bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 987: Glycoengineered MSCs for targeting platinum resistant ovarian tumors
Authors: Layek Buddhadev , Sehgal Drishti , Panyam Jayanth , Prabha Swayam 
Published: August 2019

Abstract
Tumor-targeted delivery of chemotherapeutics can improve efficacy while mitigating their debilitating side effects. However, current drug delivery approaches rely on inefficient passive accumulation of delivery systems in the tumor and suffer from significant non-specific distribution. Here, we propose a novel two-step tumor targeting strategy that can improve delivery of cytotoxic agents to both primary tumor as well as metastatic lesions, resulting in effective tumor inhibition. This strategy involves introduction of non-natural targets in the tumor tissue via glycoengineered mesenchymal stem cells (MSCs expressing targetable synthetic azide groups) followed by the delivery of drug-loaded polymeric nanoparticles (surface functionalized with dibenzyl cyclooctyne; DBCO) that have high affinity for these synthetic targets. DBCO surface functionalized, paclitaxel (PTX)-loaded nanoparticles (DBCO-PTX NP; 17.6% w/w PTX; diameter 313.7 ± 13 nm; and zeta potential -12.5 ± 1.9 mV) were formulated using poly (DL-lactide-co-glycolide) (PLGA) polymer by emulsion-solvent evaporation method. Glycoengineered MSCs (MSC-Az) were generated by culturing MSCs in N-azidoacetylmannosamine-tetraacylated supplemented media without affecting their viability or tumor homing properties. Binding of MSC-Az to DBCO-PTX NP was confirmed with confocal microscopy and flow cytometry analysis. Anticancer efficacy of two-step targeting strategy was evaluated in murine model of platinum-resistant orthotopic ovarian C200-luc tumors. Treatment with MSC-Az + DBCO-PTX nanoparticles resulted in significant inhibition of the tumor growth (p &lt; 0.05) and improved survival (p &lt; 0.05) compared to that with other controls. In summary, our results demonstrate the potential of two-step tumor targeting strategy to enhance the anticancer efficacy of conventional chemotherapeutic drugs.
Citation Format: Buddhadev Layek, Drishti Sehgal, Jayanth Panyam, Swayam Prabha. Glycoengineered MSCs for targeting platinum resistant ovarian 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 987.
Abstract 992: Comparative analyses of drug-loaded exosomal preparations from different cell types reveal distinctive loading capability, yield, and anti-tumor efficacies
Authors: KANCHANAPALLY RAJASHEKHAR , Deshmukh Sachin Kumar , Chavva Suhash Reddy , Tyagi Nikhil , Srivastava Sanjeev Kumar , Patel Girijesh Kumar , Singh Ajay P. , Singh Seema 
Published: August 2019

Abstract
Cancer remains one of the leading causes of death worldwide regardless of technological advancements. Inefficiency of current drug-delivery regimes is one of the important factors that limits the therapeutic efficacy of existing chemotherapeutics thus contributing to cancer mortality. To address this limitation, synthetic nanotechnology-based delivery systems have been developed; however, they raise concern of inducing adverse immunogenic reactions. Exosomes are non-immunogenic nano-sized vesicles that have received significant attention as efficient drug delivery system. Here we evaluated the efficacy of different cell types viz. pancreatic cancer cells (PCCs), pancreatic stellate cells (PSCs) and macrophages (MØs) for drug packaging and release into exosomes. PCCs shed the most exosomes and were the most efficient in drug loading followed by MØs and PSCs as examined by HPLC quantification. However, when compared for anti-tumor efficacy, MØs-derived exosomes-loaded with DOX (MØ-Exo-DOX) showed highest activity followed by PSCs and PCCs in WST-1 and Annexin V staining assays. These varying anti-tumor activities likely resulted from non-drug contents of exosomes since we did not observe any significant differences in their uptake by the cancer cells. Altogether, our data suggest that donor cell-specific differences exist in exosomes, which could influence their utility as drug carrier for therapeutic purposes.
Citation Format: RAJASHEKHAR KANCHANAPALLY, Sachin Kumar Deshmukh, Suhash Reddy Chavva, Nikhil Tyagi, Sanjeev Kumar Srivastava, Girijesh Kumar Patel, Ajay P. Singh, Seema Singh. Comparative analyses of drug-loaded exosomal preparations from different cell types reveal distinctive loading capability, yield, and anti-tumor efficacies [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 992.
Abstract CT045: Hyleukin-7, a long-acting interleukin-7, increased absolute lymphocyte counts after subcutaneous and intramuscular administration in healthy subjects
Authors: Lee Sang Won , Choi Donghoon , Heo MinKyu , Shin Eui-Cheol , Park Su-Hyung , Kim So Jeong , Lee Byung Ha , Yang Se Hwan , Sung Young Chul , Lee Howard 
Published: August 2019

