tbuckley/cabot-search huggingface dataset:
Abstract 5831: Clearance of therapy-induced senescent cancer cells by the senolytic ABT-263 in a model of non-small cell lung cancer
Authors: Valerie Carpenter, Tareq Saleh, David Gewirtz
Journal: Cancer Research (2020)

Abstract While most chemotherapies will initially lead to tumor reduction in patients, residual tumor cells that enter a state of dormancy can re-emerge as aggressive, recurrent disease after treatment is terminated. One mechanism by which cancer cells may escape chemotherapy-induced death is senescence. Senescence is a specialized form of cell cycle arrest that is primarily characterized as a durable, prolonged loss of proliferative capacity. While senescence was traditionally considered to be irreversible, evidence has accumulated in recent years supporting the premise that senescence is instead a durable form of growth arrest from which a subpopulation of cells can ultimately escape. Moreover, the accumulation of senescent cells post cancer therapy has been linked with a plethora of unfavorable outcomes. A sequential approach in which chemotherapy is followed by a senolytic, an emerging class of drugs that selectively kill senescent cells, may therefore delay or circumvent recurrent disease by eliminating residual senescent cells. To this end, we tested whether etoposide- or radiation-treated non-small cell lung cancer (NSCL) cells become susceptible to the BH-3 mimetic ABT-263– an established senolytic– following senescence induction. Treatment with etoposide or radiation induced a robust senescent state, as evidenced by the development of multiple senescent phenotypes. Senescent tumor cells demonstrated increased sensitivity to ABT-263 compared to non-senescent cells, undergoing rapid apoptosis subsequent to ABT-263 exposure. We further determined that ABT-263's mechanism of action appears to depend upon the disruption of the BCL-XL/Bax interaction. ABT-263's capacity to eliminate senescent cells is conserved in vivo, as tumor-bearing animals treated with etoposide followed by ABT-263 undergo rapid tumor reduction followed by tumor maintenance, while etoposide-only treated animals develop progressive disease subsequent to treatment completion. These data support the use of senolytics as complementary therapy to eliminate residual tumor cells following chemotherapy or radiation, and thereby potentially delay or reduce recurrent disease. Citation Format: Valerie Carpenter, Tareq Saleh, David Gewirtz. Clearance of therapy-induced senescent cancer cells by the senolytic ABT-263 in a model of non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5831.
Abstract 3213: DIAS, the COSMIC data integration and annotation system
Authors: Charalampos Boutselakis, Chai Kok, Bhavana Harsha, Nidhi Bindal, Shicai Wang, Siew-Yit Yong, Charlotte Cole, Zbyslaw Sondka, Simon Forbes
Journal: Cancer Research (2020)

Abstract COSMIC, the catalog of somatic mutations in cancer (https://cancer.sanger.ac.uk/) is the leading and most comprehensive global genetic resource for the exploration of somatic variation across all forms of human cancer. Since the initial inception of COSMIC 15 years ago, cancer genetics have seen substantial changes. Maintaining interoperability between COSMIC and various bioinformatics resources across the globe is a non-trivial task. Resources update at different intervals and as information is interdependent is difficult to keep synchronized. Standardization and adherence to FAIR principles have fueled the development of COSMIC DIAS (Data Integration and Annotation System).For all variants where the genomic location is known, DIAS using the ensembl VEP (Variant Effect Predictor) has ensured the re-annotation of all COSMIC variants, for all available genes and transcripts to a specific ensembl version, independently and for both the GRCh37 and GRCh38 assemblies. From release v90 we have created new stable cosmic genomic identifiers (COSV) for all simple nucleotide variants which point to the corresponding locations on the reference genome. A flip mechanism has been developed that maps the same COSV identifier to both GRCh37 and GRCh38 assemblies, easily searchable from the COSMIC website. The legacy COSM and COSN identifiers have been mapped to the COSV genomic identifiers for backwards compatibility. Additionally, where redundant variants have been identified, these were merged and website redirection has been implemented. Standardized variant annotations have been utilized that adhere to the most recent HGVS recommendations on genomic, transcriptomic and proteomic syntaxes.The cross-references between COSMIC genes and other widely-used databases, such as HGNC, RefSeq, UniProt and CCDS, have been updated and kept up-to-date.Curated cross references between COSMIC phenotypes, NCI terminologies and EFO codes are also available.All the information stored in COSMIC is easily accessible by the website where users are able to explore cancer genomics in high resolution, with the various views available in downloadable formats with a simple click (https://cancer.sanger.ac.uk/cosmic/download).The DIAS system, minimized redundancy of variants, and enhanced the interoperability of COSMIC with other variation resources enabling more precise analysis and easier integration with in-house systems for our users. Citation Format: Charalampos Boutselakis, Chai Kok, Bhavana Harsha, Nidhi Bindal, Shicai Wang, Siew-Yit Yong, Charlotte Cole, Zbyslaw Sondka, Simon Forbes. DIAS, the COSMIC data integration and annotation system [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3213.
Abstract LB-329: Pancancer proteomic investigation identifies overexpressed kinases as novel cancer dependent targets
Authors: Abdulkadir Elmas, Pedro Molina-Sanchez, Serena Tharakan, Suraj Jaladanki, Tao Liu, Amaia Lujambio, Kuan-lin Huang
Journal: Cancer Research (2020)

