bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3819: Amphiregulin in damaged tumor microenvironment potentiates therapeutic resistance and enables PD-L1-mediated immunosuppression
Authors: Xu Qixia , Coppé Jean-Philippe , Campisi Judith , Lam Eric , Sun Yu 
Published: August 2019

Abstract
Therapeutic resistance is the major barrier to conquer human cancer, the most lethal pathology that claims numerous lives per year. Although identification of resistance mechanisms is the key to develop optimal strategies, progress has been limited due to long term failure to reveal the most critical targets. Cancer cells exhibit high plasticity even in clinical settings, a phenomenon that contributes to disease refraction by developing intrinsic or acquired resistance. Here we highlight the multifaceted and genetically conserved senescence-associated secretory phenotype (SASP), which encodes a large array of soluble factors including amphiregulin (AREG). Expression of AREG is markedly inducible by DNA damage to stromal cells in the tumor microenvironment (TME), a process mediated predominantly by the NF-κB complex and C/EBP family. Stromal AREG remarkably enhances the malignancy of cancer cells including acquired resistance, mainly by activating the EGFR pathway and causing a distinct epithelial to endothelial transition (EET). Paracrine AREG induces PD-L1 expression in recipient cancer cells, thereby creating an immunosuppressive TME via immune checkpoint activation. Therapeutic targeting AREG by a monoclonal antibody not only remarkably deprived cancer cells of chemoresistance, but achieved prominent efficiency when combined with classical chemotherapy in humanized animals with restored immunocompetency. Stromal AREG enters circulation and is readily detectable in the peripheral blood of post-treatment patients, representing a novel liquid biopsy biomarker for therapeutic evaluation and disease prognosis. Our study substantiates the potential of in vivo SASP in driving the TME-mediated drug resistance and shaping an immunosuppressive niche, and provides the proof-of-principle of targeting major SASP factors to effectively improve therapeutic index with reduced mortality.
Citation Format: Qixia Xu, Jean-Philippe Coppé, Judith Campisi, Eric Lam, Yu Sun. Amphiregulin in damaged tumor microenvironment potentiates therapeutic resistance and enables PD-L1-mediated immunosuppression [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 3819.
Abstract 3843: LSD1 modulation by allosteric ligands
Authors: Emond Wei B. , Geitmann Matthis , Jarvius Malin , Koehler Konrad , Källblad Per , Niklasson Mia , Parrow Vendela , Sawant Rajiv , Sjöberg Maria , Winquist Johan , Segerman Anna , Bremberg Ulf 
Published: August 2019

Abstract
LSD1 has emerged as a potential therapeutic target for a number of cancer types (e.g. AML, SCLC, colorectal, breast, liver, prostate, glioblastoma, Ewing sarcoma), as well as sickle cell anaemia and Alzheimer’s disease. Irreversible LSD1 catalytic inhibitors have shown limited clinical efficacy in AML and SCLC, while solid tumours are largely unaddressed. This is in contrast to LSD1 knockdown with impact on a wide range of cancers, indicating that LSD1 functions other than enzymatic should be targeted.
We have developed novel small molecules that modulate LSD1 via an allosteric site - without inhibiting its enzymatic function - inducing a 60% reduction of nuclear LSD1 levels. The sensitivity profile in a cancer cell line panel is unique and dissimilar to &gt;300 diverse reference compounds. In vitro efficacy is observed in glioma-initiating clones that are highly resistant to standard-of-care temozolimide as well as catalytic LSD1 inhibitors. Efficacy in the sub-µM range is observed with other solid tumour models, e.g. prostate cancer. The compounds exhibit synergy (Bliss independence &gt;40%) with HDAC inhibitors as evaluated by viability in cellular cancer models, including lung, liver and glioblastoma.
Pharmacokinetic studies show good blood-brain-barrier penetration and oral availability of the allosteric LSD1 modulator BEA-17. A repeat dose of 25 mg/kg was well tolerated by NOD SCID mice, leading to µM level accumulation in the brain. Results from orthotopic glioblastoma PDX models, and in vivo hollow-fiber models of other solid tumours will be presented, as well as mechanistic insights from biophysical assays and gene expression analysis.
