tbuckley/cabot-search huggingface dataset:
Abstract 3927: Programmed cell death ligand 1 expression in resected colorectal adenocarcinomas: association with micrometastasis
Authors: Ilseon Hwang, Keon Uk Park, Jin Young Kim, Hun-Mo Ryoo, Yun-Han Lee
Journal: Cancer Research (2017)

Abstract Background: Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key suppressors of the cytotoxic immune response. PD-L1 expression on tumor cells may be induced by the immune microenvironment, resulting in immune escape, and an adverse prognosis in many malignancies. In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability. However, little is known about the clinicopathologic, molecular, and prognostic characteristics of colorectal carcinoma with PD-L1 expression. In surgically resected colorectal adenocarcinoma, micrometastasis should be crucial for recurrence, and micrometastasis may be related to PD-L1. The aim of this study is to assess the PD-L1 expression and its association with clinicopathologic manifestations. Methods: PD-L1 expression was evaluated in 176 resected colorectal adenocarcinomas using tissue microarrays. Immunohistochemical staining was performed to evaluate the expression of PD-L1. The relationship of clinicopathologic manifestations and PD-L1 expression in colorectal cancer were evaluated by chi-squared test, Kaplan-Meier survival and Cox regression test. Results: High PD-L1 expression was present in 52.8% colorectal adenocarcinoma and was not related pathologic T or N stage. High PD-L1 expression was associated with decreased recurrence rate (p &amp;lt; 0.001), better disease-free survival (p &amp;lt; 0.001). Cox regression analysis revealed that pathologic N stage and High PD-L1 expression was an independent prognostic factors of disease-free survival (p &amp;lt; 0.001). Conclusion: High PD-L1 expression is an independent prognostic factor, such as pathologic stage in colorectal adenocarcinoma. PD-L1 expression is independent prognostic factor, relating immune response to micrometastasis and immune suppression by PD-L1 may not be effective in micrometastasis of colorectal adenocarcinoma. Key words: PD-L1, colon, cancer, immunology, micrometastasis Citation Format: Ilseon Hwang, Keon Uk Park, Jin Young Kim, Hun-Mo Ryoo, Yun-Han Lee. Programmed cell death ligand 1 expression in resected colorectal adenocarcinomas: association with micrometastasis [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 3927. doi:10.1158/1538-7445.AM2017-3927
A randomized phase 2 study of trametinib with or without GSK2141795 in patients with advanced uveal melanoma.
Authors: Alexander Noor Shoushtari, Ragini Reiney Kudchadkar, Katherine Panageas, Rashmi Krishna Murthy, Maria Jung, Roshani Shah, Bridget O'Donnell, Talal T. Khawaja, Yelena Shames, Nana A. Prempeh-Keteku, Grazia Ambrosini, Helen X. Chen, Paul B. Chapman, Gary K. Schwartz, Richard D. Carvajal, Sapna Pradyuman Patel
Journal: Journal of Clinical Oncology (2016)