Abstract
Higher lymphocyte counts predict lower mortality in patients with various oncologic malignancies. Interleukin-7 (IL-7), a homeostatic cytokine, plays a critical and non-redundant role in developing T-cells and maintaining immune functions after development. IL-7 is a potent T-cell amplifier, thereby contributing to immune reconstitution, which may result in clinical benefits. A randomized, double-blind, placebo-controlled, dose-escalation, Phase I study was conducted to assess the safety, tolerability, pharmacokinetic and biological properties of Hyleukin-7 (human IL-7 fused to hyFcTM) administered subcutaneously (SC) and intramuscularly (IM) to healthy volunteers.
Ten subjects randomly received Hyleukin-7 or its matching placebo in an 8:2 ratio in each of three cohorts at 20 and 60 μg/kg SC and 60 μg/kg IM. Dose escalation and switch from SC to IM was determined on 28 days after study drug administration based on the safety and tolerability data. Subjects were followed up to 56 days after dose.
Hyleukin-7 was well tolerated and no subject developed cytokine release syndrome. Injection site reactions were the most common treatment-emergent adverse events, which resolved spontaneously without treatment. Hyleukin-7 was slowly but steadily absorbed and its terminal half-life ranged 48-112 hours. Furthermore, Hyleukin-7 increased absolute lymphocyte counts (ALC) in a dose-dependent manner which lasted during the observed period of 56 days after dose. The mean maximum increase in ALC from baseline was seen 3 weeks after dose. IM Hyleukin-7 increased ALC greater than SC Hyleukin-7 did at the same dose (111.4% IM vs. 75.1% SC). In all of the doses, Hyleukin-7 markedly increased the numbers of all peripheral CD4+ and CD8+ lymphocyte subsets (i.e., naïve, EM, CM and TEMRA). These increases are attributed to enhanced expression of Ki-67.
SC and IM Hyleukin-7 was safe and well-tolerated in a dose range of 20 to 60 μg/kg in healthy subjects. A single SC and IM dose of Hyleukin-7 increased ALC dose-dependently. The results of this study warrant further investigation of Hyleukin-7 as a potential immune-oncology therapeutics to treat patients with compromised T-cell immunity.
Citation Format: Sang Won Lee, Donghoon Choi, MinKyu Heo, Eui-Cheol Shin, Su-Hyung Park, So Jeong Kim, Byung Ha Lee, Se Hwan Yang, Young Chul Sung, Howard Lee. Hyleukin-7, a long-acting interleukin-7, increased absolute lymphocyte counts after subcutaneous and intramuscular administration in healthy subjects [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 CT045.
Abstract CT052: A Phase Ib and II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer
Authors: Chung Andrew W. , Ensor Joe E. , Darcourt Jorge , Belcheva Anna , Patel Tejal , Chang Jenny C. , Niravath Polly A. 
Published: August 2019