Citation Format: Wei B. Emond, Matthis Geitmann, Malin Jarvius, Konrad Koehler, Per Källblad, Mia Niklasson, Vendela Parrow, Rajiv Sawant, Maria Sjöberg, Johan Winquist, Anna Segerman, Ulf Bremberg. LSD1 modulation by allosteric ligands [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 3843.
Abstract 3846: Targeting epigenetic dysregulation in isocitrate dehydrogenase mutant glioblastoma
Authors: Sears Thomas K. , Datta Sandipan , Cortopassi Gino , Angelastro James , Woolard Kevin 
Published: August 2019

Abstract
Glioblastoma (GBM) is an incurable form of brain cancer with a median survival time (MdST) of ~15 months after treatment with chemoradiotherapy. Identification of a CpG Island Methylator Phenotype (CIMP) subtype of GBM (G-CIMP), represents a significant clinical discovery, as these patients have an enhanced survival, with a MdST of 3 years. G-CIMP is characterized by a mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2), which results in production of the oncometabolite 2-hydroxglutarate, an inhibitor of α-ketoglutarate-dependent demethylases. This results in aberrant DNA methylation, transcriptional repression, and may drive tumorigenesis. Here, we present data showing that G-CIMP is significantly more sensitive in vitro to inhibitors of the two arms of epigenetic regulation of transcription: the transcriptional activation arm and the transcriptional repression arm. Drug targets include the Bromodomain and Extraterminal (BET) and Histone Deacetylase (HDAC) proteins, involved in epigenetic transcriptional activation of oncogenes and repression of tumor suppressors, respectively. G-CIMP cells show a profound loss of cell viability at submicromolar concentrations using the small molecule inhibitors JQ1 and Panobinostat, which target BET and HDAC proteins, respectively. Western blot analysis indicates that BET inhibition elicits preferential loss of histone phosphorylation and acetylation in G-CIMP, notably serine 10 of Histone 3 and lysine 27 of Histone 3 (H3K27Ac), respectively. Both epigenetic marks are associated with positively regulating transcription. H3K27Ac is a superenhancer with known functions in activating oncogene transcription. These data ultimately suggest that G-CIMP tumor cells are reliant on established epigenetic transcriptional regulation to maintain cell viability. The global methylation status of these tumors may make them particularly sensitive to pharmacologic disruption of these epigenetic pathways. These studies provide a strong foundation for future preclinical work evaluating the prospective treatment of G-CIMP with combinatorial therapy using BET and/or HDAC inhibitors.
Citation Format: Thomas K. Sears, Sandipan Datta, Gino Cortopassi, James Angelastro, Kevin Woolard. Targeting epigenetic dysregulation in isocitrate dehydrogenase mutant 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 3846.
Abstract 3847: Knockout of DNMT1 using CRISPR gene-editing technology confers resistance to DNMT inhibitors in human breast cancer cells
Authors: Laranjeira Angelo B. , Huang Erich , Rubinstein Larry , Nguyen Dat , Yang Sherry X. 
Published: August 2019

Abstract
DNA methyltransferase (DNMT) 1 plays an important role for DNA replication and cell proliferation, and it is implicated in the maintenance and propagation of DNA methylation patterns. Targeting DNMT represents a promising approach for epigenetic therapy in cancer. To better elucidate the function of DNMT1 on the treatment effect of DNMT inhibitors in cancer cells derived from human solid tumors, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system (Cas9) to edit DNMT1 gene in MCF-7 breast carcinoma cells. The co-transfection of the DNMT1 target sequence that directs to exon 1 of the gene in pCas-guide vector and a donor DNA vector effectively knocked down DNMT1 protein in MCF-7 cells as detected by Western blot. After 96h of drug exposure, IC50s of azacitidine (5-azacytidine) and decitabine (5-aza-2’-deoxycytidine) were all higher than 10 µM in DNMT1 knockout (DNMT1-/-) cells assessed by MTT; in contrast, IC50s were 1.44 µM and 10 µM in parental (DNMT1+/+) cells. As for the cellular survival in the presence of drugs, a remarkable increase in the colony formation was observed in DNMT1-/- cells compared to DNMT1+/+ cells. The annexin-V/propidium iodide test by flow cytometry provided evidence of lower percentages of necroptosis in the DNMT1-/- cells than DNMT1+/+ cells when the cells were exposed to these inhibitors for 48 hours at 5 µM (7.12 ± 5.24 vs. 39.0 ± 2.65 by azacitidine, p = 4.11 × 10-5, and 5.77 ± 4.19 vs. 20.0 ± 6.66 by decitabine, p = 4.11 × 10-5); in addition, there were large fractions of viable cells in the DNMT1-/- cells versus DNMT1+/+ cells (85.86 ± 6.39 vs. 56.86 ± 4.00 for azacitidine treatment, p = 4.11 × 10-5 and 87.4 ± 5.56 vs. 76.2 ± 9.36 for decitabine, p = 5.60 × 10-3). The findings demonstrate that knockout of DNMT1 using CRISPR/Cas9 method leads to an increased resistance to azacitidine and decitabine, in corroboration with our previous data in DNMT1 knockout HCT116 colorectal cancer cells. Therefore, DNMT1 is critical to antitumor activity of DNMT inhibitors in human solid tumor cell lines.
