tbuckley/cabot-search huggingface dataset:
Abstract 2166: A novel etoposide-bound magnetic nanoparticle for remote targeting of cancer cells
Authors: Alexander Willis, Bhargava Karumudi, Bing Liu, Ashley Sough, Sangyeul Hwang, Ying Liu, Herbert Engelhard
Journal: Cancer Research (2019)

Abstract Background: Magnetic nanoparticles (MNPs) have potential for enhancing drug delivery in selected cancer patients. To date, successful clinical use of MNPs has been limited due to the: 1) limited capacity for targeting at human-sized distances, 2) route of delivery, and 3) choice of therapeutic component. Here, we present data related to the creation and in vitro use of a new two-part MNP system consisting of: 1) an AuFe base particle having streptavidin binding sites, and 2) biotinylated etoposide, which was bound to the base particle. Etoposide was chosen in part due to its previous clinical use within cerebrospinal fluid, which could serve as a delivery medium for the new particle. Methods: Base MNPs were manufactured by IMRA America, Inc., and combined with biotinylated etoposide to create AuFe-etoposide particles (etop-MNPs), which have not been previously described. Etop-MNPs were characterized by electron microscopy, UV-vis spectroscopy, and DLS. Etop-MNPs could be moved at a distance (e.g. 10 cm) by means of a “surface walking” phenomenon, occurring in response to a rotating neodymium-boron-iron permanent magnet, kindly provided by Pulse Therapeutics (St. Louis, MO). Cell lines (including D283, U138, and normal endothelial cells) were maintained using standard tissue culture technique. Viability of the cells in response to the MNP base particles, etoposide alone, and etop-MNPs, was studied by light microscopy and MTT assay. Results: Etoposide was successfully bound to the IMRA base particle through the streptavidin-biotin interaction. Typically, 100uM etoposide was used. Etop-MNPs could be moved remotely by the rotating magnet, which produced a tangential particle velocity of 0.15 +/- 0.026 cm/sec. With 2 hours of treatment, etop-MNPs caused morphologic changes and decreased cancer cell viability to 0.50 +/- 0.03 percent that of control values. Conclusions: These findings indicate that our novel etop-MNPs have tumoricidal effect, and can be moved relatively rapidly at physiologic distances, using a rotating magnet. Etop-MNPs, may therefore prove to be useful for magnetic drug targeting in clinical settings, such as intrathecal use within the spinal subarachnoid space. Citation Format: Alexander Willis, Bhargava Karumudi, Bing Liu, Ashley Sough, Sangyeul Hwang, Ying Liu, Herbert Engelhard. A novel etoposide-bound magnetic nanoparticle for remote targeting of cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2166.
Anal Carcinoma A comparative analysis of the standard treatment vs An hypofractionated schedule (the Tlalpan Regime) experience at the Instituto Nacional de Cancerología, México
Authors: J. Zamora Moreno, B. Macario-Pixcar, B. García Pantoja, G. Estrada, G. Sebastian Barajas, E. Naranjo Ornelas, V. Aiello-Crocifoglio
Journal: Annals of Oncology (2019)
Circulating tumor cells levels correlate with carcinoembryonic antigen in patients with high-risk colon cancer who experienced disease progression
Authors: E. Abdallah, V. Souzae Silva, S. Aguiar, R. Takahashi, B. Flores, A. Braun, V. Alves, J. Rodríguez Tarazona, L. Chinen, C. Mello
Journal: Annals of Oncology (2019)
Abstract 4542: The use of saliva proteins as biomarkers to predict the risk of lymph node metastasis in oral cancer
Authors: Tatiane De Rossi, Daniela Campos Granato, Ana Carolina Ribeiro, César Rivera, Henry Heberle, Guilherme Pimentel Telles, Carolina Moretto Carnielli, Thais Bianca Brandão, Alan Roger Santos-Silva, Márcio Ajudarte Lopes, Adriana Franco Paes Leme
Journal: Cancer Research (2019)