9511 Background: There are few treatment options for patients (pts) with advanced uveal melanoma (UM). MEK inhibition (MEKi) has demonstrated efficacy in a randomized Phase 2 trial (Carvajal et al, 2014), but resistance may be mediated via Akt signaling (Ambrosini et al, 2013). We hypothesized that adding an Akt inhibitor (Akti), GSK2141795 (GSK795), to the MEKi trametinib (TRAM) would improve progression-free survival (PFS) in pts with UM. Methods: We conducted an open-label Phase 2 trial where pts with advanced UM and no prior systemic or liver-directed therapy were randomized to one of two arms stratified by liver disease and LDH: TRAM 2mg daily (Arm A) or TRAM 1.5mg + GSK795 50mg daily (Arm B). Efficacy was assessed every 8 weeks (wk) by RECIST 1.1. Pts whose tumors progressed on TRAM could receive TRAM + GSK795. With 40 patients per arm, this design had 80% power to detect a PFS hazard ratio of 0.56 with a 5% one-sided alpha. A pre-planned futility analysis after 40 enrolled pts would cease accrual to an arm if <2/20 pts had objective responses. Matched biopsies at baseline and Day 15 were mandatory. Results: 40 pts were enrolled, of which 39 received ≥1 dose of study drug (N=18 TRAM; N=21 TRAM + GSK795). Median age 61, 55% male, 85% liver disease, 50% elevated LDH. One partial response was observed in each arm (16+ wk in Arm A, 8 wk in Arm B); thus, accrual was held on both arms. We did not detect a difference in median PFS between Arm B and Arm A (15.6 vs 15.7 wk; p=0.74, log rank). Median PFS for N=11 who crossed over to TRAM + GSK795 was 7.9 wk (range: 3.7-41+ wk). All pts had ≥1 adverse event (AE) at least possibly related to drug(s). AEs for TRAM included rash (100%, all Grade (G)1-2), diarrhea (72%, all G1-2), elevated AST/ALT (55%, 6% G3), mucositis (50%, all G1-2). 7/18 required dose reduction. AEs with TRAM + GSK795 included rash (81%, 14% G3), nausea (67%, all G1-2), diarrhea (62%, all G1-2), elevated AST/ALT (43%, 14% G3). 7/21 required dose reduction (2 TRAM, 3 GSK795, 2 both). There were no G4-5 AEs. Conclusions: The addition of Akti GSK795 to TRAM did not improve PFS, and objective responses were uncommon. Dose reductions for AEs were frequent. Ongoing analysis of 31 matched biopsies at baseline and day 15 is investigating therapeutic resistance. Clinical trial information: NCT01979523.
Abstract 5464: Catalase mediates the survival of anchorage-independent ovarian cancer cells
Authors: Cassandra L. Libbing, Calli A. Versagli
Journal: Cancer Research (2017)

Abstract Among United States women, ovarian cancer is the fifth leading cause of cancer-related death and the deadliest of the female reproductive system cancers. This is due to a lack of early detection, in effect, leading to primary diagnosis in later, metastasized stages for which there are few effective treatment options. In order to metastasize, ovarian cancer cells must be able to survive detachment from the extracellular matrix (ECM). When a non-tumorigenic mammary epithelial cell detaches from the ECM, research has shown that levels of Reactive Oxygen Species (ROS) rise in the cell and inhibit cell metabolism resulting in decreased cell survival. Previous research has also shown that ECM-detached breast cancer cells are able to utilize antioxidant enzymes to neutralize ROS thereby rescuing ATP levels and promoting cell survival. This antioxidant activity has also been shown to bolster cancer cells’ survival in anchorage independence. Although studied in breast cancer cells, no work has been done in ovarian cancer, which exhibits a very unique mode of metastasis through the peritoneal fluid. To begin to understand the role of antioxidant enzymes in metastatic ovarian cancer cells, we have worked to characterize the role of catalase, a prominent antioxidant enzyme, in the survival of ECM-detached SKOV3 ovarian cancer cells. In order to do so, we utilized short hairpin RNA (shRNA) to engineer SKOV3 cells deficient in catalase. The catalase-deficient cells were then tested for colony formation in detachment and cell viability and proliferation in both attachment and detachment. The results show that elimination of catalase expression does not have a significant effect on proliferation in attachment or detachment, but significantly decreases both cell viability and colony formation of SKOV3 cells grown in ECM-detachment. This suggests that elimination of catalase expression may hold promise for targeted treatment in late stage ovarian cancer, calling for further investigation of the mechanisms behind these results and the role that other antioxidant enzymes play in ovarian cancer. Future studies include looking at this phenomenon in other ovarian cancer cell lines, and using mouse xenograft studies to examine the effects of antioxidant compounds on survival of metastatic ovarian cancer cells. Citation Format: Cassandra L. Libbing, Calli A. Versagli. Catalase mediates the survival of anchorage-independent ovarian cancer cells [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 5464. doi:10.1158/1538-7445.AM2017-5464
Abstract 5088: Tumor penetrating RNA delivery for therapeutic benefit of pancreatic cancer
Authors: Liangliang Hao, Justin Lo, Sangeeta Bhatia
Journal: Cancer Research (2017)

