bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 928: Preventing melanoma from healing itself after therapy-induced immune attack through IPRES blockade
Authors: Piva Marco , Sun Lu , Moriceau Gatien , Yang Zhentao , Ribas Antoni , Hugo Willy , Lo Roger S. 
Published: August 2019

Abstract
Over the past few years, therapeutics development for melanoma has led the oncology field, including the development of mutant BRAF-targeted therapies (e.g., BRAF inhibitor (BRAFi)) and immune checkpoint blockade therapies (e.g., anti-PD-1 or aPD-1, aPD-L1, etc). Based on the complementary qualities of aPD-1/L1 immunotherapy (long duration of response) and MAPKi (high rate of initial response), there are currently clinical trials testing the combination of the two. However, despite a more durable tumor suppression, resistance still eventually develops in patients treated by the combination (ref: KEYNOTE-022). My earlier study reported significant intra-patient and intra-tumoral heterogeneity which affect patient-specific responses to therapy. Furthermore, I also observed complex transcriptomic and tumor microenvironment reprogramming associated with resistance to targeted- or immuno-therapies in melanoma. However, the increased immune/stromal cells in the tumor under therapy has prevented us from definitively accounting the source of such reprogramming. To address this need, I utilized the novel single cell transcriptomic analysis to discover therapy-response-associated gene programs across different types of cells within a tumor. In murine mutant BRAF melanoma YUMM1.7, regressing/responding tumors on the 6th day of BRAFi treatment showed significant infiltration of the T cells and other immune cell population and, by the 15th day, the tumor showed activation of IPRES related processes. Combination of BRAFi and aPD-L1 in YUMM1.7 increased the proportion of lymphoid population in the tumor on the 7th day but only incrementally delayed the development of BRAFi resistance. Inhibition of IPRES-related processes (anti-VEGF and/or anti-TGFB) further delayed BRAFi resistance but no complete responses were observed. However, when we employed a UV-mutated subline of the same model, named the YUMMER (Bosenberg lab, Yale), combination of BRAFi, aPD-L1 and IPRES inhibition started to result in durable complete responses in our mouse model. We are now in midst of analyzing the differential response that we observed with this model; our current working hypothesis is that YUMMER induces higher level of antigen-specific antitumor response, which is augmented by the addition of immune checkpoint blockade and IPRES suppression. The results from our study will eventually pave the way to a novel therapeutic combination to overcome melanoma.
Citation Format: Marco Piva, Lu Sun, Gatien Moriceau, Zhentao Yang, Antoni Ribas, Willy Hugo, Roger S. Lo. Preventing melanoma from healing itself after therapy-induced immune attack through IPRES blockade [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 928.
Abstract 931: The T790M mutation is acquired through 5-methylcytosine deamination after EGFR TKI treatment in lung cancer
Authors: Kadi Najwa El , Wang Luo , Davis April , Cooke Alexander , Vadnala Varun , Korkaya Hasan , Kalemkerian Gregory P. , Hassan Khaled A. 
Published: August 2019

Abstract
Background: Epidermal growth factor receptor (EGFR) activation mutations occur in 10-50% of lung adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for stage IV non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, acquired EGFR mutations are the main mechanism of on-target resistance to TKIs. T790M mutation that occurs after first generation TKI treatment, is a cytosine to thymine (C&gt;T) single nucleotide transition leading to a threonine to methionine amino acid change at position 790 (i.e. T790M). Our data suggest that resistant mutations are acquired events secondary to cytosine deamination through Activation Induced Cytosine Deamination enzyme (AICDA). Interestingly, treatment with Osimertinib, that overcomes the T790M mutation, leads to other acquired resistant mutations (C797S, G796S/R and L792F/H) that are mostly cytosine based.
Results: Sub clones of the lung adenocarcinoma cell line PC9 with no evidence of T790M mutation by digital droplet PCR (ddPCR) at baseline, were treated with EGFR TKI. After serially increasing the treatment dose, T790M mutation was detected by ddPCR associated with a significant increase in AICDA expression. Similarly, when the resistant T790M PC9 clones were treated with Osimertinib, the expression of AICDA was also induced. Knocking down AICDA by shRNA or CRISPR-Cas9, decreases the development of T790M in PC9 cell lines after TKI exposure. Using mass spectrometry, we established that cytosine at codon 790 is methylated; thus, deamination of 5-methylcytosine leads to thymine directly, explaining the T790M C&gt;T mutation. In addition, using ChIP assay and pharmacological inhibition we confirm that upon TKI exposure, NFκB binds AICDA promoter and induces its expression. In a mouse xenograft model, the induction of NFκB and AICDA after EGFR TKI exposure is abrogated by concurrent use of an NFκB inhibitor. Finally, patients treated with EFR TKI had an increased expression of AICDA upon progression.