Abstract
Triple negative breast cancer (TNBC) is an aggressive disease that currently lacks an efficacious form of therapy. Cancer relapse is thought to be initiated by chemotherapy-resistant breast cancer stem cells (BCSCs). Our previous studies revealed that BCSCs utilize inducible nitric oxide synthase (iNOS)-derived nitric oxide to promote their proliferation, migration, and self-renewal capacity. In an effort to target BCSCs, we found that iNOS inhibition with NG-monomethyl-L-arginine (L-NMMA) sensitized BCSCs to docetaxel in TNBC xenograft models, leading to decreased tumor burden. These findings suggest that BCSC resist conventional therapy in a nitric oxide-dependent manner and that combination of L-NMMA with docetaxel will effectively target BCSCs to prevent further relapse. A phase Ib/II clinical trial was conducted to determine the maximum tolerated dose, recommended phase 2 dose (R2PD), dose-limiting toxicities (DLTs), and efficacy of the L-NMMA and docetaxel combination in chemo-refractory Stage III and IV TNBC patients. For the phase Ib portion of the study, a standard Bayesian continual reassessment method is being used to investigate 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg) and two dose levels of docetaxel (75 and 100 mg/m2). Twenty patients have been recruited to date, and based on current pharmacokinetics, pharmacodynamics, and safety data, the RP2D is expected to be docetaxel 100 mg/m2 (Day 1) and L-NMMA 20 mg/kg (Days 1-5) every 3 weeks. At the RP2D, 87.5% of the patients experienced a decrease in total serum nitrates and nitrates at Day 2 (p = 0.0156, Wilcoxon Signed-Rank) as compared to baseline, and 75% experienced a decrease at Day 5 (p = 0.1484). Two and three patients received 15 mg/kg L-NMMA + 75 mg/m2 docetaxel and 17.5 mg/kg L-NMMA + 100 mg/m2 docetaxel, respectively. Of these 5 patients, one partial responder completed 8 cycles before discontinuing treatment due to taxane-associated neuropathy. Among the nine patients treated at the RP2D, only one taxane-associated DLT occurred. The overall response rate for patients treated at the higher doses was 33.3% as determined by RECIST 1.1. Early results of the phase Ib/II trial indicate the safety, tolerability, and promising activity of the first-in-class pan-NOS inhibitor L-NMMA in combination with chemotherapy in the treatment of chemo-refractory TNBC.
Citation Format: Andrew W. Chung, Joe E. Ensor, Jorge Darcourt, Anna Belcheva, Tejal Patel, Jenny C. Chang, Polly A. Niravath. A Phase Ib and II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in 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 CT052.
Abstract CT149: A Phase II study of Genexol-PM and cisplatin as induction chemotherapy in locally advanced head and neck squamous cell carcinoma
Authors: Lee Keun-Wook , Keam Bhumsuk , Kim Jin-Soo , Lee Se-Hoon 
Published: August 2019

Abstract
Background Genexol-PM is a polymeric micellar formulation of paclitaxel without Cremophor EL. We investigated the efficacy and safety of Genexol-PM plus cisplatin as induction chemotherapy (IC) in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
Methods Patients received Genexol-PM (230 mg/m2) and cisplatin (60 mg/m2) every 3 weeks as IC. After 3 cycles of IC, definitive treatment of either concurrent chemoradiotherapy (CCRT) with weekly cisplatin (30 mg/m2) or surgery was performed. The primary endpoint was objective response rate (ORR) after IC.
Results Of 52 patients enrolled, 47 completed three cycles of IC and the ORR was 55.8% (95% confidence interval, 42.3-69.3). Although there was one treatment-related death, toxicity profiles to IC were generally favorable and the most common grade 3 or 4 toxicities were neutropenia (15.4%), anorexia (7.7%) and general weakness (7.7%). Fifty one patients received the definitive treatment [CCRT (n=44) or radical surgery (n=7)]. The rate of complete response following CCRT was 81.8% (36/44). After a median follow-up of 39 months, estimates of progression-free survival and overall survival at 3 years were 54.3% and 71.3%, respectively.
Conclusions IC with Genexol-PM and cisplatin demonstrated modest tumor response with well-tolerated toxicity profiles for patients with LA-HNSCC.
Citation Format: Keun-Wook Lee, Bhumsuk Keam, Jin-Soo Kim, Se-Hoon Lee. A Phase II study of Genexol-PM and cisplatin as induction chemotherapy in locally advanced head and neck squamous cell carcinoma [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 CT149.
Abstract DDT01-01: BI 905677: A first-in-class LRP5/6 antagonist targeting Wnt-driven proliferation and immune escape
Authors: Zinzalla Vittoria , Drobits-Handl Barbara , Savchenko Alexander , Rinnenthal Jörg , Bauer Markus Johann , Sanderson Michael , Blake Sophia Maria , Schweifer Norbert , Vries Robert Gerhardus Jacob , Clevers Hans , Kraut Norbert 
Published: August 2019