Citation Format: Angelo B. Laranjeira, Erich Huang, Larry Rubinstein, Dat Nguyen, Sherry X. Yang. Knockout of DNMT1 using CRISPR gene-editing technology confers resistance to DNMT inhibitors in human breast cancer 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 3847.
Abstract 3873: CHOP10/TRB3/Akt signaling regulates ER stress apoptosis in colon cancer cells treated with prostamide-J
Authors: Albassam Hussam , Ladin Daniel A. , Dross Rukiyah Van 
Published: August 2019

Abstract
The endoplasmic reticulum (ER) is a cellular organelle that is primarily responsible for oxidative protein folding. When the protein folding load in cells exceeds the protein folding capacity, ER stress occurs. The ER stress pathway is a prominent regulator of cancer cell death and as a result, ER stress inducers are being exploited pharmacologically. Cytotoxic ER stress is typically regulated by the transcription factor, C/EBP homologous protein 10 (CHOP10). Transcriptional products of CHOP10 include pro-apoptotic genes, such as tribbles-related protein 3 (TRB3), death receptor-5 (DR5), and ER oxidoreductase 1α (ERO1α). Our previous data showed that apoptosis mediated by 15deoxy, Δ12,14 prostamide J2 (15dPMJ2) occurred in an ER stress-dependent manner. However, the signaling pathway that regulates 15dPMJ2 mediated ER stress apoptosis has not been identified. Therefore, the goal of this study is to determine the role of CHOP10 and its transcriptional targets in ER stress apoptosis that is induced by 15dPMJ2 in colon cancer cells. According to our data, 15dPMJ2 was 3-fold more effective in inducing apoptosis in the human colon cancer cell line, HCT116, compared to the non-tumorigenic colon cell line, FHC. The induction of apoptosis in HCT116 cells occurred coincident with a significant increase in CHOP10 protein expression. In addition, blockade of the ER stress pathway with 4-phenylbuterate (PBA) or salubrinal prevented apoptosis indicating that cell death is reliant upon ER stress. To determine the role of CHOP10 in this process, CRISPR/Cas9 CHOP10 knockout HCT116 cells (CHOP10-KO-HCT116) were generated. As anticipated, 15dPMJ2 increased CHOP10 expression in wt-HCT116 cells but not in CHOP10-KO-HCT116 cells. Furthermore, 15dPMJ2 increased the expression of ERO1α, DR5, TRB3, and it induced apoptosis in wt-HCT116 cells, but not in CHOP10-KO cells. Interestingly, the induction of TRB3, but not DR5 or ERO1α, was completely inhibited in cells devoid of CHOP10 expression. Therefore, the activity of protein kinase B (PKB)/Akt, a known TRB3 target, was investigated. CHOP10 stimulation by 15dPMJ2 inactivated Akt in wt-HCT116 cells, but not in CHOP10-KO cells. These findings suggest the importance of CHOP10, TRB3, and Akt in the control of the ER stress-mediated apoptosis in response to 15dPMJ2 treatment. Thus, 15dPMJ2 is a potential chemotherapeutic agent that inhibits PKB/Akt survival signaling by upregulating the CHOP10/TRB3 pathway to prevent colon cancer growth.