Conclusion: In EGFR driven lung adenocarcinoma, NFκB pathway is activated upon exposure to EGFR TKIs which induces AICDA expression. AICDA deaminates cytosine into other nucleotides leading to treatment resistance.
Citation Format: Najwa El Kadi, Luo Wang, April Davis, Alexander Cooke, Varun Vadnala, Hasan Korkaya, Gregory P. Kalemkerian, Khaled A. Hassan. The T790M mutation is acquired through 5-methylcytosine deamination after EGFR TKI treatment in 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 931.
Abstract 955: Musashi-2 regulates EGFR expression in NSCLC, cell proliferation and survival, response to EGFR inhibitors in EGFR-mutant NSCLC
Authors: Kudinov Alexander , Makhov Petr , Faezov Bulat , Bychkov Igor , Deneka Alexander , Nicolas Emmanuelle , Caid Kathy Q Q. , Brebione Rohan , Avrilf Eleanor , Nikonova Anna S. , Serebriiskii Ilya G. , Borghaei Hossein , Golemis Erica A. , Boumber Yanis 
Published: August 2019

Abstract
Musashi-2 (MSI2) is an RNA-binding protein that regulates mRNA translation. We recently established that MSI2 is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression and drives NSCLC metastasis, in part based on activity supporting a TGF-beta/SMAD3/claudin signaling cascade. Here, reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+;P53R172HΔG/+ murine NSCLC cell lines identified a significant upregulation of HER3 (ERBB3) upon MSI2 depletion. Negative MSI2-dependent regulation of ERBB3 protein was confirmed in multiple murine and human NSCLC models, based on analysis of MSI2 depletion or overexpression. Further, MSI2 positively regulated expression of the epidermal growth factor receptor (EGFR) protein in the same models. Comparing EGFR and KRAS driven models, we found that MSI2 depletion significantly impairs cell proliferation and clonogenicity only in EGFR-mutant NSCLC cell lines. Using RNA immunoprecipitation analysis coupled with qPCR, we show that MSI2 directly binds to EGFR and, to a lesser extent, to HER3 mRNA. MSI2 mRNA binding was correlating with the presence of predicted MSI2 binding sites in corresponding mRNAs. Taken together, this data suggest direct regulation of EGFR protein expression by MSI2 at post transcriptional level. NSCLC lung tissue microarray immunohistochemistry analysis revealed that MSI2 total positivity by H-score, 2+/3+ and 3+ positivity correlated with EGFR 3+ staining. Finally, EGFR inhibitors erlotinib and afatinib synergized with MSI2 depletion in EGFR mutant models, suggesting that therapeutic targeting of MSI2 could be of clinical value, especially in EGFR-mutant lung cancer. In vivo experiments of erlotinib treatments of wild type or MSI2 depleted tumors are ongoing and these results will be presented.
Citation Format: Alexander Kudinov, Petr Makhov, Bulat Faezov, Igor Bychkov, Alexander Deneka, Emmanuelle Nicolas, Kathy Q Q. Caid, Rohan Brebione, Eleanor Avrilf, Anna S. Nikonova, Ilya G. Serebriiskii, Hossein Borghaei, Erica A. Golemis, Yanis Boumber. Musashi-2 regulates EGFR expression in NSCLC, cell proliferation and survival, response to EGFR inhibitors in EGFR-mutant NSCLC [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 955.