Abstract Pancreatic cancer remains a deadly disease with a median survival of less than one year, in part because we lack effective therapeutic strategies. Mutations of the oncogene KRAS and the tumor suppressor genes TP53, INK4A, and DPC4 play important roles in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC); however, these driver events have proven to be challenging targets for drug development. RNA interference through small interfering RNA (siRNA) delivery has the potential to have an impact on silencing ‘undruggable’ targets; however, siRNA delivery in tumors has been challenging in general and worsened in PDAC by the stromal barriers to drug delivery. Herein, we integrated biomedical engineering, materials science, and pre-clinical investigation to establish a novel class of tumor-penetrating nanoparticles (TPNs) to enhance delivery of siRNAs in PDAC for therapeutic benefit. Specifically, we adapted self-assembled nanoparticles comprised of siRNA complexed with tandem tumor-penetrating and membrane-translocating peptides, which enabled the specific delivery of siRNA deep into the tumor parenchyma. Specifically, to establish efficacious siRNA delivery vehicles, we characterized and selected tandem peptides that incorporate novel tumor-penetrating peptide domains known to target PDAC in mice. In parallel, we optimized the particle stability through incorporation of hydrophilic molecules, focusing on achieving desirable pharmacokinetic properties which will reduce off-target delivery and increase potency of a given siRNA dose. The resulting TPNs carry siRNA into the cytosol of monolayer cultures of tumor cells, and also exhibit penetration in pancreas organoids derived from primary mouse and human tumors. As a proof-of-concept, we used TPN in vivo to knockdown KRAS in a murine PDAC model, using subcutaneously-implanted, autochthonous KRASG12D/+p53-/- tumors. Treatment of tumor-bearing mice with systemically administrated KRAS-specific TPNs suppressed the growth of established tumors. With the delivery platform established, the ongoing goals of this project are to identify siRNA targets that synergize with the suppression of oncogenic KRAS, and to validate synthetic lethal targets by interfering with signature PDAC driver events uncovered by functional genomic efforts. Together, these studies will provide a foundation for translational studies involving new targets and delivery technology in pancreatic cancer. Citation Format: Liangliang Hao, Justin Lo, Sangeeta Bhatia. Tumor penetrating RNA delivery for therapeutic benefit of pancreatic cancer [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 5088. doi:10.1158/1538-7445.AM2017-5088
Abstract LB-222: A nanoscale optical reporter implant for miRNA biomarkers <i>in vivo</i>
Authors: Daniel A. Heller, Jackson D. Harvey, Prakrit V. Jena, Ryan M. Williams, Thomas V. Galassi, Hanan A. Baker, Daniel Roxbury, Gül Zerze, Jeetain Mittal
Journal: Cancer Research (2017)

Abstract MicroRNAs and other small oligonucleotides in biofluids are promising biomarkers, but conventional assays require complex processing steps unsuitable for point-of-care assays or implantable/wearable sensors. Single-walled carbon nanotubes are an ideal material for implantable sensors due to emission in the near-infrared spectral region, photostability, and exquisite sensitivity. We engineered a carbon nanotube-based platform capable of real-time optical quantification of hybridization events of microRNA and other oligonucleotides for use in vivo. The sensor mechanism derived from competitive effects between displacement of both oligonucleotide charge groups and water from the nanotube surface, resulting in a solvatochromism-like response. The platform allowed detection via single molecule sensor elements and multiplexing using multiple nanotube species. The sensor monitored toehold-based strand displacement events, reversing the sensor response and regenerating the sensor complex. The sensor functioned in whole urine and serum, and it non-invasively measured DNA and microRNA biomarkers after implantation into live mice. Citation Format: Daniel A. Heller, Jackson D. Harvey, Prakrit V. Jena, Ryan M. Williams, Thomas V. Galassi, Hanan A. Baker, Daniel Roxbury, Gül Zerze, Jeetain Mittal. A nanoscale optical reporter implant for miRNA biomarkers in vivo [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 LB-222. doi:10.1158/1538-7445.AM2017-LB-222
Abstract 4370: ASNS and other significant mutations in head and neck squamous cell carcinomas: mutational landscape in a South Asian population
Authors: Sadiq Rehmani, Safina Abdul Razzak, Sarosh Madhani, M Kamran Azim, Rashdia Ahmed, Mumtaz Khan, Kulsoom Ghias
Journal: Cancer Research (2017)

