tbuckley/cabot-search huggingface dataset:
Abstract 2261: Synergistic effect and VEGF/HSP70-hom haplotype analysis: Relationship to prostate cancer risk and clinical outcome
Authors: Sana Sfar, Hamadi Saad, Faouzi Mosbah, Lotfi Chouchane
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is a complex disorder resulting from the combined effects of multiple environmental and genetic factors. Our previous single-locus analysis showed that VEGF and HSP70-hom polymorphisms were significantly associated with PCa susceptibility and prognosis. Both genes encoding these proteins were located on chromosome 6p21, and combining the neighboring single nucleotide polymorphisms (SNPs) into haplotypes may increase the association with the disease. Three tagging polymorphisms, the HSP70-hom 2437 T/C, the VEGF-1154 G/A, and the VEGF-634 G/C SNPs were genotyped in 101 cases and 80 controls. For the combined analysis of VEGF and HSP70-hom, we found a positive gradient in the odds ratios (ORs) related to the number of high-risk genotypes with a 3.53-fold increase of prostate carcinoma risk (OR= 3.53; p= 0.015). Furthermore, the TAG and CAG haplotypes at positions HSP70-hom, VEGF-1154 and VEGF -634 exhibited a two-fold (OR= 0.46; p= 0.014) and a seven-fold (OR= 0.14; p= 0.00005) reduction in PCa risk, respectively. Regarding PCa prognosis, the TAG haplotype had a negative association with the aggressive phenotype as defined by the histopathological grade (OR= 0.28; p= 0.006). Our findings confirm the role of at-risk haplotype across the HSP70-hom/VEGF gene cluster in determining susceptibility to PCa. Note: This abstract was not presented at the meeting. Citation Format: Sana Sfar, Hamadi Saad, Faouzi Mosbah, Lotfi Chouchane. Synergistic effect and VEGF/HSP70-hom haplotype analysis: Relationship to prostate cancer risk and clinical outcome [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 2261. doi:10.1158/1538-7445.AM2017-2261
Abstract 2211: Characterization of monoclonal antibodies specific for HPV-positive head and neck cancer
Authors: Hsuan-Chen Liu, Falguni Parikh, Thomas Kraus, Thomas Moran, Andrew Sikora
Journal: Cancer Research (2017)

Abstract HPV-driven head and neck squamous cell carcinoma (HNSCC) are among the fastest growing cancers. Although, HPV-HNSCC patients have an overall favorable prognosis, a significant number of patients relapse post-treatment, and currently there is no specific therapeutic approach targeting the unique biology of HPV-driven HNSCC. Our ongoing efforts to target HPV-HNSCC focus on the identification of cell surface antigens that are upregulated by HPV infection. We have developed an "antigen-agnostic" approach for generating HPV-HNSCC-targeting monoclonal antibodies for cancer diagnosis and treatment that does not rely on prior identification of target antigens. We used HPV-HNSCC membrane fractions to immunize recipient mice and generated HPV-specific hybridomas. We then screened five thousand hybridoma colonies by flow cytometry to test the specificity of binding to HPV-positive cancer cell lines (2HNSCC and 2 Cervical Cancer) and HPV-negative cancer cell lines (4 HNSCC and 1 CC). After primary screening, we narrowed down to forty-four clones; among these hybridoma clones, 6D8 and 6B3 bound preferentially to HPV-positive cancer cell lines. The binding targets of 6D8 and 6B3 were identified by immunoprecipitation and mass spectrometry; their targets are integrin alpha6 (ITGA6) and tissue factor (F3) respectively. Future work will validate the biological function of these mAbs in in vitro and in vivo models, and continue identifying more binding target of mAbs. We propose mAbs specifically targeting membrane-expressed antigens on HPV-related cancer cells as a potential approach for early diagnosis and targeted therapy. Citation Format: Hsuan-Chen Liu, Falguni Parikh, Thomas Kraus, Thomas Moran, Andrew Sikora. Characterization of monoclonal antibodies specific for HPV-positive head and neck 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 2211. doi:10.1158/1538-7445.AM2017-2211
Abstract 4983: T cells expressing chimeric PD1 receptors that contain a Dap10 costimulatory domain are a potential treatment for multiple types of cancer
