bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-204: DNA vaccine co-expressing Her2/ErbB2 antigen, fused with LAMP, elicits strong antitumor effects in vivo by increasing tumor infiltration with CD8+ T cells
Authors: Xu Renhuan , Heiland Teri 
Published: August 2019

Abstract
DNA vaccines have emerged as an attractive immunotherapeutic approach against infectious diseases and cancer due to its fast, efficient design and validation. It remains, however, a challenge in clinical settings due to historically low levels of immunogenicity in humans. In order to enhance the immunogenicity of DNA vaccines used as a cancer therapy, we have developed a nucleic acid platform, UNITE (UNiversal Intracellular Targeted Expression), which combines novel delivery methods and adjuvants which complement our lysosomal targeting technology. Fusing a tumor associated antigen (TAA) with the Lysosomal Associated Membrane Protein 1 (LAMP-1), we can activate Ag specific CD4+ T cells by targeting the major histocompatibility complex II compartment. In this study, we selected ErbB2/Her2 as the cancer target because it is a broadly overexpressed and well-characterized oncoantigen.
Mice vaccinated with Her2-LAMP DNA demonstrate robust Her2-specific CD4+ and CD8+ T cells, in addition to antibody responses, which in turn have significant antitumor effect in murine breast and bladder tumor models. Moreover, we demonstrate that the Her2-LAMP vaccine promotes CD8+ T cell tumor infiltration to a greater degree than when compared to a traditional DNA vaccine without LAMP. In summary, we show that UNITE as a nucleic acid platform, can enhance antitumor immunity in vivo.
Citation Format: Renhuan Xu, Teri Heiland. DNA vaccine co-expressing Her2/ErbB2 antigen, fused with LAMP, elicits strong antitumor effects in vivo by increasing tumor infiltration with CD8+ T 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 LB-204.
Abstract LB-236: Genomic characterization of circulating tumor cells in de novo metastatic prostate cancer
Authors: Chai Shoujie , Malihi Paymaneh D. , Apariciop Ana M. , Chapin Brian F. , Lin Matthew , Storgard Ryan , Velasco Carmen Ruiz , Kolatkar Anand , Hicks James , Kuhn Peter 
Published: August 2019

Abstract
Background: The absence of biomarkers that identify clinically meaningful biological subsets of prostate cancer results in the homogeneous application of systemic therapies to a heterogeneous disease and hampers therapy development. This heterogeneity may become more evident at the molecular level under the pressure of androgen withdrawal. Here, we longitudinally characterized peripheral blood circulating tumor cells (CTCs) from patients with de novo metastatic prostate cancer to examine the phenotypic and genomic changes induced by androgen suppression.
Methods: Peripheral blood samples were collected at MD Anderson Cancer Center from a cohort of DNM1PCa patients under clinical trial NCT01751438. Timepoints of collection includes baseline (BSL, before treatment) and 6 months (6mo, after 6 months of systemic therapy). We used the High-Definition Single Cell Assay (HD-SCA) workflow for CTC enumeration, morphology (nuclear size, DAPI intensity, cytokeratin (CK), androgen receptor (AR) intensity and genomics (whole-genome copy number aberration analysis) evaluation. This workflow utilizes an enrichment-free fluorescence based (DAPI/ CK/ CD45/ AR) CTC identification system and single-cell genomic sequencing.
Results: Twenty-nine of the 58 available blood samples contained CTCs: 15 of the 28 (53.6%) collected at BSL (median 2.00 CTCs/mL, range 0.84-74.15) and 14 of the 30 (46.7%) collected at 6mo (median 2.43 CTCs/mL, range 0.96-13.85). However, at the 6mo timepoint, the CTCs had undergone a significant morphological shift in nuclear area local ratio (BSL vs 6mo: 1.036 vs 1.165, p=0.039), DAPI intensity (0.199 vs 1.030, p=0.036), CK intensity (18.978 vs 15.651, p=0.006), AR intensity (0.681 vs -0.468, p=0.037) and AR+ percentage (36.25% vs 15.38%, p=0.020). Further, genomic analysis of two patients at BSL indicated copy number aberrations including PTEN, TP53, RB1 and BRCA2 loss and MYC gain.
Discussion: This study aims at characterizing changes induced by systemic therapies in CTC potential biomarkers that identify distinct subsets of disease biology. The changes observed in patient subsets may serve as clinically relevant biomarkers to optimize treatment and improve prognosis.
Citation Format: Shoujie Chai, Paymaneh D. Malihi, Ana M. Apariciop, Brian F. Chapin, Matthew Lin, Ryan Storgard, Carmen Ruiz Velasco, Anand Kolatkar, James Hicks, Peter Kuhn. Genomic characterization of circulating tumor cells in de novo metastatic 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 LB-236.
Abstract LB-252: Group-based smoking cessation treatment for incarcerated men: A pilot study
Authors: Valera Pamela , Acuna Nicholas 
Published: August 2019