Abstract Head and neck cancers are the sixth most common cancer type globally and contribute significantly to the burden of disease in South Asia. Specifically in Pakistan, they are the most commonly diagnosed cancer in males and the second most common in females. The increasing burden of head and neck squamous cell carcinoma (HNSCC) in the region along with a unique set of risk factors merited a deeper investigation of the disease at the genomic level. Whole exome sequencing of HPV-negative HNSCC samples and matched normal genomic DNA (n = 7) was performed. Smoking, oral tobacco use and alcohol were identified risk factors in the study cohort. Significant somatic single nucleotide variants (SNVs) were identified and pathway analysis performed to determine most frequently affected signaling pathways. Significant, novel recurrent mutation in ASNS (asparagine synthetase) and driver mutations in previously reported genes, including TP53, PIK3CA, FGFR2, ARID2, MLL3, MYC and ALK, were identified. Using the IntOGen platform, we identified MAP kinase, cell cycle, actin cytoskeleton regulation, PI3K-Akt signaling and other pathways in cancer as among the most commonly affected pathways in all the samples. This data is the first of its kind from the Pakistani population. The results of this study can guide a better mechanistic understanding of HNSCC in the population, ultimately contributing new, rational therapeutic targets for the treatment of the disease. Citation Format: Sadiq Rehmani, Safina Abdul Razzak, Sarosh Madhani, M Kamran Azim, Rashdia Ahmed, Mumtaz Khan, Kulsoom Ghias. ASNS and other significant mutations in head and neck squamous cell carcinomas: mutational landscape in a South Asian population [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 4370. doi:10.1158/1538-7445.AM2017-4370
Abstract 946: Characterize and identify secreted high molecular weight heparanase from PC3M conditioned medium
Authors: Donghong Ju, Mary A. Kosir
Journal: Cancer Research (2017)

Abstract Introduction: Neutrophils, platelets, lymphocytes are typical sources of NAP-2 which is associated with heparanase activity. Heparanase degrades polymeric heparan sulfate molecules into shorter oligosaccharides, participating in extracellular matrix degradation. It is active under acidic conditions during tumor invasion and inflammatory processes. Our lab previously found that some cell lines like androgen independent prostate cancer cells (PC3M) can secrete a protein that reacts with anti-NAP-2 antibody, but has a much higher molecular weight(&amp;gt;50KD) than NAP-2 (MW~6-14 KD), and has heparanase activity. The purpose of this study is to characterize and identify this protein. Procedures: Immunoprecipitation was performed using Pierce DirectIP kit according the manufacturer’s instructions. Heparin binding affinity column used HiTrap™ Heparin HP column from GE Healthcare Bio-Sciences. The binding buffer was 10mM NaAcetate pH 5.0, the eluting buffers were 0.5M-2M NaCl in 10mM NaAcetate pH 5.0. The mass spectrometry was done by KCI Proteomics Core facility. Data: The immunoprecipitation method confirmed that this higher molecular weight protein indeed can be pulled down by the NAP-2 antibody, and after using heparin binding affinity column to purify, we can still get the &amp;gt; 50KD band on the western blot for NAP-2, meaning it is a heparin binding protein. Conclusions: A protein identified with NAP-2 antibody, but with higher molecular weight than native NAP-2 is found in the conditioned medium of PC3M cells that binds heparin, further confirming a potential role in tumor progression for prostate cancer. Citation Format: Donghong Ju, Mary A. Kosir. Characterize and identify secreted high molecular weight heparanase from PC3M conditioned medium [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 946. doi:10.1158/1538-7445.AM2017-946
Abstract 5885: Sialyl Lewis X-P-selectin connection between ovarian tumor-mesothelium in early stage metastasis
Authors: Shan-Shan Li, Carman K. M. Ip, Ayon A. Hassan, Matthew Y. H. Tang, Susan Yung, Tak-Mao Chan, Ho Cheung Shum, Alice S. T. Wong
Journal: Cancer Research (2017)