Authors: Kelsey Deal, Emily Nylen, Amorette E. Barber
Journal: Cancer Research (2017)

Abstract Adoptive transfer of tumor-reactive T cells is a promising anti-tumor therapy for many cancers. To enhance tumor recognition by T cells, chimeric antigen receptors (CAR) consisting of signaling domains fused to receptors that recognize tumor antigens can be created and expressed in T cells. One receptor that is a prospective target for a new chimeric antigen receptor is PD1 because the ligands for the PD1 receptor are expressed on many cancer types. Therefore we developed a murine chimeric PD1 receptor (chPD1) consisting of the PD1 receptor extracellular ligand recognition domain and the activation domain of CD3 zeta. In addition, current chimeric antigen receptor therapies utilize various costimulatory domains to enhance anti-tumor efficacy. Therefore, we also compared the inclusion of CD28, Dap10, 41BB, GITR, ICOS, or OX40 costimulatory domains in our chPD1 receptor to determine which costimulatory domain induced optimal anti-tumor immunity. To determine if this novel CAR could potentially target a wide variety of tumors, the anti-tumor efficacy of chPD1 T cells against murine lymphoma, melanoma, kidney, pancreatic, liver, and colon cancer cell lines was measured. Of the ten cell lines tested, all expressed PD1 ligands on their cell surface, making them potential targets for chPD1 T cells. Regardless of the costimulatory domain in the CAR, all of the chPD1 T cells induced similar levels of T cell proliferation and tumor cell lysis. However, differences were observed in the cytokine secretion profiles depending on which costimulatory receptor was included in the CAR. While most of the chPD1 T cell receptor combinations secreted both pro-inflammatory (IFNγ, TNFα, IL-2, GM-CSF, IL-17, and IL-21) and anti-inflammatory cytokines (IL-10 and IL-5) as determined by ELISA and LegendPlex analysis, chPD1 T cells containing a Dap10 costimulatory domain secreted high levels of proinflammatory cytokines, but did not secrete a significant amount of anti-inflammatory cytokines. Therefore, adoptive transfer of chPD1 T cells could be a novel therapeutic strategy to treat multiple types of cancer and inclusion of the Dap10 costimulatory domain in chimeric antigen receptors may induce a preferential cytokine profile for anti-tumor therapies. Citation Format: Kelsey Deal, Emily Nylen, Amorette E. Barber. T cells expressing chimeric PD1 receptors that contain a Dap10 costimulatory domain are a potential treatment for multiple types of 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 4983. doi:10.1158/1538-7445.AM2017-4983
Abstract 3000: Defining the subclonal landscape of high-risk neuroblastoma
Authors: Jo Lynne Harenza, Maura A. Diamond, Derek A. Oldridge, Olivia Padovan-Merher, Pichai Raman, Yael P. Mosse, John M. Maris
Journal: Cancer Research (2017)

Abstract We recently showed that relapsed neuroblastoma (NB) tumors harbor an increased somatic mutational burden, enriched for ALK or RAS-MAPK activating lesions, nominating targeted therapeutic strategies for a condition that is largely incurable. We also showed that these mutations can be present in subclonal tumor cell populations at diagnosis, suggesting that they may contribute to acquired chemoradiotherapy resistance. We hypothesize that subclonal mutations in NB oncogenes are common at diagnosis, are biomarkers for treatment failure, and can be targeted in conjunction with standard chemotherapy to improve patient survival. Here, we focus on the first aspect of this broad hypothesis by presenting the subclonal landscape of diagnostic, high-risk neuroblastomas. A meta-analysis of our previously published primary/relapse (N=23), whole exome (N=232) and whole genome (N=159) diagnostic data, and recent sequencing study of 78 diagnostic and 67 relapse cases were used to inform design of a custom amplicon panel for ultra-deep sequencing. The 28-gene panel covers 57 mutations in frequently mutated genes. Here, 250 high-risk primary tumors were sequenced to an average depth of 50,000X. More subclonal mutations were called (mean=36) compared to