Citation Format: Hussam Albassam, Daniel A. Ladin, Rukiyah Van Dross. CHOP10/TRB3/Akt signaling regulates ER stress apoptosis in colon cancer cells treated with prostamide-J [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 3873.
Abstract 3885: Evaluation of pharmacokinetics of proxalutamide, a novel androgen receptor antagonist, in treatment for mCRPC patients via CTC enumeration and AR biomarker analysis
Authors: Chu Lincy , Zhang Phoebe , Anderson Amanda , Landers Mark , Wang Yipeng , Zhou Karl 
Published: August 2019

Abstract
Introduction: Proxalutamide (code name: GT-0918) is a novel androgen receptor (AR) blocker and has shown efficacy in the treatment of castration resistant prostate cancer. Proxalutamide binds to AR and inhibits androgen-induced receptor activation. A Phase 1/2 clinical trial (ClinicalTrials.gov Identifier: NCT02826772) was conducted to identify dose-limiting toxicities (DLTs) and to assess safety, tolerability, and PK of GT0918 in pts with mCRPC who have progressed on standard of care and experimental therapies in the United States. To better understand patient responses and pharmacokinetics of GT0918, we sought to examine CTC enumeration, AR-N term expression, and AR-V7 nuclear expression using Epic CTC platform for patients treated with GT0918.
Methods: A total of 18 metastatic castrate resistant prostate cancer (mCRPC) patients were recruited under either dose escalation or expansion studies and blood samples were collected at 3 time points: C1D1, C3D1, and C6D1/EOS. Patients with histologically confirmed mCRPC who had progressed after both hormonal therapy (abiraterone or enzalutamide) and chemotherapy (e.g., docetaxel) were eligible. Dosages of 300, 400, and 500 mg were evaluated in this study. CTCs were detected using the Epic Sciences platform and assessed for full length AR status using an AR N-terminus specific antibody and for nuclear localized AR-V7 truncation. AR-V7 nuclear localization was confirmed by trained technician.
Results: 18/18 (100%) of patients had detectable CTCs, with 12/18 (67%) patients having AR-N term+ CTCs. 7/12 (58%) of AR-N term+ patients were AR-V7 positive. Reduction of CTC/mL, AR+ CTC/mL and % of AR+ CTC in follow up draws were observed in the whole cohort, with 500mg dose group showing more reduction than others. Sample accrual and patient follow up is ongoing and the correlation of CTC, AR, and AR-V7 status with the clinical outcomes will be investigated once the data becomes mature.
Conclusions: In this clinical trial, we evaluated the pharmokinetic effects of GT0918 on CTC enumeration and Androgen Receptor CTC status. GT0918 might serve as a potential alternative for late stage mCRPC patients who have developed resistance to both hormone and chemotherapy treatments. The role of CTC as PK marker or patient selection device is ongoing.
Citation Format: Lincy Chu, Phoebe Zhang, Amanda Anderson, Mark Landers, Yipeng Wang, Karl Zhou. Evaluation of pharmacokinetics of proxalutamide, a novel androgen receptor antagonist, in treatment for mCRPC patients via CTC enumeration and AR biomarker 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 3885.
Abstract 3896: Distinct pharmacokinetics, tissue distribution and CNS penetration of ABI-009 (nab-Sirolimus)
Authors: Hou Shihe , Schmid Anita , Desai Neil 
Published: August 2019

Abstract
Background: Activation of the mTOR signaling pathway is frequently observed in multiple types of cancer. The poor solubility and low oral bioavailability of the mTOR inhibitor sirolimus limit its development as an anticancer therapy. ABI-009 (nab-sirolimus) is an injectable nanoparticle form of human albumin-bound sirolimus developed with a proprietary nanoparticle albumin-bound (nab®) technology. Currently, numerous phase 1 and 2 clinical studies are ongoing with ABI-009, including a registrational phase 2 study for the treatment of malignant perivascular epithelioid cell carcinoma (PEComa), and various oncology (bladder cancer, soft-tissue sarcomas, neuroendocrine tumors, colorectal cancer, glioblastoma, and various childhood cancers) as well as in non-oncology indications (pulmonary arterial hypertension (PAH), pediatric epilepsy, and mitochondrial diseases). Several nonclinical studies were conducted to evaluate pharmacokinetics, tissue distribution and in particular, CNS penetration of ABI-009.
