that EW-7197 treatment improved anti-BAFF-R antibody mediated ADCC of drug resistant ALL cells, in vivo, even if treatment is started late.
Conclusion: Combination treatment using BAFF-R antibody, NK cells and EW-7197 is a potential strategy to treat advanced drug resistant ALL patients with BAFF-R expressing blasts.
Citation Format: Yorleny M. Vicioso, Rose Beck, Herman Gram, Abhishek Asthana, keman Zhang, Derek Wong, John Letterio, Reshmi Parameswaran. A novel combination therapy for treating advanced drug resistant acute lymphoblastic leukemia [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 3186.
Abstract 3197: BI-907828, a novel and potent MDM2-p53 antagonist, acts synergistically in a triple combination with anti-PD-1 and anti-LAG-3 antibodies in syngeneic mouse models of cancer
Authors: Rudolph Dorothea , Weyer-Czernilofsky Ulrike , Reschke Markus , Sykora Martina , Rinnenthal Jörg , Blake Sophia , Gremel Gabriela , Wernitznig Andreas , Gollner Andreas , Kraut Norbert , Moll Jürgen 
Published: August 2019

Abstract
MDM2-p53 antagonists block the interaction between the Tumor Protein p53 and MDM2, its key negative regulator, and represent a new therapeutic concept for cancer therapy. MDM2-p53 antagonists are designed to restore p53 activity in TP53 wild-type tumors. Several MDM2-p53 antagonists are currently being evaluated in early clinical development. BI-907828 is a novel and potent MDM2-p53 antagonist with optimized drug-like properties that has shown efficacy in human tumor xenograft models at daily low oral dose as well as intermittent high dose schedules. Recent preclinical studies in syngeneic mouse models of cancer have demonstrated that BI-907828, apart from its direct tumor-targeting activity, also has immunomodulatory activity shown to contribute to efficacy. Single-agent BI-907828 induced anti-tumor immunological memory that controlled tumor growth in a re-challenge study. Moreover, a dual combination with an anti-mouse PD-1 checkpoint inhibitor resulted in synergistic efficacy in a syngeneic mouse model of cancer (AACR 2018, abstract 4866). Here we present data for the triple combination of BI-907828 with two checkpoint inhibitors. In syngeneic mouse tumor models (Colon-26 and B16-F10), the combination of BI-907828 with tool antibodies against mouse PD-1 and mouse LAG-3 shows high response rates of 50-90% with tumor regressions observed for even very large tumors. Moreover, efficacy of the triple combination is superior to each single agent and all dual combinations. An antibody-mediated depletion study suggests a contribution of CD8+ T cells but not of CD4+ T cells to full efficacy of the triple combination. FACS analysis of tumors isolated from Colon-26 tumor-bearing mice indicates that treatment with the triple combination leads to expansion of tumor-infiltrating CD8+ T cells. In summary, BI-907828 is a novel, potent, orally bioavailable MDM2-p53 antagonist that shows synergistic efficacy in a triple combination with antibodies targeting the immune checkpoints PD-1 and LAG-3 in syngeneic mouse models of cancer. BI-907828 is currently under evaluation in a Phase I clinical study (NCT03449381).
Citation Format: Dorothea Rudolph, Ulrike Weyer-Czernilofsky, Markus Reschke, Martina Sykora, Jörg Rinnenthal, Sophia Blake, Gabriela Gremel, Andreas Wernitznig, Andreas Gollner, Norbert Kraut, Jürgen Moll. BI-907828, a novel and potent MDM2-p53 antagonist, acts synergistically in a triple combination with anti-PD-1 and anti-LAG-3 antibodies in syngeneic mouse models of 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 3197.
Abstract 3199: Targeting LHRH-R to improve immune response in ovarian cancer
Authors: Kim Mark S. , Ma Shaolin , Leuschner Carola , Lee Sanghoon , Coleman Robert L. , Sood Anil K. 
Published: August 2019