Abstract
Introduction. Cigarette smoking is the leading cause of morbidity and mortality that contributes to over six million deaths worldwide and is projected to cause more than eight million deaths per year by 2030. Overall cigarette smoking rates in the United States (U.S.) is estimated at 14%, but this number increases to 50-83% of smokers within correctional populations.
Methods. Using a cohort study design, sixteen incarcerated male smokers from a Northeastern state maximum prison facility in the U.S. participated in a 4-week group-based smoking cessation treatment program with nicotine replacement therapy and a one-month follow-up period to determine quit behaviors and abstinence. The goal of this pilot study was to explore the feasibility, acceptability, and efficacy of a smoking cessation group treatment intervention for incarcerated smokers where tobacco products are permitted.
Results. In this feasibility study, the average age of participants enrolled was 43 (SD = 13.69), and their first incarceration was at 19 (SD = 7.30). The majority of the participants identified as African American/Black (62.5%), 31.3% identified as Caucasian/White, and 6.3% identified as Hispanic/Latino as their race/ethnicity. The average age where individuals started smoking was 13.8 (SD = 3.2) and the total number of years smoked is 25.6 (SD = 14.9). The mean of cigarettes smoked each day was 13.0 (SD = 9.8). More than half of the people in the study indicated that they relight their cigarettes. Additionally, the two brands that participants indicated as their favorite were Kite (18.8%) and Newport (68.8%). Of all the participants, 87.5% indicated that they smoked menthol cigarettes. Majority of the participants indicated the importance of quitting tobacco (8.80 ± 1.82) and that they had a very difficult time during their previous quit attempts (43.8%). Previous quit attempts included forced abstinence while in solitary confinement or administrative segregation. At the 4-week follow up period, half of the participants that were enrolled in the group-based smoking cessation treatment and completed the program indicated that they did not smoke or use tobacco in the past 7-days or since their initial quit date (50.0%).
Conclusion. Group-based smoking cessation treatment should be prioritized as an effective intervention to aid incarcerated smokers to quit smoking. This study builds upon our growing knowledge of tobacco dependence and smoking cessation treatment, with a focus on individuals involved in the criminal justice system.
Citation Format: Pamela Valera, Nicholas Acuna. Group-based smoking cessation treatment for incarcerated men: A pilot study [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 LB-252.
Abstract LB-255: Acquired and intrinsic resistance to vemurafenib in BRAFv600e-driven melanoma brain metastases
Authors: Gooijer Mark C. de , Zhang Ping , Buil Levi C. , Freriks Stephan , Li Gang , Beijnen Jos H. , Tellingen Olaf Van 
Published: August 2019