Abstract 974: The molecular and genomic drivers of immunologically cold tumors: Novel discoveries from pan-cancer analysis
Authors: Han Guangchun , Wang Ruiping , Shen Jianfeng , Singh Pankaj , Zhang Shaojun , Rao Arvind , Gao Jianjun , Lazar Alexander , Futreal Andrew , Peng Guang , Rai Kunal , Wang Linghua 
Published: August 2019

Abstract
Immune-checkpoint blockade (ICB) is able to elicit remarkable immune response but currently the durable response is limited to a minority of cancer patients. Recent evidence suggests that a prerequisite for the efficacy of ICB, for example the PD-1 inhibitor, is T-cells infiltration in the tumor microenvironment (TME). The immunologically ‘quite’ and T-cell depleted (immune ‘desert’) tumors are less likely respond to ICB. However, we still lack a detailed understanding of the genomic and molecular determinants that drive the ‘cold’ immune phenotypes. We here performed a comprehensive pan-cancer analysis to define and characterize the immunologically ‘hot’ (inflamed) and ‘cold’ (quite or T-cell depleted) tumors by high-dimensional, multi-platform data integration of 9,887 tumors from The Cancer Genome Atlas (TCGA). This study provided an unprecedented catalog of the molecular and genomic drivers of immune ‘cold’ tumors by analyzing the immune cell composition, patterns of their spatial organization within the TME, the dysregulated chemokines networks, somatic mutations, DNA copy-number alterations, aneuploidy status, differentially expressed immune regulatory genes, and enriched signaling pathways. We showed that the immunologic status is highly heterogeneous within and across TCGA tumor types and subtypes. We integrated the information of T-cell spatial organization with our immune phenotypes and found that the ‘band-like’ spatial organization (T cells clustered at the invasive margin of the tumor and didn’t get into the tumor body) pattern is strongly associated with the ‘cold’ phenotype, particularly in colon and stomach cancers. Our analysis revealed a number of other factors that are associated with the ‘cold’ phenotype by either preventing T-cell infiltration or promoting T-cell dysfunction, and we performed functional validation on several targets of interest. This study provided an in-depth understanding of the genomic and molecular determinants of immunologically ‘cold’ tumors and suggested potential biomarkers that can be targeted for the development of novel combination therapy strategies to convert the ‘cold’ tumors into ‘hot’ ones and improve the odds of cancer immunotherapy success.
Citation Format: Guangchun Han, Ruiping Wang, Jianfeng Shen, Pankaj Singh, Shaojun Zhang, Arvind Rao, Jianjun Gao, Alexander Lazar, Andrew Futreal, Guang Peng, Kunal Rai, Linghua Wang. The molecular and genomic drivers of immunologically cold tumors: Novel discoveries from pan-cancer 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 974.
Abstract 981: Degradation of immuno-oncology targets via proprietary PROTAC platform integrating DNA-encoded library technology and rational drug design
Authors: Andersen Jannik N. , McRiner Andrew J. , Fouser Lynette A. , Zhang Junyi , Arora Shilpi , Cordeau Michael , Zhang Ying , Cuozzo John , Briskin Michael , Clark Matt , Ezzeddine Diala 
Published: August 2019

Abstract
Since the first small molecule proteolysis targeting chimera (PROTAC) was reported about a decade ago, great progress has been made in the field of targeted protein degradation. Specially designed, small molecules can recruit the ubiquitin-proteasome system (UPS) to tag a protein of interest (POI) for degradation. Based on the ability to knock down a therapeutic POI (instead of inhibiting the target protein activity), this new modality has emerged as a paradigm-shifting approach and opened new avenues for small molecule drug discovery. At Xios Therapeutics, we have applied targeted protein degradation to a number of immuno-oncology (IO) drug targets and we present here the strategy and lessons learned from building our PROTAC platform in collaboration with X-Chem. Specifically, we have leveraged a vertical integration of DNA-encoded library screening (DEL), structural biology, medicinal chemistry, biochemical binding assays and cellular biomarker readouts for the rapid identification of cell potent degraders. We exemplify a modular, ‘fit-for-purpose’ PROTAC matrix that allows for rapid exploration of optimal E3 ligase-binders conjugated to a POI-binder using either existing or novel ligands identified via DEL. We delineate the structure-activity/property relationship (SAR and SPR) analysis of linker with VHL- and CRBN-based binders for a promising IO target achieving potent protein degradation (&gt;90% degradation and nM DC50 potency) and pathway inhibition in cancer cells. Notably, our affinity-based screening of chemical libraries of unprecedented size (~200 billion molecules) with a priori knowledge of the vector point of attachment from the DNA barcode directly informs the rational design of bifunctional PROTAC molecules. In conclusion, our integrated approach allows us to find new, unexplored compound binding sites for both E3 ligases- and POI-binders that can be utilized by the PROTAC platform to create potent selective degraders and to access targets that have previously been considered undruggable.