Abstract Dysregulated oncogenic signaling is a key hallmark of cancer. Protein kinase alterations, including genomic mutations and copy-number amplifications, are known druggable targets in multiple cancer types. Thus, kinase inhibitor drugs act on protein and direct observation of protein/phospho-level overexpression may reveal new treatment opportunities. Herein, we developed and applied a new algorithm, OPPTI, to provide a catalog of overexpressed kinases across 10 cancer types using curated global mass spectrometry proteomic data of 1,071 cases. Aside from overexpressed proteins through genomic mutations, amplifications, or fusions, including ERBB2, AKT2, and EGFR, kinase overexpression also occurred in cancers without genomic-level alterations, such as CDK6 in hepatocellular carcinoma (HCC), FGFR1/2 in ovarian cancer, and PDGFRA in both gastric cancer and lung adenocarcinoma. Integrating cancer-cell dependency data, we further identified 38 new cancer vulnerability targets overexpressed in &amp;gt;10% of the patient cohorts, including TK1 in breast and gastric cancers, NRBP2 in liver and lung cancers, and CKB in ovarian, endometrial, and colorectal cancers. A fraction of overexpressed kinases was validated by immunostainings and correlated with phosphosignaling pathway activities. Finally, we demonstrated that a subset of HCC mouse models that overexpressed PDGFRB -as detected in parallel in human HCC cohorts- could be specifically treated by a receptor tyrosine kinase inhibitor. Overall, our results suggest that proteomic-level alterations not readily observed by genomics represent cancer vulnerabilities that need to be carefully considered as potential targets for personalized treatments. Citation Format: Abdulkadir Elmas, Pedro Molina-Sanchez, Serena Tharakan, Suraj Jaladanki, Tao Liu, Amaia Lujambio, Kuan-lin Huang. Pancancer proteomic investigation identifies overexpressed kinases as novel cancer dependent targets [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-329.
Abstract CT144: PD-1-CD28-enhanced receptor and anti-CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors
Authors: Xinfeng Chen, Xuan Zhao, Liping Wang, Weiyue Gu, Yi Zhang
Journal: Cancer Research (2020)

Abstract Purpose: Limited expansion ability and cytotoxic function are major problems of using tumor-infiltrating lymphocytes (TILs) in vivo. We sought to determine whether adoptive transfer of autologous modified TILs mediates regression of advanced tumors. Experimental Design: First, anti-tumor effects of switching PD-1 to CD28 signaling and anti-CD19 CAR-modified NY-ESO-1-TCR T cells (hereafter “PD-1-CD28 TCR-T” and “Anti-CD19 CAR-TCR-T” cells, respectively) were tested in vitro and in vivo. Furthermore, the safety and anti-tumor ability of S-TILs (TILs modified by transducing with anti-CD19 CAR and PD-1-CD28 vectors) were evaluated in vivo. PD-1-CD28 TCR-T cells produced formidable anti-tumor ability overcoming PD-1/PD-L1 signaling in vivo. Results: Anti-CD19 CAR-TCR-T cells stimulated with CD19+ B cells exhibited powerful expansion and anti-tumor ability in vitro and in vivo. Three patients with refractory solid tumors received S-TIL infusion. There was no treatment-related mortality, and none of the patients experienced severe side effects. One patient with melanoma achieved a partial response and two patients with colon or kidney cancer achieved long-term stable disease following S-TIL therapy. Conclusions: To our knowledge, this is the first report describing the safety and efficacy of adoptive transfer of autologous S-TILs to control disease in patients with advanced cancers, suggesting that S-TILs may be a promising alternative therapy for cancer treatment. Citation Format: Xinfeng Chen, Xuan Zhao, Liping Wang, Weiyue Gu, Yi Zhang. PD-1-CD28-enhanced receptor and anti-CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT144.
Abstract 6375: Development of novel Pt-based drugs using Deferasirox as ligand to diminish systemic toxicity and resistance induced by CisPt
Authors: Yamixa Delgado, Mallesh Pandrala, Daraishka Perez, Eddian Velazquez, Jaisy Vega, Melissa Milian, Anamaris Torres
Journal: Cancer Research (2020)