Abstract
Purpose: BRAFV600-mutated melanoma brain metastases (MBMs) are generally responsive to BRAF and MEK inhibitors, albeit that responses are generally less durable than of extracranial metastases. We have studied the impact of the drug efflux proteins P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) at the blood-brain barrier (BBB) on the efficacy of vemurafenib against BRAF-mutated A375 MBMs.
Experimental design: We have implanted BRAF-mutated A375 tumor cells in the brains of wildtype and Abcb1a/b;Abcg2-/- mice. We characterized the BBB in the tumors, treated the mice with oral vemurafenib, analyzed drug levels in plasma and brain lesions and determined the efficacy in brain metastases and subcutaneous lesions.
Results: Although A375 MBMs disrupt the integrity of the BBB, as shown by contrast-enhanced MRI, vemurafenib achieves greater antitumor efficacy in Abcb1a/b;Abcg2-/- mice compared to wild-type mice. P-gp and BCRP in brain tumor vessels limit vemurafenib penetration into A375 MBMs. Vemurafenib efficacy in both strains was similar against subcutaneous A375 tumors. Intriguingly, although initially responsive, A375 MBMs rapidly developed therapy resistance, even in Abcb1a/b;Abcg2-/- mice, and this was unrelated to pharmacokinetic or target inhibition issues. Rather, MBMs likely resorted to non-canonical growth signaling, as target inhibition of canonical MAPK and PI3K pathway signaling components was maintained in resistant intracranial A375 tumors.
Conclusions: In line with clinical data, BRAFV600E-positive MBMs are less responsive to vemurafenib. This is partly due to protection by the BBB, but also because they rapidly acquire further resistance by resorting to non-canonical growth signaling.
Citation Format: Mark C. de Gooijer, Ping Zhang, Levi C. Buil, Stephan Freriks, Gang Li, Jos H. Beijnen, Olaf Van Tellingen. Acquired and intrinsic resistance to vemurafenib in BRAFv600e-driven melanoma brain metastases [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 LB-255.
Abstract LB-256: PDGFRβ blockade bypasses resistance to combined MEK1/2-JAK2 inhibition in triple-negative breast cancer via intratumoral CD8+ T-cells infiltration
Authors: Kalimutho Murugan , Khanna Kum Kum 
Published: August 2019

Abstract
Despite the increasing progress in breast cancer research, currently there is no targeted therapy available for TNBC. Here, we demonstrated a novel resistance mechanism mediated by PDGFRβ in TNBC cells. We showed that TNBC cells exposed to JAK2 or MEK1/2 inhibitors promote PDGFRβ upregulation. Using publically available databases, we found that basal-like breast cancer patients expressing high PDGFRβ exhibit poor relapse-free survival. We found that JAK2 overexpression controls PDGFRβ protein degradation. Blockade of PDGFRβ with JAK2 and MEK1/2 inhibitors significantly impacted the CD44+/CD24- stem-cell-like cells and the growth of basal-like breast cancer xenografts in vivo through intratumoral CD8+ T cells in a manner that is reversed by anti-CD8 antibody treatment. Together, these findings reveal a novel regulatory role of JAK2-mediated PDGFRβ proteolysis and provide an example of a PDGFRβ-mediated resistance mechanism upon JAK2 and MEK1/2 inhibition in TNBC.
Citation Format: Murugan Kalimutho, Kum Kum Khanna. PDGFRβ blockade bypasses resistance to combined MEK1/2-JAK2 inhibition in triple-negative breast cancer via intratumoral CD8+ T-cells infiltration [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 LB-256.
Abstract LB-262: Targeting of the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting the induction of glucocorticoid receptor
Authors: Adelaiye-Ogala Remi M. , Kelly Kathleen , VanderWeele David 
Published: August 2019