Citation Format: Jannik N. Andersen, Andrew J. McRiner, Lynette A. Fouser, Junyi Zhang, Shilpi Arora, Michael Cordeau, Ying Zhang, John Cuozzo, Michael Briskin, Matt Clark, Diala Ezzeddine. Degradation of immuno-oncology targets via proprietary PROTAC platform integrating DNA-encoded library technology and rational drug design [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 981.
Abstract 986: High content analysis of 2D and 3D oncology models for target and phenotypic drug discovery
Authors: Lachize Servane , Bospoort Rhea van de , Silva Marta da Silva da , Steentraten Niki van der , Gowers Ian , Clark Roger , DeGroot Jeroen , Waddell Ian , Schiewe Hajo , Jain Shushant 
Published: August 2019

Abstract
Charles River (CR) has developed many disease-relevant cellular models to screen small molecules and genetic modifiers for target and phenotypic based drug discovery. Our expertise and portfolio in bespoke oncology model development (e.g. patient derived xenografts) covers a wide variety of target classes such as inhibitors of cell cycle, cellular motility and migration and transcription factor translocation. Complex cellular models derived from primary cells, patient derived embryonic stem cells and induced pluripotent stem cells have been adapted for phenotypic screening. Models have been further developed to produce physiologically relevant multicellular structure co-cultures. Combining complex biological systems with multiparametric high content analysis provides detailed single cell quantification of cellular and subcellular biology. Such validated High Content assays can be applied to both target and phenotypic based drug-discovery platforms to support preclinical drug discovery and improve translation of targets and compounds to the clinic.
Citation Format: Servane Lachize, Rhea van de Bospoort, Marta da Silva da Silva, Niki van der Steentraten, Ian Gowers, Roger Clark, Jeroen DeGroot, Ian Waddell, Hajo Schiewe, Shushant Jain. High content analysis of 2D and 3D oncology models for target and phenotypic drug discovery [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 986.
Abstract CT001: Biomarkers of systemic inflammation associated to reduced clinical activity of atezolizumab monotherapy in patients with metastatic triple negative breast cancer
Authors: Li Yijin , Fassò Marcella , Emens Leisha A. , Molinero Luciana 
Published: August 2019

Abstract
Background: Immune checkpoint blockade by anti-PD-L1 antibody atezolizumab has demonstrated clinical benefits in metastatic triple negative breast cancer (mTNBC). IL-6 and IL-8 myeloid inflammation is linked to poor prognosis in cancer patients treated with chemotherapy, but its association with single agent atezolizumab-treated patients with mTNBC remains unknown. In this study, we investigated the association of biomarkers (BM) of systemic inflammation with clinical outcomes in patients with mTNBC treated with atezolizumab monotherapy.
Methods: Baseline pre-treatment plasma samples were collected from mTNBC patients enrolled in the Phase I atezolizumab monotherapy clinical trial PCD4989g (NCT01375842, n = 116). IL-6, IL-8 and CRP were tested by ELISA or Luminex assays and their levels were assessed for association with baseline clinical demographic characteristics and atezolizumab clinical activity for response rate (ORR), progression free (PFS) and overall survival (OS).
Results: Baseline IL-6, IL-8, and CRP levels were positively associated with the clinical prognostic traits ECOG performance status (&gt;0), presence of liver metastases, large size of target lesions (&gt;=6.5cm), and increased LDH (&gt;=1.5xULN). Elevated baseline IL-6 and CRP, but not IL-8, were also linked with later lines of therapy (&gt;=2). Univariate analyses showed that IL-6 (&gt;=15pg/ml), IL-8 (&gt;=11.4pg/ml) and CRP (&gt;=3mg/L) were associated with reduced OS and PFS (Table), but only CRP was associated to reduced ORR. Multivariate analyses considering the aforementioned clinical demographic variables showed that IL-6 (HR 2.00 [1.16-3.38]); and CRP (HR 2.74 [1.49-5.28]), but not IL-8 (HR 1.07 [0.78-1.74]), were associated with OS.
Conclusion: The systemic IL-6/CRP inflammatory axis is an independent factor linked with poor outcomes of mTNBC patients treated with atezolizumab monotherapy and may play unique roles in affecting the anti-tumor activity in this hard to treat patient population.