clonal alterations (mean=3), demonstrating the complex subclonal architecture in these tumors. We validated five clonal ALK mutations we originally discovered and identified 15 additional pathogenic ALK mutations with mutant allele frequencies (MAFs) ranging from 0.03-23%. Known ALK activating mutations were found at codons 1170, 1174, 1196, 1245, 1275 in 15 of 38 diagnostic primary tumors. This 39.5% frequency is much higher than the 14% frequency defined by us using Sanger or other sequencing methods. Improvement of subclonal mutation detection of actionable, relapse-specific driver mutations demonstrates the clinical utility of utilizing this sequencing methodology at diagnosis to enable timely improvement of outcomes for children with high-risk refractory NB. Citation Format: Jo Lynne Harenza, Maura A. Diamond, Derek A. Oldridge, Olivia Padovan-Merher, Pichai Raman, Yael P. Mosse, John M. Maris. Defining the subclonal landscape of high-risk neuroblastoma [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 3000. doi:10.1158/1538-7445.AM2017-3000
Abstract 5287: Recent trends in racial and regional disparities in cervical cancer incidence and mortality
Authors: Wonsuk Yoo, Sangmi Kim, Steven Coughlin, Sejong Bae, Edward Partridge, Warner Huh, Sarah Dilley, Yunmi Chung
Journal: Cancer Research (2017)

Abstract Background: Although black and Hispanic women experienced greater cervical cancer rate reduction in recent years, they continue to have higher incidence rates than whites. Great variations also exist among geographic regions of the US, with the South having both the highest incidence and mortality rates compared to other regions. The present study explores the question of whether living in the South is associated with greater racial disparity in cervical cancer incidence and mortality by examining race- and region-specific rates and the trend between 2000 and 2012. Methods: The Surveillance, Epidemiology, and End Results (SEER) 18 Program data was used. Incidence and mortality rates, annual percent changes, and disparity ratios of cervical cancer were calculated using SEER*Stat software and Joinpoint regression for four groups: US14-Non-Hispanic White (NHW), US14-Non-Hispanic Black (NHB), South-NHW, and South-NHB, where the South included 4 registries from Georgia and Louisiana. Results: The incidence and mortality rates were much higher among NHB women compared to NHW in the South and the US. The degree of racial disparities between NHB and NHW women was greater in terms of mortality rates than incidence rates. For all age groups, NHB women in the South consistently had higher incidence rates than NHB women in the US14 region. The mortality disparity ratios was highest among NHB women, followed by NHW women in the South, NHW women in US14, and finally NHB women in the South. Conclusions: Although racial disparity has been narrowed in recent years, there has been little change or even a growing gap between white women in the South and their counterparts in the US14 region. Age-specific analysis further indicated that the emerging regional gap observed among white women might be attributable to the excess number of new cases and deaths among young women. Citation Format: Wonsuk Yoo, Sangmi Kim, Steven Coughlin, Sejong Bae, Edward Partridge, Warner Huh, Sarah Dilley, Yunmi Chung. Recent trends in racial and regional disparities in cervical cancer incidence and mortality [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 5287. doi:10.1158/1538-7445.AM2017-5287
Abstract LB-070: Nano self-assemblies of paclitaxel for breast cancer treatment
Authors: Prashanth Kumar Bhusetty Nagesh, Pallabita Chowdhury, Sumeeth S. Chauhan, Elham Hatami, Sheema Khan, Bilal Hafeez, Subhash C. Chauhan, Meena Jaggi, Murali M. Yallapu
Journal: Cancer Research (2017)