Abstract Today, CisPt is one of the most successful chemotherapeutic metallodrugs. Unfortunately, the use of CisPt is restricted by the dose-limiting toxic effects and the acquired resistance, especially in lung cancer. As an alternatively, FDA-approved drugs for different diseases which target cancer metabolic pathways, are considered an attractive strategy to diminish systemic toxic effects. In the same way, the mechanistic pathways activated/inactivated by this drug could potentially overcome the acquired resistance induced by CisPt. For this reason in our approach, we incorporated deferasirox (Def), a clinical drug for iron (Fe) overload, as the ligand in the development of novel Pt complexes. In cancer progression, Fe plays a key role as a nutrient for cell growth and energy production. In consequence, we have synthesized and characterized our first library of three Pt-Def complexes: Pt(Def-COOH), Pt(Def-CONH2), Pt(Def-COOCH3). In this strategy, we have modified the OH of the carboxylic group of the Def to see the effects in the metabolic pathways. Viability assay results showed that Pt(Def-CONH2) induced a dramatic decrease in the IC50 in non-small lung adenocarcinoma cells after 24 h of incubation compared to CisPt, Def and Def-CONH2. Gene expression studies were conducted for cell growth, resistance and metastases related genes, where Pt(Def-CONH2) showed a significant downregulation of all of them. In addition, insight into target sites and metabolic pathways (apoptosis, caspase 3, ROS, cell cycle) inhibited or activated was garnered. This study will afford the optimization of the rationale to fine tune the structure of novel potential drugs. Citation Format: Yamixa Delgado, Mallesh Pandrala, Daraishka Perez, Eddian Velazquez, Jaisy Vega, Melissa Milian, Anamaris Torres. Development of novel Pt-based drugs using Deferasirox as ligand to diminish systemic toxicity and resistance induced by CisPt [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6375.
Abstract LB-251: Investigation of few-shot deep learning techniques on a small, high dimensional head and neck carcinoma dataset for prediction of cancer recurrence
Authors: Frank G. Ondrey, Dalton Schutte
Journal: Cancer Research (2020)

Abstract Introduction: Artificial Intelligence (AI) techniques may be useful in predictive oncology. We examined the feasibility of applying open source Few-shot learning to genomics data for the purpose of predicting head and neck cancer recurrences. We compared basic feed forward neural networks (vanilla networks) to a special architecture designed for few-shot learning called a Siamese network. Methods: Affymetrix U133A gene chip data (D=22,215, 41 tumor/13 normal) of patients with non-recurrent (46.34%) and recurrent (53.66%) head and neck carcinomas (nRHNC and RHNC, respectively) was analyzed. Shallow (one-layer) and deep (three-layer) variants were examined for both vanilla and Siamese networks to predict RHNC using the PyTorch framework. Four models were built using PyTorch: one shallow vanilla (SV) network with a single layer of 100 neurons, based on the top performing model from the authors' previous work, one deep vanilla (DV) network with layers of 256, 64, and 8 neurons, one shallow Siamese (SS) network with a single layer of 100 neurons, and one deep Siamese (DS) network with layers of 256, 64, and 8 neurons. Each model was initialized, trained, and evaluated 11 times. Kaiming initialization and Stochastic Gradient Descent with Nesterov Momentum (0.5) was employed with typical assumptions. Results: The model with the highest mean F1 score, AUC, and sensitivity was the SV network (0.7001, 0.6667, and 0.6800 respectively) the model with the highest sensitivity was DV (0.7217). When comparing the mean metrics for the following pairs: SV/DV, SS/DS, SV/SS, and DV/DS, the only difference of means that were found to be statistically significant was the SV/SS pairing for F1, AUC, and specificity. Conclusion: The simplest model, with the least representational capacity, performed best but not in a statistically significant manner in nearly all cases. Interestingly, the DS model performed better than the SS model AUC and specificity while the SV model performed better than its deep counterpart in those metrics. In this initial analysis, we conclude that it is feasible to apply PyTorch AI to Affymetrix gene chips to obtain meaningful data about head and neck cancer recurrences. Citation Format: Frank G. Ondrey, Dalton Schutte. Investigation of few-shot deep learning techniques on a small, high dimensional head and neck carcinoma dataset for prediction of cancer recurrence [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-251.
Abstract 5545: Neutralization of interleukin-10 by genetically engineered macrophages increase cancer cell death in metastatic colorectal cancer
Authors: Kevin P. Labadie, Shannon A. Kreuser, Katherine J. Brempelis, Xiuyun Jiang, Sara K. Daniel, Courtney A. Crane, Venu G. Pillarisetty
Journal: Cancer Research (2020)