Abstract
Background: An evolving concept that contributes to the understanding of resistance to androgen deprivation therapy and/or androgen receptor (AR) antagonist in prostate cancer is the ability of the cells to bypass AR blockade and turn on compensatory hormone signaling for survival. Recent preclinical and clinical studies demonstrate that induction of GR expression confers resistance to AR-targeted therapy. Hence therapeutic strategies to overcome GR-mediated resistance are warranted.
Experimental Design: Prostate cancer cell-lines and patient derived xenograft (PDX) models were exposed to the pan-AKT inhibitor ipatasertib or other PI3K/AKT- pathway inhibitors with or without AR blockade. AR and GR array determined differentially expressed AR/GR target genes. Protein expression levels were measured. Cell viability and tumor growth was determined in response to treatment.
Results: AKT inhibitor as monotherapy significantly decreases cell viability across multiple prostate cancer models. The cytotoxic effect is enhanced by AR inhibition and is most pronounced in models that induce compensatory GR expression. The pan-AKT inhibitor ipatasertib as well as other inhibitors of the PI3K/AKT pathway decreased GR activity through AR-dependent and AR-independent mechanisms. Importantly, AKT inhibition, with and without AR blockade, demonstrated significant anti-tumor activity in several in vivo prostate cancer models with no noticeable toxicity.
Conclusion: Inhibition of the PI3K/AKT pathway blocks GR activity and overcomes GR-mediated resistance to AR-targeted therapy. This therapeutic approach has immediate clinical relevance as ipatasertib is currently in advanced clinical development and provides a supportive tool for how to manage patients with acquired resistant to AR-targeted therapy.
Citation Format: Remi M. Adelaiye-Ogala, Kathleen Kelly, David VanderWeele. Targeting of the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting the induction of glucocorticoid receptor [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 LB-262.
Abstract LB-274: Identification and characterization of LY3410738, a novel covalent inhibitor of cancer-associated mutant Isocitrate Dehydrogenase 1 (IDH1)
Authors: Brooks Nathan , DeWalt Robin , Boulet Serge , Lu ZhaoHai , Kays Lisa , cavitt Rachel , Gomez Sandra , Strelow John , Milligan Paul , Roth Kenneth , Bauer Renato , Antonysamy Stephen , Hahn Patric , Rankovic Zoran , McCann Denis , Mo Gary , Tiu Ramon , Burkholder Timothy , Geeganage Sandaruwan , Gilmour Raymond 
Published: August 2019

Abstract
Somatic gain-of-function mutations in IDH1 have been identified in multiple tumor types including AML, glioma, cholangiocarcinoma and chondrosarcoma. The neo-enzymatic activity of mutant IDH1 results in accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), leading to a hyper-methylation phenotype, a block in cell differentiation, and tumor growth. Using a structure-based drug design approach, we have developed a highly potent covalent inhibitor of mutant IDH1. LY3410738 modifies a single cysteine (Cys269) in the allosteric binding pocket and rapidly inactivates the enzyme with a KI/Kinact = 84,257 M-1sec-1. The compound selectively inhibits the 2-HG in IDH1 mutant tumor cells without depleting the levels of a-ketoglutarate. Using patient-derived primary AML cells, we demonstrated that LY3410738 was more potent than AG120 in reversing the block in differentiation associated with IDH1 mutant activity. In vivo, LY3410738 displayed prolonged pharmacodynamic activity, depleting 2-HG levels in tumors at low circulating exposures and for an extended time after clearance of compound. Importantly, LY3410738 has the ability to cross the blood-brain barrier and can achieve concentrations in the brain that exceed those needed to engage the target. Consistent with this, LY3410738 effectively inhibits 2HG in orthotopic glioma models. Using patient-derived IDH1 mutant orthotopic AML models, we demonstrated that LY3410738 effectively inhibited 2-HG, induced differentiation, and cleared AML from mice. Collectively, LY3410738 represents the first covalent brain-penetrant mutant IDH1 inhibitor with potential for Best-in-Class activity.
Citation Format: Nathan Brooks, Robin DeWalt, Serge Boulet, ZhaoHai Lu, Lisa Kays, Rachel cavitt, Sandra Gomez, John Strelow, Paul Milligan, Kenneth Roth, Renato Bauer, Stephen Antonysamy, Patric Hahn, Zoran Rankovic, Denis McCann, Gary Mo, Ramon Tiu, Timothy Burkholder, Sandaruwan Geeganage, Raymond Gilmour. Identification and characterization of LY3410738, a novel covalent inhibitor of cancer-associated mutant Isocitrate Dehydrogenase 1 (IDH1) [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 LB-274.
Abstract LB-276: Farnesyltransferase inhibitor (FTI)-induced growth inhibition of HRAS-mutant head and neck cancers is enhanced by concurrently inhibiting compensatory upregulation of the ERK-MAPK kinase cascade
Authors: Javaid Sehrish , Nguyen Victoria V. , Waters Andrew M. , Goodwin Craig M. , Der Channing J. , Cox Adrienne D. 
Published: August 2019