Abstract
Aberrant Wnt/β-catenin signalling has been shown to play a key role in tumorigenesis and resistance to immunotherapy in several tumor indications. Wnt ligand-mediated signals are transduced by two distinct receptor types, the serpentine receptor Frizzled (FZD) and the closely related single-span transmembrane proteins LRP5 and LRP6. Formation of the FZD-Wnt-LRP5/6 trimeric complex induces phosphorylation of LRP5 or LRP6 intracellular domains leading to inactivation of the β-catenin degradation complex, allowing stabilized β-catenin to enter the nucleus, bind to the TCF transcription factors, and act as a transcriptional activator of Wnt target genes. We have developed a first-in-class LRP5/6 antagonist, a bi-paratopic antibody comprising two modules binding to distinct epitopes of LRP5 (or LRP6). BI 905677 is a highly potent blocker of signalling induced by the Wnt family of ligands and shows anti-tumor activity in cancer models harbouring genomic alterations in upstream regulators of the Wnt pathway, such as RNF43 mutations or RSPO fusions. Furthermore, BI 905677 in combination with an anti-PD-1 immune checkpoint inhibitor induces dendritic cell activation and T cell infiltration in tumor tissues leading to complete responses in syngeneic tumor models. A Phase I clinical trial is underway in patients with advanced cancer to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and efficacy of BI 905677 (NCT03604445).
Citation Format: Vittoria Zinzalla, Barbara Drobits-Handl, Alexander Savchenko, Jörg Rinnenthal, Markus Johann Bauer, Michael Sanderson, Sophia Maria Blake, Norbert Schweifer, Robert Gerhardus Jacob Vries, Hans Clevers, Norbert Kraut. BI 905677: A first-in-class LRP5/6 antagonist targeting Wnt-driven proliferation and immune escape [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 DDT01-01.
Abstract LB-005: Allosteric SHP2 phosphatase inhibition: Multiple mechanisms and chemotypes
Authors: LaMarche Matthew J. , Bagdanoff Jeff , Acker Mike , Chen Ying-Nan , Chan Homan , Dore Michael , Firestone Brant , Fodor Michelle , Garcia-Fortanet Jorge , Hentemann Murphy , Kato Mitsunori , Koenig Robert , Bonte Laura La , Liu Shumei , Mohseni Movarid , Ntaganda Rukundo , Sarver Patrick , Smith Troy , Sendzik Martin , Stams Travis , Spence Stan , Towler Chris , Wang Hongyun , Wang Ping , Williams Sarah , Chen Zhouliang , Hao Huaixiang , Liu Gang , Liu Chen , McNeill Eric , Yu Bing 
Published: August 2019

Abstract
Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator due to its role in the programmed cell death PD-L1/PD-1 pathway. Small molecule inhibition of SHP2 has been widely investigated including our previous reports describing SHP099, which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies led to the identification of multiple, potent inhibitor chemotypes, an additional and distinct allosteric binding site, and the identification of SHP394, an orally efficacious inhibitor of SHP2 with improved potency and enhanced pharmacokinetic properties. Overall, this work improves upon our previously described allosteric inhibitors, and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism.
Citation Format: Matthew J. LaMarche, Jeff Bagdanoff, Mike Acker, Ying-Nan Chen, Homan Chan, Michael Dore, Brant Firestone, Michelle Fodor, Jorge Garcia-Fortanet, Murphy Hentemann, Mitsunori Kato, Robert Koenig, Laura La Bonte, Shumei Liu, Movarid Mohseni, Rukundo Ntaganda, Patrick Sarver, Troy Smith, Martin Sendzik, Travis Stams, Stan Spence, Chris Towler, Hongyun Wang, Ping Wang, Sarah Williams, Zhouliang Chen, Huaixiang Hao, Gang Liu, Chen Liu, Eric McNeill, Bing Yu. Allosteric SHP2 phosphatase inhibition: Multiple mechanisms and chemotypes [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-005.
Abstract LB-030: Interferon signaling contributes to prostate cancer drug resistance
Authors: Agarwal Supreet , McGowen Kerry , Elloumi Fathi , Cam Maggie , Beshiri Mike , Corey Eva , Kelly Kathleen 
Published: August 2019