Abstract Metastasis is one of the major challenges for the treatment of ovarian cancer. Unlike other solid tumors, ovarian cancer primarily disseminates within the peritoneal cavity. A crucial step in metastasis formation is the adhesion of ovarian cancer cells onto the peritoneal mesothelium under ascitic shear flow. However, the adhesion mechanisms engaged in this tumor-mesothelium interaction remain elusive due to a lack of physiologically relevant model to manipulate and investigate this dynamic process. In this study, using a 3D microfluidic platform, we found that the metastatic population of cancer stem cells (M-CSCs) exhibited slower rolling velocity and higher binding ability to the peritoneal mesothelium than non-metastatic (NM)-CSCs under flow condition. This adhesion cascade was mediated by P-selectin which expressed on the peritoneal mesothelium. The key carbohydrate determinant on M-CSCs was a glycoprotein, but not a glycolipid, with its recognition as sialyl-Lewis X (sLeX) in a sialic acid- and fucose-dependent manner. Moreover, several glycosyltransferase genes including B4GALT4, ST3GAL3, ST3GAL4 and FUT-5 involved the synthesis of sLeX were upregulated in M-CSCs. Knocking down FUT-5 significantly inhibited ovarian tumor cell adhesion on the mesothelium in vitro and reduced the metastatic potential in vivo. Taken together, our findings revealed that a distinct sLeX-P-selectin axis of ovarian tumor-mesothelium interaction in early metastasis and may offer the possibility of new therapeutic targets. (This work is supported by RGC grant 17122014) Citation Format: Shan-Shan Li, Carman K. M. Ip, Ayon A. Hassan, Matthew Y. H. Tang, Susan Yung, Tak-Mao Chan, Ho Cheung Shum, Alice S. T. Wong. Sialyl Lewis X-P-selectin connection between ovarian tumor-mesothelium in early stage 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 5885. doi:10.1158/1538-7445.AM2017-5885
Abstract 4691: Polarization of macrophages with STING agonists
Authors: Kimiora L. Henare, Sofian M. Tijono, Lai-Ming Ching
Journal: Cancer Research (2017)

Abstract The functional plasticity of macrophages and their ability to support tumour growth or promote potent antitumor immunity make them an attractive target cancer therapy. Macrophages have been implicated in the complex antitumor activity of murine STING agonist, DMXAA, including disruption of tumor vasculature, induction of cytokine production, and promotion of durable antitumor immune responses. Many of these activities are lost in STING-/- mice, and DMXAA does not bind to human STING, providing a pertinent explanation for why the anti-tumour effects of DMXAA observed in mice were not recapitulated human clinical trials. Using PMA-differentiated THP-1 macrophages, we sought to identify human active analogues of DMXAA in vitro, comparing their capacity to induce cytokines indicative of a classically activated antitumour phenotype; the non-canonical STING agonist 2'3'-cGAMP was also included in our investigation. IP-10 (CXCL10) production, measured by ELISA, was used as an initial marker for activity, followed by multiplex cytokine analysis for broader characterisation compared to M(IFN-γ/LPS), M(IL-4/IL-13), and ‘resting’ M(media alone) macrophage phenotypes. Parallel experiments were also conducted with RAW264.7 murine macrophages to compare the DMXAA-induced cytokine profile directly with that of 2'3'-cGAMP. 2'3'-cGAMP induced 22-fold and 18-fold increases in IP-10 production in resting and M(IL-4/IL-13) THP-1 macrophages, respectively. By comparison, THP-1 macrophages were much less responsive to DMXAA and analogues tested to date. Furthermore, 2'3'-cGAMP induced a spectrum of cytokines similar to that observed in M(IFN-γ/LPS) macrophages, and markedly different to that of M(IL-4/IL-13) THP-1 macrophages. DMXAA, and analogues previously shown to have cytokine-inducing activity in human leukocytes did not produce cytokine spectra indicative of a classic M(IFN-γ/LPS) phenotype. Unlike human cells, however, cytokine spectra produced by RAW264.7 murine macrophages were comparable between DMXAA- and 2'3'-cGAMP-treated cells. These findings support previous data that suggest that STING agonists can promote macrophage polarisation towards an antitumour phenotype. While DMXAA is active in murine macrophages, only 2'3'-cGAMP can induce in human THP-1 cells, an M(IFN-γ/LPS)-like spectrum of cytokines often attributed to an antitumour macrophage phenotype. Citation Format: Kimiora L. Henare, Sofian M. Tijono, Lai-Ming Ching. Polarization of macrophages with STING agonists [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 4691. doi:10.1158/1538-7445.AM2017-4691