Abstract
Background: While immune checkpoint inhibitors have revolutionized the treatment of multiple cancers, such therapies have had limited efficacy in ovarian cancer. We hypothesized that a lytic peptide could stimulate local immune response and enhance efficacy of checkpoint blockade. Here, we tested the effects of a synthetic lytic peptide targeting the luteinizing hormone receptor (LHRH-R), EP-100, on immune therapy in ovarian cancer models.
Methods: We carried out series of in vitro (MTT assay, immunoblot analysis, cytokine array, and immune profiling assay) and in vivo (orthotopic mouse model) experiments to determine the biological effects of EP-100 monotherapy and its combination with checkpoint blockade, α-PD-L1.
Results: We found that LHRH-R positive murine ovarian cancer cells (ID8, IG10, IF5, and 2C12) were sensitive to EP-100 and were specifically killed at low micromolar levels through LHRH-R. The in vivo syngeneic mouse models (ID8 and IG10) demonstrated that EP-100 reduced tumor volume, tumor weight, and ascites volume as a single agent. The greatest effects on tumor volume reduction and ascites volume were observed with the combination of EP-100 and α-PD-L1 antibody, indicating a potentially synergistic effect in vivo. Immune profiling of tumors showed that the population of CD8+ T cells, NK cells, dendritic cells, and macrophages were significantly increased in tumor and ascites treated with α-PD-L1, EP-100 and in the combination group. However, monocytic myeloid suppressor cells, B cells, and regulatory T cells were decreased in tumors treated with α-PD-L1, EP-100 and in the combination group. We found similar effects of EP-100 combination with α-PD-L1 antibody in ascites from each group. These data indicate that EP-100 promotes a tumor microenvironment that is favorable for immune response. In vitro cytokine arrays revealed that EP-100 induced IL-1α, IL-33, CCL20, VEGF, and LDLR secretion. Among them, we validated increasing Il-33 level following EP-100 treatment in vivo and in vitro and determined the specific biological role of CD8+ T cell activation with IL-33 gene silencing using siRNA and Cas9-CRISPR approaches. In addition, we found that CD8+ T cell expressed a low level of LHRH-R and had minimal direct effects from EP-100. Conclusion: These data demonstrate strong efficacy of EP-100 and checkpoint blockade therapy. Our results provide new directions to enhance the efficacy of immune therapies for ovarian cancer.
Citation Format: Mark S. Kim, Shaolin Ma, Carola Leuschner, Sanghoon Lee, Robert L. Coleman, Anil K. Sood. Targeting LHRH-R to improve immune response in ovarian 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 3199.
Abstract 3200: Immunotuning CD8+ T cells with BCAT1 inhibition to increase the efficacy of anti-PD-1 therapy and to eradicate moderately immunogenic tumors
Authors: Papathanassiu Adonia E. , Kim Dong-Wook , Park Kwon-Sik , Ko Jeong Hun , Behmoaras Jacques V. 
Published: August 2019

Abstract
Activation and differentiation of adaptive and innate immune cells require metabolic reprogramming involving diverse metabolic processes. Understanding these processes affords the opportunity to influence and ultimately re-direct the function and fate of these cells. Here, we present data suggesting that exposure of newly activated human CD8+ T cells to a small molecule inhibitor (ERG245; 50-400 μM) of BCAT1 (the cytosolic isoform of the enzyme responsible for the first step in the catabolism of leucine, isoleucine, and valine) resulted in inhibition of T cell proliferation, inhibition of IFNγ and Granzyme B production, and upregulation of PD-1. The antiproliferative effect, as determined by CFSE dilution, required inhibition of BCAT1 during the first 24 hrs of T cell activation and it was reversible upon early withdrawal of the inhibitor. Early withdrawal of ERG245 reversed the observed immunosuppression, ultimately giving rise to CD8+ T cells with higher proliferative capacity and increased cytotoxicity compared to untreated control cells. Exposure of CD8+ T cells to ERG245 resulted in a distinct metabolic phenotype including reduced concentrations of α-ketoglutaric acid (αKG), and lower levels of trimethylation of the lysine 4 (K4) and lysine 27 (K27) sites of histone 3 (H3), which implies that BCAT1 inhibition has epigenetic effects on human CD8+ T cells by modulating αKG-dependent histone demethylases. Similar observations were made with CD8+ T cells, isolated from the spleens of Bcat1 KO mice. In vivo, ERG245 (given at 5 mg/kg ip, bid at days 0, 1 and 2 of treatment), dramatically increased the efficacy of an anti-PD-1 antibody (clone RMP1-14; given at 10 mg/kg at days 0, 4, 7, and 11 of treatment) in the CT26 colon cancer model. Specifically, the combination of ERG245 and anti-PD-1 eradicated established tumors within a week of treatment initiation (cure rate of &gt;80%), whereas the monotherapies (ERG245 or anti-PD-1 alone) did not improve the disease outcome. The data suggest that the temporal exposure of moderately immunogenic tumors to BCAT1 inhibition sensitizes the tumors to checkpoint inhibition.
Citation Format: Adonia E. Papathanassiu, Dong-Wook Kim, Kwon-Sik Park, Jeong Hun Ko, Jacques V. Behmoaras. Immunotuning CD8+ T cells with BCAT1 inhibition to increase the efficacy of anti-PD-1 therapy and to eradicate moderately immunogenic tumors [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 3200.