tbuckley/cabot-search huggingface dataset:
Abstract 2657: PD-L1 blockade enhances T cell cytotoxicity against primary mediastinal B cell lymphoma
Authors: Tishi Shah, Wen Luo, Aradhana Awasthi, Janet Ayello, Jessica Hochberg, Mitchell Cairo
Journal: Cancer Research (2017)

Abstract Background: Primary Mediastinal B cell Lymphoma (PMBL) represents 2-4% of Non-Hodgkin Lymphomas (NHL) in adolescents and young adults (AYA) (Gerrard/Cairo et al., Blood, 2013). Disease progression, relapse and long-term toxicity remain a concern for patients treated on current chemo-immunotherapy and mediastinal radiotherapy. Alternative therapeutic regimens are urgently needed, especially in patients without an early response to therapy. Programmed Death 1 (PD-1) is a negative co-stimulatory receptor critical for suppression of T-cell activation, with binding of PD-1 and Programmed Death Ligand 1 (PD-L1) resulting in T cell exhaustion (Postow/Wolchok et al., J Clin Oncol, 2015). Gain in 9p associated with amplification of PD-L1 has been reported in up to 60% of PMBL specimens, leading to overexpression of PD-L1 and potential immune cell evasion of PMBL (Rosenwald/Staudt et al., J Exp Med, 2003; Twa/Steidl et al., Blood, 2014). Blockade of PD-1/PD-L1 interaction, therefore, constitute a potentially promising alternative for treatment of resistant PMBL. Objective: In the current study, we sought to investigate whether PD-L1 blockade enhances T cell responses in PD-L1 expressing PMBL. Methods: PD-L1 expression on Karpas 1106p PMBL treated with or without IFN γ was investigated by western blotting and flow cytometry analyses. T cells were isolated from human PBMC followed by activation and expansion using anti-CD2, anti-CD3 and anti-CD28 Biotinylated MACSiBead particles. T cell activation was confirmed by CD25 and CD69 expression using flow cytometry. Activated T cells were incubated with or without anti-PD-L1 (Clone 6E11, Genentech) at a dose of 10 ug/ml together with Karpas 1106p cells treated with or without IFN γ. Cell proliferation was assessed with MTS assays after incubation for 24 hours. Results: We demonstrated that Karpas 1106p cells express a low level of PD-L1. However, following IFN γ treatment (48 hours) there was a significant increase in PD-L1 expression. Anti-PD-L1 had no significant effect on T cell mediated inhibition of cell proliferation in Karpas 1106p cells with low PD-L1 expression. However, anti-PD-L1 and T cell treatment significantly inhibited cell proliferation in IFN γ treated Karpas 1106p cells when compared to T cell treatment alone (32±18% vs. 3±3% at E:T=5:1, p=0.048). Conclusion: PD-L1 blockade enhances T cell cytotoxicity against PMBL, which is dependent on PD-L1 expression level on PMBL cells. Future in-vivo NSG xenograft studies are ongoing. Citation Format: Tishi Shah, Wen Luo, Aradhana Awasthi, Janet Ayello, Jessica Hochberg, Mitchell Cairo. PD-L1 blockade enhances T cell cytotoxicity against primary mediastinal B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2657. doi:10.1158/1538-7445.AM2017-2657
Abstract 4511: HIF-1-dependent regulation of creatine kinase metabolism promotes breast cancer invasion and metastasis
Authors: Hilaire Barch, Danielle L. Brooks, Raya Krutilina, Luciana P. Schwab, Deanna Parke, Tiffany N. Seagroves
Journal: Cancer Research (2017)

Abstract Dysregulated tumor cell metabolism is a hallmark of cancer progression and therapeutic resistance. In a screen for Hypoxia-Inducible Factor (HIF)-dependent genes regulating metabolism, we identified creatine kinase, brain isoform (CKB) as down-regulated in HIF-1 knockout mammary tumor cells. Creatine kinases (CKs) reversibly catalyze the transfer of a high-energy phosphoryl group from ATP to creatine, generating phosphocreatine in the forward reaction, and ATP in the reverse reaction. CKs are up-regulated in a variety of solid tumors, including ovarian, breast, colon, lung and brain. Knockdown of CKB in the polyoma middle T (PyMT) transgenic mouse model of metastatic breast cancer suppressed the production of intracellular ATP and invasion in vitro, and inhibited metastasis from the mammary gland to the lung in vivo. CK activity is known to be inhibited by cyclocreatine, a creatine kinase substrate that represses CK-dependent generation of ATP from phosphocreatine. When female FVB/Nj mice were injected with wild type PyMT cells in a tail vein assay and then treated with cCr (1g/kg/day, IP), lung metastasis