Abstract Objectives: Breast cancer (BC) is second leading cause of cancer-related deaths in the United States. Paclitaxel (Ptx) is an FDA-approved and frequently used chemotherapeutic agent against various cancers, including BC. However its adverse side effects and chemoresistance against it, limits its use in the clinic. Minimizing the toxicity issues of Ptx through nanoparticle technology (such as Ptx bound to human serum albumin nanoformulation, i.e., Abraxane®) is feasible and has displayed encouraging outcomes. With this background, we aim to generate Ptx self-assemblies (PSAs) using various biocompatible polymers and surfactants, and to evaluate its efficacy against BC cells. Methods: PSAs composed of Ptx dispersion or a core formation with a polymer at a weight ratio of 1:50. The extent of Ptx assembly/binding efficiency was determined using a fluorescence quenching study. FT-IR spectral study was employed to confirm the presence of Ptx in PSAs. The optimal polymers for forming PSAs were identified through measurement of particle size, zeta potential and TEM. Another check point of generating a better PSAs was evaluated by its extent of cellular internalization in BC cells and through hemolytic assay. Finally, the finalized PSAs were examined for in vitro activity in BC cells using proliferation, colony formation, and immunoblotting assays. Results: We screened 22 biocompatible polymers for PSA formation, out of which 8 were finalized due to excellent Ptx binding profiles, appropriate particle size ranges (40-300 nm), zeta potentials (-14.0 to -4.0 mV), and superior internalization in BC cells. The optimized PSAs exhibited enhanced anti-cancer capability in MCF-7 and MDA-MB-231 BC cells in proliferation and colony formation assays, compared to free Ptx. This was further affirmed through tubulin stabilization studies. Further, PSA treatment in BC cells demonstrates a distinct induction of the expression of apoptosis-associated proteins and distinct downregulation of anti-apoptotic proteins. Conclusion: Overall this study suggests a simple and feasible Ptxl self-assembly approach for achieving superior anti-cancer activity with Ptx. Citation Format: Prashanth Kumar Bhusetty Nagesh, Pallabita Chowdhury, Sumeeth S. Chauhan, Elham Hatami, Sheema Khan, Bilal Hafeez, Subhash C. Chauhan, Meena Jaggi, Murali M. Yallapu. Nano self-assemblies of paclitaxel for breast cancer treatment [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-070. doi:10.1158/1538-7445.AM2017-LB-070
Abstract 416: Identification of therapeutic combinations in glioblastoma using personalized gene expression networks
Authors: Vasileios Stathias, Michele Forlin, Bryce Allen, Stephan Schürer, Nagi G. Ayad
Journal: Cancer Research (2017)

Abstract The goal of our study was to identify patient-specific gene expression networks from Glioblastoma Patient-Derived Xenografts (PDXs) and determine novel therapeutic compound combinations using those networks. Glioblastoma is the most common malignant primary adult brain tumor with a standard of care consisting of maximal surgical resection followed by radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. However, despite medical advances in the field, recurrence is almost universal, suggesting the need for more personalized and targeted therapeutic approaches. For this, we obtained, transcriptional data from Glioblastoma PDXs and used them to identify their respective differentially expressed genes. Patient-specific gene expression networks were then created and their biological relevance was supplemented by integrating them with TCGA Glioblastoma transcriptional data. In order to identify compound combinations specific for those networks, we used the extensive chemical perturbation signatures from the Library of Network-based Cellular Signatures (LINCS). From the large number of L1000 transcriptional data we extracted gene expression signatures that were indicative of specific LINCS compounds. We then compared those signatures to the patient-specific networks in order to prioritize compound combinations that were inducing discordant transcriptional changes in distinct sub-networks of the PDXs transcriptome. The most orthogonal compound combinations were then chosen and used in in-vitro cell viability assays of Glioblastoma PDXs in order to evaluate their effectiveness. The above process can be used to prioritize compound combinations with potential therapeutic effect in a patient-specific manner. Citation Format: Vasileios Stathias, Michele Forlin, Bryce Allen, Stephan Schürer, Nagi G. Ayad. Identification of therapeutic combinations in glioblastoma using personalized gene expression networks [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 416. doi:10.1158/1538-7445.AM2017-416