Abstract Background. The most common oral cancer in the world is squamous cell carcinoma (OSCC), accounting for more than 90% of all cases of cancer in the oral cavity. Thus, the research on molecular markers associated with the development and progress of human diseases has been the subject of intense research. The findings that saliva has molecular profiles indicating systemic diseases urge the study of non-invasive diagnosis using saliva as source of potential diagnosis, prognosis and predictive based on proteomics. Methods. 204 proteotypic peptides were selected previously based on DDA data from our own studies or retrieved from the SRMAtlas. Heavy labeled synthetic peptides were synthetized and SRM method was developed using Skyline v3.6. Saliva samples were collected from patients with lymph node metastasis (n=26) and without lymph node metastasis (n=14). Saliva proteins were digested with trypsin. Samples were randomized in R environment and analyzed in a triple-quadrupole mass spectrometer (Xevo TQ-XS, Waters). A Peptide Retention Time Calibration Mixture was spiked into the samples. Data comparison between groups was performed using Wilcoxon Mann Whitney test in R environment. Results. In the SRM method, we monitored 68 proteins and 24 of them were found decreased in patients with lymph node metastasis in comparison with patients without lymph node metastasis. The data analysis showed that at least one protein has, by itself, a higher relative risk in the development of lymph node metastasis in patients with OSCC. Two other panel of proteins presented the same relative risk described before. Conclusions. This study indicates a panel of potential OSCC marker proteins, which can contribute to the prognostic evaluation, the patient's risk profile and the possibility of recurrence, and guide therapeutic intervention strategies. Note: This abstract was not presented at the meeting. Citation Format: Tatiane De Rossi, Daniela Campos Granato, Ana Carolina Ribeiro, César Rivera, Henry Heberle, Guilherme Pimentel Telles, Carolina Moretto Carnielli, Thais Bianca Brandão, Alan Roger Santos-Silva, Márcio Ajudarte Lopes, Adriana Franco Paes Leme. The use of saliva proteins as biomarkers to predict the risk of lymph node metastasis in oral 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 4542.
Abstract 16873: Obesity is Associated With Improved Survival in Pulmonary Hypertension
Authors: Jeff Min, Mazin T Abdelghany, Rachel C Frank, Eugene Pomerantsev, Vijeta Bhambhani, Jennifer E Ho
Journal: Circulation (2017)

Introduction: Obesity leads to pulmonary hypertension (PH) in animal models. PH in turn is associated with worse survival, yet obesity is protective in patients with heart failure, termed the obesi...
Abstract 4844: A novel anti-TIGIT antibody (YH29143) enhances T cell activity and suppresses Treg cell activity and synergizes with anti-PD-L1 antibody
Authors: Kwang-Hoon Lee
Journal: Cancer Research (2019)