was repressed to the same extent as Ckb gene knockdown. Moreover, when cCr therapy was administered 7 days after tail vein injection, cCr was effective in preventing the transition of lung micrometastases to macrometastases. To explore the role of CK activity in regulating cell proliferation, survival in suspension, cellular metabolism and invasion, we next created CKB loss- and gain-of-function models using human breast cancer cell lines, and compared phenotypes to cCr treatment. Whereas deletion of CKB had no effect on cell proliferation or survival in adherent conditions or in suspension, either deletion of CKB or cCr therapy potently reduced ATP levels and invasive potential in vitro. Preliminary data also indicate that pre-treatment of triple negative breast cancer cell lines with cCr sensitizes cells to doxorubicin. Together, these data suggest that inhibition of CK activity may be effective in treating stage IV breast cancer. We are currently testing whether cCr has anti-metastatic efficacy as a monotherapy, or in combination with conventional chemotherapies, using luciferase-labeled patient-derived xenograft (PDX) models. This work was sponsored by the NIH (CA138488), the Dept. of Defense (BC150640), the METAvivor foundation, and the West Cancer Center in Memphis, TN. Citation Format: Hilaire Barch, Danielle L. Brooks, Raya Krutilina, Luciana P. Schwab, Deanna Parke, Tiffany N. Seagroves. HIF-1-dependent regulation of creatine kinase metabolism promotes breast cancer invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4511. doi:10.1158/1538-7445.AM2017-4511
Abstract 1401: Deterring breast cancer progression. The critical role of a lipid-sphingolipid epigenetic mechanism of cell fate
Authors: Stefano Rossetti, Vincenzo Gagliostro, Nicoletta Sacchi
Journal: Cancer Research (2017)

Abstract Genetic and environmental factors cooperate to assure precise genome-wide epigenetic regulation of the mammary epithelia cell transcriptome. Our interest in regulatory epigenetic mechanisms that, by determining mammary epithelial cell decisions, are pivotal to deter the onset and progression of breast cancer, let us identify a regulatory epigenetic mechanism of mammary morphogenesis that links a physiological regulatory lipid of environmental origin (all-trans retinoic acid, RA) with sphingolipids capable of determining either cell death (ceramide, CER) or cell life (sphingosine 1 phosphate, S1P). Whenever RA, for different reasons, fails to perform the epigenetic transcriptional control of neutral sphingomyelinase 2 (nSMase2/SMDP3), involved in the synthesis of pro-apoptotic CER, S1P fosters both pro-proliferative and pro-invasive activity. Apparently, in the absence of epigenetic control of CER production by RA, S1P contributes to determine RA tumorigenic action. This study provides the rationale for combination therapeutic approaches with epigenetic drugs and inhibitors of either sphingosine kinase, the enzyme involved in S1P synthesis, or S1P receptors. This study was supported by the NCI R01 CA127614 grant (NS). Citation Format: Stefano Rossetti, Vincenzo Gagliostro, Nicoletta Sacchi. Deterring breast cancer progression. The critical role of a lipid-sphingolipid epigenetic mechanism of cell fate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1401. doi:10.1158/1538-7445.AM2017-1401
Abstract 3378: Whole exome sequencing identifies recurrent alterations of genes in malignant phyllodes tumors in nine Korean individuals
Authors: Jihui Yun, Hyeong-Gon Moon, Tae-Kyung Yoo, Eunshin Lee, Jeesoo Chae, Sam Hur, Jiwoo Lee, Jong-Il Kim, Dong-Young Noh
Journal: Cancer Research (2017)

Abstract Phyllodes tumors of the breast are rare fibroepithelial neoplasms with variable clinical behavior accounting for about 1% of all breast neoplasms. Phyllodes tumors are classified into benign, borderline, and malignant grades on the basis of histological features. Among those categories, Malignant phyllodes tumor has a higher propensity for local recurrence and distant metastasis, however the malignant potential of phyllodes tumors is difficult to assess on initial pathologic examination. In previous studies, an important role of mediator complex subunit 12 (MED12) in phyllodes tumors has been frequently revealed. However, except that, genetic abnormalities that drive tumor initiation and progress in malignant phyllodes tumor remain still unclear. Here, by performing whole exome sequencing of 9 malignant