Abstract 3695: The interplay between neutrophils &amp;It CDThe interplay between neutrophils and CD8+ cell improves survival in human colorectal cancer
Authors: Valeria Governa, Emanuele Trella, Valentina Mele, Raul Droeser, Serenella Eppenberger-Castori, Luigi Maria Terracciano, Giandomenica Iezzi, Giulio Cesare Spagnoli
Journal: Cancer Research (2017)

Abstract Purpose: Tumor infiltration by different T lymphocyte subsets is known to be associated with favorable prognosis in colorectal cancer (CRC). Still debated is the role of innate immune system. We investigated clinical relevance, phenotypes &amp;it functional features of CRC infiltrating CD66b+ neutrophils &amp;it their crosstalk with CD8+ T cells. Experimental design: CD66b+ &amp;it CD8+ cell infiltration was analyzed by immunohistochemistry on a tissue microarray including &amp;gt;650 evaluable CRC samples. Phenotypic profiles of tissue infiltrating and peripheral blood CD66b+ cells were evaluated by flow cytometry. CD66b+/ CD8+ cells crosstalk was investigated by in vitro experiments. Results: CD66b+ cell infiltration in CRC is significantly associated with increased survival. Interestingly, neutrophils frequently co-localize with CD8+ T cells in CRC. Functional studies indicate that although neutrophils are devoid of direct antitumor potential, co-culture with peripheral blood or tumor associated neutrophils (TANs) enhances CD8+ T cell activation, proliferation and cytokine release induced by suboptimal concentrations of anti-CD3 monoclonal antibody (mAb). Moreover, under optimal activation conditions, CD8+ cells initially stimulated in the presence of CD66b+ cells show decreased expression of PD-1 “exhaustion” marker and are significantly less susceptible to apoptosis induced by T- cell receptor triggered re-stimulation. Importantly, combined tumor infiltration by CD66b+ and CD8+ T lymphocytes is associated with significantly better prognosis, as compared to CD8+ T cell infiltration alone. Conclusions: Neutrophils enhance the responsiveness of CD8+ T cells to TCR triggering. Accordingly, infiltration by neutrophils enhances the prognostic significance of CRC infiltration by CD8+ T cells, suggesting that they might effectively promote antitumor immunity. Note: This abstract was not presented at the meeting. Citation Format: Valeria Governa, Emanuele Trella, Valentina Mele, Raul Droeser, Serenella Eppenberger-Castori, Luigi Maria Terracciano, Giandomenica Iezzi, Giulio Cesare Spagnoli. The interplay between neutrophils &amp;It CDThe interplay between neutrophils and CD8+ cell improves survival in human colorectal 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 3695. doi:10.1158/1538-7445.AM2017-3695
FolamiRs: Ligand-targeted, vehicle-free delivery of microRNAs for the treatment of cancer
Authors: Esteban A. Orellana, Srinivasarao Tenneti, Loganathan Rangasamy, L. Tiffany Lyle, Philip S. Low, Andrea L. Kasinski
Journal: Science Translational Medicine (2017)

MicroRNAs are small RNAs that negatively regulate gene expression posttranscriptionally. Because changes in microRNA expression can promote or maintain disease states, microRNA-based therapeutics are being evaluated extensively. Unfortunately, the therapeutic potential of microRNA replacement is limited by deficient delivery vehicles. In this work, microRNAs are delivered in the absence of a protective vehicle. The method relies on direct attachment of microRNAs to folate (FolamiR), which mediates delivery of the conjugated microRNA into cells that overexpress the folate receptor. We show that the tumor-suppressive FolamiR, FolamiR-34a, is quickly taken up both by triple-negative breast cancer cells in vitro and in vivo and by tumors in an autochthonous model of lung cancer and slows their progression. This method delivers microRNAs directly to tumors in vivo without the use of toxic vehicles, representing an advance in the development of nontoxic, cancer-targeted therapeutics.