Table (univariate)BMLow mPFSBMHigh mPFSPFS HR (CI 95%)BMLow mOSBMHigh mOSOS HR (CI 95%)IL-6 (&gt;=15pg/ml)1.45 mo1.35 mo1.87 (1.23-2.83)12.6 mo2.6 mo2.55 (1.63-4.01)IL-8 (&gt;=11.4pg/ml)1.94mo1.34 mo2.00 (1.36-2.95)12.6 mo6.42 mo2.05 (1.34-3.14)CRP (&gt;=3mg/L)2.50 mo1.35 mo2.07 (1.31-3.25)20.5 mo6.9 mo3.33 (1.91-5.79)
Citation Format: Yijin Li, Marcella Fassò, Leisha A. Emens, Luciana Molinero. Biomarkers of systemic inflammation associated to reduced clinical activity of atezolizumab monotherapy in patients with metastatic triple negative breast 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 CT001.
Abstract CT028: Drug-drug interaction potential of EZH2 inhibitor tazemetostat (TAZ)
Authors: Amengual Jennifer E. , Schwartz Gary K. , Inclan Lora , Kumar Abhijeet , Robles-Medina Patricia , Singh-Kandah Shahnaz , Suttle Benjamin , Beelen Melissa , Persky Daniel 
Published: August 2019

Abstract
TAZ, a selective, oral EZH2 inhibitor, is in the phase 2 clinical investigation stage for the treatment of advanced solid tumors (AdvST) and B-cell non-Hodgkin lymphoma (NHL). Drug-drug interaction (DDI) potential of TAZ was investigated in study EZH-105, a phase 1, open-label, 2-part study in adults with AdvST or NHL. In Part A, patients received TAZ 400 mg twice-daily (BID) days 1-24, then 800 mg BID continuously. Moderate CYP3A inhibitor fluconazole 400 mg was administered once daily (QD) days 16-19. Serial blood samples for pharmacokinetic analysis were collected on days 15 and 19. Patients in Part B received TAZ 800 mg BID continuously starting day 2. The CYP2C8 probe repaglinide 0.25 mg and CYP2C19 probe omeprazole 20 mg were administered on day 1 and 1 hour following TAZ administration on day 16. Omeprazole 20 mg QD continued days 17-19. Serial blood samples were collected on days 1, 16, and 19. DDIs were evaluated based on AUC and Cmax. Other primary endpoints included safety of TAZ. As of August 14, 2018, 27 patients were enrolled (n=17 AdvST, n=10 NHL). Median age was 60 years. Preliminary pharmacokinetic results are displayed in the Table. Median treatment exposure was 70 days in Part A and 57 days in Part B. Two patients, both in Part B, discontinued due to treatment emergent adverse events (TEAEs). Grade ≥3 TEAEs were reported in 12 patients. The most frequent treatment-related TEAEs (any grade) included diarrhea (n=6), fatigue (n=6), and nausea (n=3). In conclusion, the likelihood of a clinically significant DDI in the presence of TAZ is minimal.
Table.Preliminary study EZH-105 PK resultsPart A. The effect of fluconazole on TAZParameterTAZ alone Day 15 Mean (%CV)TAZ + fluconazole Day 19 Mean (%CV)TAZ, n=14Cmax, ng/ml426 (95)968 (80)AUC0-12h, ng*h/mL1590 (81)5180 (66)Part B. The effect of TAZ on REP and OMPREP + OMP Day 1 Mean (%CV)REP + OMP + TAZ Day 16 Mean (%CV)REP, n=12Cmax, ng/ml5 (109)10 (78)AUC0-7h, ng*h/mL9 (110)17 (65)OMP, n=12Cmax, ng/ml263 (266)220 (250)AUC0-7h, ng*h/mL677 (340)558 (231)Part B. The effect of OMP on TAZTAZ prior to OMP Day 16 Mean (%CV)TAZ + OMP Day 19 Mean (%CV)TAZ, n=9Cmax, ng/ml613 (91)663 (68)AUC0-12h, ng*h/mL2200 (58)2820 (62)AUC, area under the concentration curve; CI, confidence interval; Cmax, maximum plasma concentration; CV, coefficient of variation; REP, repaglinide; OMP, omeprazole; PK, pharmacokinetic; TAZ, tazemetostat.
Citation Format: Jennifer E. Amengual, Gary K. Schwartz, Lora Inclan, Abhijeet Kumar, Patricia Robles-Medina, Shahnaz Singh-Kandah, Benjamin Suttle, Melissa Beelen, Daniel Persky. Drug-drug interaction potential of EZH2 inhibitor tazemetostat (TAZ) [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 CT028.