phyllodes tumors with matching normal cases, we frequently observed mutations in MED12 (3/9, 33.34%). Additionally, non-silent mutations in p53(TP53) and epidermal growth factor receptor (EGFR) were recurrently identified. Whole-gene amplifications of EGFR were also found in six cases (6/9, 66.67%). We suggest that EGFR has an underlying role in malignant phyllodes tumors. This study identifies potential therapeutic targets in malignant phyllodes tumors, including EGFR. Citation Format: Jihui Yun, Hyeong-Gon Moon, Tae-Kyung Yoo, Eunshin Lee, Jeesoo Chae, Sam Hur, Jiwoo Lee, Jong-Il Kim, Dong-Young Noh. Whole exome sequencing identifies recurrent alterations of genes in malignant phyllodes tumors in nine Korean individuals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3378. doi:10.1158/1538-7445.AM2017-3378
Abstract 5040: The plasma and cerebrospinal fluid pharmacokinetics of pegylated liposomal doxorubicin after intravenous administration in non-human primates
Authors: Christine Higham, Robert Murphy, Cynthia McCully, Katherine Warren, Brigitte Widemann
Journal: Cancer Research (2017)

Abstract Background: Pegylated liposomal doxorubicin (PLD) exhibits altered plasma pharmacokinetics (PK) compared to doxorubicin, with a longer half-life (55 hours), large area under the concentration-time curve (AUC), lower rate of clearance, and markedly smaller volume of distribution. The cerebrospinal fluid (CSF) PK of PLD are unknown. We evaluated the plasma and CSF PK of PLD in a non-human primate (NHP) model. Methods: PLD was given as single dose (1 mg/kg = low adult recommended dose of 20 mg/m2) intravenously over 60 minutes to 3 NHP with indwelling central venous catheters and central nervous system ventricular reservoirs or lumbar ports. Serial blood and CSF samples were obtained for 96 hours after completion of the infusion. The total doxorubicin concentration (liposome bound + protein bound + free) was quantified with a validated liquid chromatography/tandem mass spectrometry assay (lower limit of quantification plasma=0.29 ng/mL, and CSF=0.06 ng/mL). PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUCCSF:AUCplasma. Results: PLD was well tolerated. Total doxorubicin plasma concentration time curves were characterized by sustained PLD exposure, comparable to the exposure observed in humans at a similar dose. The terminal elimination phase was not captured. In CSF, doxorubicin was measurable and still present at the last time point in all animals, but the CSF penetration was limited (Table). Conclusions: Using a sensitive assay, we could quantify doxorubicin in CSF. However, the CSF penetration is limited in NHP with intact blood brain barrier. Our assay analyzed the total doxorubicin concentration in plasma. It is unknown if PLD can penetrate into the CSF, therefore we could not determine if the CSF penetration represents total versus free. Plasma and CSF PK of pegylated liposomal doxorubicin in NHPAnimalCmax Plasma(ng/mL)Tmax Plasma(h)AUC0-96h Plasma(ng*h/mL)Cmax CSF (ng/mL)Tmax CSF (h)AUC0-96h CSF (ng*h/mL)CSF Penetration (%)19396487.24E+051.84524.210.3323044901.76E+060.71618.750.113374670.081.91E+063.251036.410.2Mean25770161.46E+061.93726.460.21 Citation Format: Christine Higham, Robert Murphy, Cynthia McCully, Katherine Warren, Brigitte Widemann. The plasma and cerebrospinal fluid pharmacokinetics of pegylated liposomal doxorubicin after intravenous administration in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5040. doi:10.1158/1538-7445.AM2017-5040
07.04 Partial elimination of intestinal microbiota dampens t helper 17 cell differentiation and established collagen-induced arthritis in mice
Authors: Rebecca Rogier, Heather Evans-Marin, Birgitte Walgreen, Monique M Helsen, Liduine A van den Bersselaar, Peter M van der Kraan, Fons A.J. van de Loo, Peter L.E.M. van Lent, Jose U Scher, Wim B van den Berg, Marije I Koenders, Shahla Abdollahi-Roodsaz