Methods: Rats were intravenously (IV) administered with a single dose of ABI-009 at 1.7, 9.5, and 17 mg/kg. Blood and organs were collected at 2, 8, 24, 72, and 120 hrs to analyze for sirolimus concentrations.
Results: There is a generally linear dose response with sirolimus concentrations in blood, heart, lung, liver, and pancreas following a single dose of IV ABI-009. Sirolimus concentrations in blood and well-perfused organs had high peaks at earlier time points but dropped quickly with time, with the highest concentrations observed in lung. In contrast, sirolimus concentrations in brain rose slowly at first, but maintained at a steady level over time. After 5 days, sirolimus level in the brain was similar to other organs, suggesting substantial and prolonged drug distribution to the brain with ABI-009. Organ/blood ratios of most organs increased with time, with the brain/blood ratios increasing more significantly over time. Higher initial dose of ABI-009 resulted in increased brain/blood ratios.
Conclusions: ABI-009 administered IV demonstrated a distinct PK profile compared with oral mTOR inhibitors. The PK of ABI-009 is characterized by higher Cmax and AUC, and rapid tissue distribution. Combined with efficient tumor penetration observed in a xenograft study, results of this study support the potential use of ABI-009 for the treatment of cancers in different organ sites, including lung, brain, liver, and pancreas. These findings also warrant further clinical studies in non-oncology indications including PAH and disorders involving the CNS.
Citation Format: Shihe Hou, Anita Schmid, Neil Desai. Distinct pharmacokinetics, tissue distribution and CNS penetration of ABI-009 (nab-Sirolimus) [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 3896.
Abstract 3906: PK-PD modelling of an anti-CTLA-4 antibody on immune checkpoint humanized mice
Authors: Lee Madeline , Xiang Jie , Gan Tian , Shen Yuelei , Guo Chaoshe 
Published: August 2019

Abstract
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; also known as CD152) is expressed on the surface of T cells, where it primarily suppresses the early stages of T cell activation. In preclinical studies, blockade of CTLA-4 led to an increase in T-cell proliferation. Anti-CTLA-4 monoclonal antibodies (mAbs) have been shown to be an effective approach for tumor immunotherapy. Preclinical pharmacokinetic (PK) and pharmacodynamic (PD) characterization of these antibodies is essential for designing first-in human trials.
PK prediction is especially challenging for monoclonal antibodies attributed to target-mediated drug disposition (TMDD). We generated a humanized B-hCTLA-4 mouse model, in which exon 2 of the murine CTLA-4 gene was replaced with its human counterpart. In homozygous mice, only human protein expression can be detected, while mouse CTLA-4 was knocked out. Using B-hCTLA-4 mice, we developed a mAb PK/PD model to characterize the anti-tumor effects of hCTLA-4 antibodies.
MC38 cancer cells were inoculated into both C57BL/6 wild type and humanized CTLA-4 animals. After administering different antibody concentrations (ranging from 3.0, 1.0, 0.3, 0.1mg/kg), serum samples from each animal were taken at specific time points for PK/PD analysis. An NCA approach was used to determine serum concentrations of mAb in mice. The levels of 13 cytokines (IL-23, IL-1α, IFN-r, TNF-a, IL-6 etc.) were quantified using LEGENDplex bead-based immunoassays. The PK half-life was 50~100h and the cytokine concentration ranged from 0-2000pg/ml depending on the dose used. The Tumor Growth Inhibition (TGI) value was also evaluated as a PD effect in the MC38/B-hCTLA-4 model. The TGI value reached nearly 100% when the dose was above 0.3mg/kg. The PK/PD assays showed that the anti hCTLA-4 mAb tested has a dose-dependent tumor inhibition effect in hCTLA-4 mice. Results from TMDD model data showed that the humanized mice reached QuasiSteady State faster than wild type mice, indicating that the humanized mice are an appropriate TMDD model. In conclusion, humanized B-hCTLA-4 mice are a promising PK/PD model for CTLA-4 mAb preclinical trials.
Citation Format: Madeline Lee, Jie Xiang, Tian Gan, Yuelei Shen, Chaoshe Guo. PK-PD modelling of an anti-CTLA-4 antibody on immune checkpoint humanized mice [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 3906.