Abstract
Activating mutations in the HRAS oncogene are present in 5-11% of head and neck squamous cell carcinomas (HNSCC), but whether mutant HRAS drives HNSCC growth was not known. The clinical candidate FTI, tipifarnib, is currently under investigation in HRAS-mutant HNSCC, but whether patient responses to tipifarnib are due to blocking HRAS membrane association or due to action on another FTI target/s is also unclear. We found that the FTIs tipifarnib and lonafarnib inhibited the growth of HRAS-mutant HNSCC in a target-dependent manner, blocking HRAS farnesylation and membrane association. We also found that genetic depletion of mutant HRAS inhibited the anchorage-dependent and -independent growth of HRAS-mutant HNSCC cell lines in vitro and robustly induced apoptosis, indicating HNSCC dependence on mutant HRAS and a correlation between FTI-mediated growth inhibition and blockade of HRAS function. Tumor types driven by other RAS isoforms, such as KRAS-driven pancreatic cancer, are highly dependent on the ERK MAPK effector pathway and are sensitive to pharmacological inhibitors of ERK1/2 (ERKi: SCH772984, BVD-523). In contrast, we found that HRAS-driven HNSCC was resistant to growth inhibition by ERKi alone, despite strong target inhibition as indicated by decreases in pRSK and MYC protein levels. Consistent with this finding, genetic depletion of HRAS not only failed to reduce MAPK signaling but instead caused compensatory upregulation. Similarly, FTI treatment also induced upregulation of MAPK signaling, which is typically growth-promoting. We therefore speculated that the addition of ERKi would enhance responses to FTIs, and indeed found that ERKi synergistically enhanced FTI-mediated apoptosis and growth inhibition. Our results provide a mechanistic rationale for adding ERKi to FTI to improve clinical responses in HRAS-mutant HNSCC, and suggest that monitoring MAPK pathway activation may be a useful marker for emerging FTI resistance in this patient population.
Citation Format: Sehrish Javaid, Victoria V. Nguyen, Andrew M. Waters, Craig M. Goodwin, Channing J. Der, Adrienne D. Cox. Farnesyltransferase inhibitor (FTI)-induced growth inhibition of HRAS-mutant head and neck cancers is enhanced by concurrently inhibiting compensatory upregulation of the ERK-MAPK kinase cascade [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 LB-276.
Abstract LB-284: miRNAs/Ago2/YY1/PcG protein/DNMT complex mediates epigenetic silencing in bortezomib-induced apoptosis of leukemia
Authors: Wang Ju-Ming 
Published: August 2019

Abstract
miRNAs are a class of non-coding RNAs, which bind to the 3'-untranslated regions of their target mRNAs to repress translation. However, the details of miRNA-mediated epigenetic regulation targeting genomic DNA remained largely unknown. Here, we demonstrated that transcription factor CCAAT/enhancer binding protein delta (CEBPD) was responsive to the anticancer drug bortezomib, is a highly selective reversible inhibitor for leukemia treatment, and resulting in caspase activation and apoptosis. Interestingly, following the identification of CEBPD-induced miRNAs, we found that miR-744, miR-3154 and miR-3162 feedback to suppress the transcription of CEBPD itself and genes adjacent to its 5'-flanking region, including protein kinase DNA-activated catalytic polypeptide (PRKDC), minichromosome maintenance-deficient 4 (MCM4) and ubiquitin-conjugating enzyme E2 variant 2 (UBE2V2), upon bortezomib treatment. Additionally, we previously demonstrated that the Yin Yang 1 (YY1)/polycomb group (PcG) protein/DNA methyltransferase (DNMT) complex is important for mediating epigenetic silencing of the CEBPD gene; we further found that Argonaute 2 (Ago2) interacts with YY1 and binds to the CEBPD promoter. Moreover, we revealed that miRNA binding plays a key role for YY1/PcG group protein/DNMT complex-mediated epigenetic gene silencing and is associated with bortezomib-induced methylation on genomic DNA. Altogether, we provided new insights for miRNA-mediated epigenetic regulation in the case of bortezomib-induced cell death in leukemia.
Citation Format: Ju-Ming Wang. miRNAs/Ago2/YY1/PcG protein/DNMT complex mediates epigenetic silencing in bortezomib-induced apoptosis of 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 LB-284.