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background/objectives</h3> Both germ-free condition and administration of oral antibiotics before the onset of arthritis modulate T cell differentiation and attenuate arthritis in mice. However, it is not known whether and how the modulation of intestinal microbiota after the onset of arthritis may influence the disease. Here, we investigated the involvement of commensal intestinal microbiota in the progression of established arthritis in both T cell-dependent and -independent mouse models. <h3>Materials and methods</h3> Mice with established collagen-induced arthritis (CIA) as well as mice with K/BxN serum-transfer arthritis were treated orally with broad-spectrum antibiotics for one week to partially eliminate intestinal microbiota. 16S rRNA gene high-throughput sequencing was performed to assess the effect of arthritis and antibiotic treatment on the gut microbiota composition. Arthritis was assessed macroscopically and by histology. Differentiation of Th1, Th17 and regulatory T (Treg) cells and production of their prototypic cytokines in intestinal lamina propria and joint-draining lymph nodes were assessed by flow cytometry and Luminex cytokine array. <h3>Results</h3> Induction of arthritis as such resulted in significant alterations in the gut microbiota. Antibiotic treatment of CIA mice eliminated the majority of the gut microbiota, while the microbiota composition of control mice remained relatively stable. Partial elimination of intestinal microbiota during ongoing CIA specifically suppressed intestinal Th17 cell differentiation without affecting Th1 and Treg cells. Accordingly, production of IL-17, but not IFNγ, IL-4 and IL-10, by lamina propria lymphocytes was significantly diminished in antibiotic-treated mice. Importantly, elimination of intestinal microbiota resulted in suppressed Th17 cell differentiation in joint-draining lymph nodes and reduced the severity of established CIA. In contrast, antibiotic treatment did not influence disease severity in the T cell-independent K/BxN serum-transfer arthritis. Intriguingly, the abundance of intestinal Th17 cells strongly correlated with the severity of arthritis in the CIA mice. However, elimination of intestinal microbiota after disease onset did not affect the development of anti-collagen type II auto-antibodies. <h3>Conclusion</h3> These observations suggest that modulation of commensal intestinal microbiota during established arthritis specifically suppresses Th17 differentiation and dampens T cell-mediated arthritic processes. Our study supports the notion that inflammatory signals provided by the gut microbiota continue to promote arthritis after its onset.
Abstract SY03-02: Preclinical assessment of JTX-2011, an agonist antibody targeting ICOS, supports evaluation in ICONIC clinical trial
Authors: Jennifer S. Michaelson, Christopher Harvey, Kutlu Elpek, Ellen Duong, Lindsey Shallberg, Matthew Wallace, Robert Mabry, Jenny Shu, Amit Deshpande, Tong Zi, Stephen Sazinsky, Joshua Apgar, Barbara Mounho-Zamora, Michael Briskin, Elizabeth Trehu, Jason Reeves, Heather Hirsch, Sriram Sathyanarayanan, Deborah Law
Journal: Cancer Research (2017)

Abstract ICOS (the inducible T-cell co-stimulator) is a co-stimulatory molecule expressed on the surface of T cells and a member of the CD28 family, which includes clinically validated targets of cancer immunotherapies, such as PD-1 and CTLA-4. Clinical data identified ICOS as a potentially key molecule in providing optimal antitumor benefit following anti-CTLA-4 therapy. We have developed a species cross-reactive humanized IgG1 agonist antibody, JTX-2011, that binds ICOS and is designed to induce an antitumor immune response. Our preclinical data suggest that JTX-2011 functions through a dual mechanism of action, by stimulating T effector cells (Teff) and depleting intratumoral T regulatory cells (Tregs). The ICOS antibody is efficacious as a single agent in mouse syngeneic tumor models and demonstrates enhanced activity when administered in combination with anti-PD-1. Single-agent activity in the preclinical models appears to correlate with ICOS expression, with greater efficacy observed in tumor models that exhibit a higher percentage of ICOS-expressing immune cell infiltrate. An integrated expression analysis of human tumors identified non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) as indications with higher percentages of ICOS-expressing cell infiltrate. Preclinical studies performed in rodent and monkeys evaluated safety, pharmacokinetics, and pharmacodynamics of JTX-2011 to inform the first in-human study. The ICONIC phase I/II clinical trial is currently ongoing for evaluation of JTX-2011 alone or in combination with the anti-PD-1 antibody Nivolumab in patients with advanced solid tumors and incorporates a patient enrichment strategy design based on the preclinical and translational findings. Citation Format: Jennifer S. Michaelson, Christopher Harvey, Kutlu Elpek, Ellen Duong, Lindsey Shallberg, Matthew Wallace, Robert Mabry, Jenny Shu, Amit Deshpande, Tong Zi, Stephen Sazinsky, Joshua Apgar, Barbara Mounho-Zamora, Michael Briskin, Elizabeth Trehu, Jason Reeves, Heather Hirsch, Sriram Sathyanarayanan, Deborah Law. Preclinical assessment of JTX-2011, an agonist antibody targeting ICOS, supports evaluation in ICONIC clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY03-02. doi:10.1158/1538-7445.AM2017-SY03-02