Abstract TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a T cell coinhibitory receptor, highly expressed on regulatory and memory CD4+, CD8+ T cells and natural killer (NK) cells. TIGIT binding of PVR (poliovirus receptor) on the surface of antigen presenting cells leads to downregulation of CD8+ T cell and NK cell responses in tumors. In this study, we sought to determine the efficacy of TIGIT blockade in antitumor immunity and demonstrate the synergistic effect of treatment with other checkpoint blockade such as anti-PD-L1. We generated anti-TIGIT monoclonal antibody that binds TIGIT with high affinity and blocks ligand binding. Anti-TIGIT antibody YH29143 was shown to increase T cell activities and suppress Treg cell activities from in vitro cell-based assays. We determined the crystal structure of YH29143 Fab fragment in complex with TIGIT and identified its epitope that overlaps with the PVR-binding interface. We also studied in vivo efficacy of YH29143 whether to inhibit the growth of tumor in two syngeneic colon tumor-bearing mouse models (CT26 and MC38). YH29143 reduced growth of both tumors compared to that of control IgG. In addition to these results, YH29143 showed synergistic efficacy for inhibition of tumor growth in combination with anti-PD-L1 antibody. From these tumor tissues, the ratio of CD8+ T cells to Treg cells was increased by treatment of anti-TIGIT antibody. Taken together, we evaluated the efficacy of YH29143, a potent anti-TIGIT monoclonal antibody, which enhanced T cell activation and suppressd Treg cell function in vitro, and efficiently inhibited tumor growth in vivo having synergistic effect with anti-PD-L1 antibody. These data also provide the rationale for YH29143 as a potential combination candidate for cancer immunotherapy with other immune checkpoint blockades. Citation Format: Kwang-Hoon Lee. A novel anti-TIGIT antibody (YH29143) enhances T cell activity and suppresses Treg cell activity and synergizes with anti-PD-L1 antibody [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 4844.
Abstract CT218: SYNERGY-AI: Artificial intelligence based precision oncology clinical trial matching and registry
Authors: Selin Kurnaz, Arturo Loaiza-Bonilla
Journal: Cancer Research (2019)

Abstract Background: Precision oncology encompasses the implementation of high level of evidence disease-specific and biomarker-driven diagnostic and treatment recommendations for optimized cancer care. Artificial Intelligence (AI), telemedicine and value-based care may optimize clinical trial enrollment (CTE) and overall cost-benefit. This ongoing, international registry for cancer pts evaluates the feasibility and clinical utility of an AI-based precision oncology clinical trial matching tool, powered by a virtual tumor boards (VTB) program, and its clinical impact on pts with advanced cancer to facilitate CTE, as well as the financial impact, and potential outcomes of the intervention. Methods: The SYNERGY-AI Registry is an international prospective, observational cohort study of eligible adult and pediatric pts with advanced solid and hematological malignancies, for whom the decision to consider CTE has already been made by their primary providers (PP). Using a proprietary application programming interface (API) linked to existing electronic health records (EHR) platforms, individual clinical data is extracted, analyzed and matched to a parametric database of existing institutional and non-institutional CTs. Machine learning algorithms allow for dynamic matching based on CT allocation and availability for optimized matching. Patients voluntarily enroll into registry, which is non-interventional with no protocol-mandated tests/procedures—all treatment decisions are made at the discretion of PP in consultation with their pts, based on the AI CT matching report, and VTB support. CTE will be assessed on variables including biomarkers, barriers to enrollment. Study duration anticipated as ~36 mo (~24-mo enrollment followed by 12 mo of data collection, to occur every 3 mo). The primary analysis will be performed 12 mo after last pt enrolled. The impact time to initiation of CTE on PFS and OS will be estimated by Kaplan-Meier and Cox multivariable survival analysis. Enrollment is ongoing, with a target of ≥ 1500 patients. Key inclusion criteria: Pts with solid and hematological malignancies; cancer-related biomarkers. Key exclusion criteria: ECOG PS &amp;gt; 2; abnormal organ function; hospice enrollment. ClinicalTrials.gov Identifier: NCT03452774 https://clinicaltrials.gov/ct2/show/NCT03452774 Citation Format: Selin Kurnaz, Arturo Loaiza-Bonilla. SYNERGY-AI: Artificial intelligence based precision oncology clinical trial matching and registry [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 CT218.
Abstract 4108: Preclinical evaluation of half-life extended Affimer® biotherapeutics targeting the PD-L1 pathway
Authors: Amrik Basran, Emma Jenkins, Estelle Adam, Floriane Laurent, Michele Writer, Assa Oumie, Jyrki Sivula, Maureen West, Emma Stanley, Jennifer Hillman, Viviana Robles-munoz
Journal: Cancer Research (2019)