Abstract
Contrary to the anti-proliferative interferon (IFN) signaling, IFN related DNA damage resistance signature (IRDS) has pro-survival function and is responsible for cancer cell intrinsic therapy resistance. This signature encompasses a subset of STAT1-driven genes that have been associated with breast cancer therapy resistance. Interestingly, our RNAseq analysis of organoids from FACS-sorted Pten/Tp53-null PCa luminal progenitors have revealed a robust IRDS expression. Based on our previous findings that the luminal progenitors display intrinsic resistance to androgen deprivation therapy (ADT), we hypothesized that the IRDS expression might in part account for survival of PCa cells following ADT or genotoxic therapies. Our analysis of human PCa datasets revealed IRDS as a prognostic marker for progression in the TCGA primary PCa cohort (p&lt;0.05). Further, high IRDS-expressing castrate resistance PCa (CRPC) patients in SU2C dataset were enriched for low AR signaling (r= -0.33, p&lt; 0.05). Patients in IRDS-hi cohort showed enrichment for stem cell phenotype and for gene-sets associated with therapy resistance. In line with our analysis of clinical samples, real time PCR, immunofluorescence and western blot analysis of organoid cultures initiated from castration-resistant Pten/Tp53-nulltumor progenitors showed high levels of unphoshorylated STAT1 (U-STAT1) in tumor luminal organoids than WT organoids whereas pSTAT1 (Y701) was not detectable. Similarly, U-STAT1 was overexpressed in Pten/Tp53-null tumor relative to the WT tissue. Knockdown of STAT1 in tumor organoids decreased number of progeny organoids in subsequent generations suggesting either a direct or indirect effect upon self-renewal of luminal tumor stem cells. Altogether, U-STAT1 regulated signaling has pro-survival function in Pten/Tp53-null advanced PCa. Several PDXs originating from metastatic PCa express high levels of U-STAT1 dependent IFN signaling. STAT1 depletion in 5 tested PDXs significantly reduced self-renewing ability of PDX derived organoids, consistent with mouse luminal tumor organoids. Interestingly, STAT1 depletion synergized with sensitivity to chemotherapy ex vivo. These findings indicate that U-STAT1 dependent IFN signaling may contribute to treatment resistance. Overall, our findings suggest U-STAT1 dependent IRDS is correlated with poorly differentiated PCa and IRDS expression in part accounts for intrinsic therapy resistance in prostate cancer.
Citation Format: Supreet Agarwal, Kerry McGowen, Fathi Elloumi, Maggie Cam, Mike Beshiri, Eva Corey, Kathleen Kelly. Interferon signaling contributes to prostate cancer drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-030.
Abstract LB-032: NOG-FcgR KO hIL-15 Tg mice provide a highly sensitive assay system for ADCC activity of human NK cells
Authors: Katano Ikumi , Ito Ryoji , Kawai Kenji , Yagoto Mika , Suemizu Hiroshi , Ito Mamoru , Takahashi Takeshi 
Published: August 2019

Abstract
We have reported that a human interleukin (hIL)-15-gene introduced NOD-scidnullil2rgnull (NOG-hIL-15 Tg) mouse strain was useful for examination of in vivo antibody dependent-cellular cytotoxicity (ADCC) mediated by human NK cells in the presence of therapeutic Ab (Katano I et al. Sci. Rep. 2017). However, murine phagocytic cells including monocytes/macrophages (Mo/MΦ) in NOG mice still retain a significant capacity to kill target cells by antibody dependent-cellular phagocytosis (ADCP). Here, we newly generated a NOG-hIL-15 Tg strain deficient for Fcγ receptor genes (NOG-FcγR KO-hIL-15 Tg) and investigated whether ADCP by mouse Mo/MΦ could be abolished. The F4/80+ Mo/MΦ in NOG-FcγR KO mice did not bind human immunoglobulin, while those from NOG mice did. NOG-FcγR KO or NOG mice were intravenously transferred with a CD20+ human Burkitt’s lymphoma cell line, Daudi, followed by treatment with anti-hCD20 Ab, Rituximab (Rtx). The tumor growth in control NOG mice was significantly suppressed with Rtx-alone, whereas NOG-FcγR KO mice did not show tumor regression by Rtx treatment. After confirming engraftment of human NK cells in NOG-FcγR KO/hIL-15 Tg mice, we set up in vivo ADCC experiments. Daudi-transplanted NOG-FcγR KO/hIL-15 Tg mice were intravenously transferred with human NK cells and treated with Rtx. Only the mouse group with both human NK cells and Rtx treatment showed a significant suppression in the tumor growth.
These results suggest that NOG-FcγR KO mice are free of murine cell mediated ADCP, and that NOG-FcγR KO/hIL-15 Tg mice enable more specific detection of in vivo ADCC than NOG-hIL-15 Tg mice.
Citation Format: Ikumi Katano, Ryoji Ito, Kenji Kawai, Mika Yagoto, Hiroshi Suemizu, Mamoru Ito, Takeshi Takahashi. NOG-FcgR KO hIL-15 Tg mice provide a highly sensitive assay system for ADCC activity of human NK 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-032.