Abstract 4584: High PD-1 expression on regulatory and effector T cells in lung cancer draining lymph nodes
Authors: Rieneke Van De Ven, Anna-Larissa N. Niemeijer, Anita G. Stam, Sayed M. Hashemi, Christian G. Slockers, Johannes M. Daniels, Erik Thunnissen, Egbert F. Smit, Tanja D. de Gruijl, Adrianus J. de Langen
Journal: Cancer Research (2017)

Abstract The treatment of advanced non-small cell lung cancer (NSCLC) with PD-1 immune checkpoint inhibitors has improved clinical outcome for a proportion of patients. The current challenge is to find biomarkers that will identify patients likely to benefit from this therapy. In this study we assessed the difference of T cell subsets and PD-1 expression levels on T cells in tumor-draining lymph nodes (TDLN), non-TDLN (NTDLN) and peripheral blood mononuclear cells (PBMC). To evaluate this, flow cytometric analyses were performed on endobronchial ultrasound-guided (EBUS) fine-needle aspirates (FNA) from TDLN and NTDLN of patients with NSCLC and compared to PBMC. Our data show that the frequency of PD-1+ CD4+ and CD8+ T cells, as well as the PD-1 expression level on activated regulatory T (aTreg) and CD4+ and CD8+ T cells, are higher in TDLNs as compared to NTDLNs or PBMC. These elevated PD-1 expression levels in TDLN may reflect tumor-specific T cell priming and may serve as a predictive or early response biomarker during PD-1 checkpoint blockade. Citation Format: Rieneke Van De Ven, Anna-Larissa N. Niemeijer, Anita G. Stam, Sayed M. Hashemi, Christian G. Slockers, Johannes M. Daniels, Erik Thunnissen, Egbert F. Smit, Tanja D. de Gruijl, Adrianus J. de Langen. High PD-1 expression on regulatory and effector T cells in lung cancer draining lymph nodes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4584. doi:10.1158/1538-7445.AM2017-4584
Abstract 1229: RNAi-based β-catenin inhibition in combination with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance
Authors: Shanthi Ganesh, Serena Shui, Girish Chopda, Martin Koser, Kevin Craig, Chaitali Dutta, Cheng Lai, Hank Dudek, Weimin Wang, Bob D. Brown, Marc Abrams
Journal: Cancer Research (2017)

Abstract Despite recent advances in early detection and therapeutic intervention, colorectal cancer (CRC) remains one of the most deadly cancers in the United States. The Wnt/β-catenin and KRAS/BRAF-driven MAPK pathways were reported to cooperate in inducing CRC initiation and progression. Several studies have also identified Wnt signaling as a resistance mechanism in MAPK pathway-activated CRCs. Thus far, independent targeting of these single oncogenic events in CRC has yielded limited therapeutic success. RNA interference (RNAi) triggers are capable of silencing any expressed mRNA with high potency and specificity, including previously un-druggable targets such as β-catenin, an oncogene frequently dysregulated in CRC. DCR-BCAT is a chemically-optimized DsiRNA targeting CTNNB1, the gene which encodes β-catenin, formulated in a second-generation EnCore lipid nanoparticle. We have previously reported extensive preclinical pharmacology for DCR-BCAT in mouse tumor models of diverse origin. (Ganesh et al, Mol Cancer Ther 2016). Here we demonstrate that the dual inhibition of β-catenin and MEK demonstrates synergistic efficacy in not only primary CRC, but also in aggressive liver metastases of CRC in preclinical models. This combination of DCR-BCAT and the MEK inhibitor trametinib was also efficacious in tumors which are known to be resistant to trametinib, as well as tumors which acquire resistance due to drug exposure. These data support clinical development of these combination approaches for this first-in-class RNAi therapeutic. Citation Format: Shanthi Ganesh, Serena Shui, Girish Chopda, Martin Koser, Kevin Craig, Chaitali Dutta, Cheng Lai, Hank Dudek, Weimin Wang, Bob D. Brown, Marc Abrams. RNAi-based β-catenin inhibition in combination with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1229. doi:10.1158/1538-7445.AM2017-1229