Abstract Programmed Cell Death-Ligand 1 (PD-L1) binds to its receptor, Programmed Cell Death protein (PD-1) and is expressed on a range of activated immune cells and is upregulated by tumor cells and by immune cells in the tumor microenvironment. PD-L1 immunotherapies have emerged as effective treatments both as monotherapies and in combinations, providing long term responses in a subset of patients. Phage display selections have identified a range of potent Affimer biotherapeutic antagonists to both human and mouse programmed death-ligand 1 (PD-L1). We have demonstrated when formatted as bivalent molecules they have improved sub nM affinity, half-life extension in a mouse PK study, blocking activity in vitro and in vivoefficacy in syngeneic or xenograph mouse models. Affimer biotherapeutics are a 14kDa monomeric scaffold protein based on the human protease inhibitor Stefin A, lacking post-translational modifications such as disulfide bonds and glycosylation. Large diverse phage display libraries have been created by engineering in two nine amino acid peptide loops into the scaffold backbone. We have identified a range of affinity competitive binders to mouse or human PD-L1 confirmed by performing competition ELISA and SPR using Fc formatted antigen. Half-life extension of lead Affimer proteins was achieved by fusing to human IgG1Fc or as an in-line fusion (ILF) fused to serum albumin binding Affimers. We demonstrated avidity for binding to target antigen, binding to cells in vitro and blockade of the PD-1L/PD-1 interaction using Promega cell based assay. The PK properties of the formatted Affimers in mouse showed half-life extension from 40-120 hours depending on the clone and half-life extension technology used. We have demonstrated that the Affimer scaffold has the necessary properties to be developed as an immunotherapy. The anti-PD-L1 Affimer scaffold proteins were formatted as Fc fusion and in-line fusion formats which showed in vivo efficacy. These molecules will be developed further for both bispecific and drug conjugates to generate new novel biotheraputics that will give greater efficacy in the clinic. Citation Format: Amrik Basran, Emma Jenkins, Estelle Adam, Floriane Laurent, Michele Writer, Assa Oumie, Jyrki Sivula, Maureen West, Emma Stanley, Jennifer Hillman, Viviana Robles-munoz. Preclinical evaluation of half-life extended Affimer® biotherapeutics targeting the PD-L1 pathway [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 4108.
Abstract 4632: A new mouse model for rapid identification of key factors driving prostate cancer progression and invasiveness
Authors: Maria Riedel, Latifa Bakiri, Martin F. Berthelsen, Michael Borre, Mikkel H. Vendelbo, Erwin F. Wagner, Martin K. Thomsen
Journal: Cancer Research (2019)

Abstract Prostate Cancer is amongst the most frequently diagnosed malignancies and the second leading cause of cancer-related death in men worldwide accompanied by an increasing incidence. Until now its heterogeneity has been a major challenge in the establishment of good in vivo models for fast validation of potential driver genes. Classic in vivo models are costly, time-consuming and often target the majority of the prostate epithelium. We successfully introduced a novel prostate cancer mouse model based on CRISPR/Cas9 technology, ensuring multiplexed gene editing. In this model, specific in vivo gene editing was obtained in murine prostate epithelium cells of a transgenic mouse strain, harboring the CRISPR associated protein 9 (Cas9) endonuclease. Prostate epithelium cells were transduced by an Adeno-associated virus (AAV), carrying multiple single guide RNAs (sgRNA). Genetically different viral constructs were designed, each expressing different sgRNA combinations against Pten, representing the main driver in prostate cancer, tumor suppressor Trp53 and either one of the AP1 transcription factor subunits Junb or Fos, or tumor suppressor Smad4. Since viral transduction occurs in only a few cells, edited cell clones can clonally expand and undergo a natural selection process. Furthermore, the simultaneous gene knockouts reflect the human scenario of tumor heterogeneity. Mouse prostates were isolated and analyzed three to nine months post-injection to obtain insight on whether or not a gene appears crucial for tumor development in a specific tissue and wherein different gene combinations correlate with tumor severity. Histological analysis revealed increased proliferation, increased AKT activation, as well as invasiveness in samples with multiple gene knockouts compared to controls with single Pten knockout. Furthermore, loss of SMAD4 accelerated cancer progression when compared to the loss of the AP-1 transcription factor. Surprisingly, knockout of Trp53 was rarely observed in prostate samples while it occurred frequently in other tumor types in the same model system. This indicates that knockout of Trp53 may not be required for prostate cancer initiation. Overall, we established an in vivo model system of simultaneous, multiplexed gene editing in the prostate epithelium to address the biological cross-talk between various, altered pathways in prostate cancer initiation and progression. Citation Format: Maria Riedel, Latifa Bakiri, Martin F. Berthelsen, Michael Borre, Mikkel H. Vendelbo, Erwin F. Wagner, Martin K. Thomsen. A new mouse model for rapid identification of key factors driving prostate cancer progression and invasiveness [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 4632.
Abstract 2845: The role of PSAT1 in triple negative breast cancer metastasis
Authors: Stephanie Metcalf, Traci Kruer, Susan Dougherty, Rumeysa Biyik-Sit, Carolyn Klinge, Brian Clem
Journal: Cancer Research (2019)

Abstract Breast cancer is the number one diagnosed cancer type among women in the United States (NCI). This disease can be stratified into different molecular subtypes, including triple negative breast cancer (TNBC), each of which can have different therapeutic options, patient prognosis, and survival outcomes. TNBC disease readily metastasizes and different processes have been implicated in the development of metastatic disease. The serine synthesis pathway (SSP) is responsible for de novo production of serine and consists of three enzymes, including phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). PSAT1 catalyzes the second step in this pathway, is elevated in more aggressive tumor types such as basal breast cancer (Pollari, 2011) and has clinically been associated with poorer distant metastatic free survival and overall survival (unpublished from KMPlotter) in breast cancer patients. These prior studies combined with our own preliminary data underscores the hypothesis that PSAT1 promotes the metastatic potential of triple negative breast cancer. This hypothesis was first evaluated through immunohistochemistry examination of patient samples which demonstrated that expression of PSAT1 increases with TNBC tumor grade. In vitro assays of proliferation showed no difference upon loss of PSAT1, however, metastasis (migration and invasion) was significantly inhibited upon PSAT1 suppression. In a tail-vein experimental metastasis model, suppression of PSAT1 significantly inhibited the formation of tumor nodules. Mechanistically, the relevance for de novo serine synthesis pathway was examined in vitro via suppression of PHGDH. Decreased PHGDH did not affect proliferation or the metastatic capability of either cell line. Further, addition of exogenous serine could not rescue metastatic deficiencies upon loss of PSAT1. Our results suggest that PSAT1 does contribute to metastasis in TNBC and that this affect appears to be independent of its metabolic role in serine synthesis. While studies are ongoing, this points to the potential of a non-canonical function of PSAT1 being a therapeutic target for patients with TNBC that are currently lacking treatments options. Citation Format: Stephanie Metcalf, Traci Kruer, Susan Dougherty, Rumeysa Biyik-Sit, Carolyn Klinge, Brian Clem. The role of PSAT1 in triple negative breast cancer metastasis [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 2845.
Abstract 12697: In vivo Expansion of Regulatory T Cells Attenuates Aortic Aneurysm Formation in Angiotensin II- Infused Apolipoprotein E-deficient Mice
Authors: Keiko Yodoi, Naoto Sasaki, Taiji Mizoguchi, Takuya Matsumoto, Takuo Emoto, Yoshihiro Sasaki, Kazuyuki Kasahara, Tomoyuki Kita, Tomoya Yamashita, Ken-ichi Hirata
Journal: Circulation (2013)

Background: Recent studies have shown that pathogenic immune responses might be involved in the acceleration of abdominal aortic aneurysm (AAA) formation as well as atherosclerotic plaque developme...