Abstract Background Interleukin-10 (IL-10) is an immunosuppressive cytokine that inhibits innate and adaptive antitumor immune responses in the tumor microenvironment (TME). Antibody neutralization of IL-10 in organotypic tumor slice cultures (TSC) in colorectal cancer liver metastases (CRCLM) leads to cancer cell death through. To target IL-10 blockade to the TME, we genetically engineered macrophages (GEM) to produce an IL-10 neutralizing antibody which we hypothesized would reactivate tumor infiltrating immune cells and increase cancer cell death in TSC. Methods We created a lentiviral construct to transduce GEMs with a publicly available neutralizing IL-10 antibody sequence (BT-063). CD14+ monocytes were isolated from healthy donor peripheral blood mononuclear cells and differentiated into macrophages, which were transduced with lentivirus to create control (cGEMs) and anti-IL-10 GEMs (αIL10 GEMs). To test the efficacy of αIL10 GEMs, punch biopsies (6 mm) were obtained from resected CRCLM, sliced to 250 um thickness with a vibratome and placed in individual culture wells. Slices were treated in triplicates with either 20ug/mL of human monoclonal αIL10 (αIL10), 1e5 cGEMs or αIL10 GEMs + 20ug/mL αIL10. GEMs and tumor cells were visualized with a Leica SP8X confocal microscope and apoptosis was measured with SR-FLICA fluorescent poly-caspase assay kit. Supernatant interferon-gamma (IFN-γ) levels were measured with Bioplex immunoassay and IL-10 neutralizing antibody was quantified with an enzyme-linked immunosorbent assay. Results Allogenic GEMs were transduced with BT-063-T2A-CD19t at 31% efficiency. cGEMs and αIL10 GEMs persisted in tumor slice culture for at least 6 days. αIL10 GEM-treated slice cultures contained 6.6ng/mL and 6.5ng/mL of αIL10 antibody after 3 and 6 days, respectively. At day 6 in culture, cancer cell apoptosis was increased in the αIL10 treated groups with 7%, 15%, 25%, 31% and 39% of cells were apoptotic in the no treatment control, cGEM, αIL10, cGEM + αIL10 and αIL10 GEM groups, respectively (One-way ANOVA, p = 0.0004). Elevation in IFN-γ was observed on day 6 in slices treated cGEMs (7.2ng/mL+4.3) and αIL10 GEMs (9.2ng/mL+5) compared to isotype control. Conclusion GEMs transduced with lentivirus encoding IL-10 neutralizing antibody maintain its production and are associated with increased cancer cell apoptosis. Citation Format: Kevin P. Labadie, Shannon A. Kreuser, Katherine J. Brempelis, Xiuyun Jiang, Sara K. Daniel, Courtney A. Crane, Venu G. Pillarisetty. Neutralization of interleukin-10 by genetically engineered macrophages increase cancer cell death in metastatic colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5545.
Abstract 4962: Tumor heterogeneity driven by cancer stem cell expressing POU5F1
Authors: Norikatsu Miyoshi, Shiki Fujino, Masaru Sasaki, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Chu Matsuda, Tsunekazu Mizushima, Hidetoshi Eguchi, Yuichiro Doki
Journal: Cancer Research (2020)

Abstract Background: The gene POU5F1, encoding the POU domain, class 5, is a transcription factor. and the expression is found in embryonic stem cells. In these pluripotent stem cells, POU5F1 gene controls self-renewal and differentiation, regulating the pluripotency and proliferation. Regarding the tumor heterogeneity and microenvironment, primary culture of cancer cells derived from the patient's tumor can provide important information of the “individual tumor,” representing the tumor heterogeneity. We focused on the gene expression and the relationship between colorectal cancer stem cells and the tumor heterogeneity, in the primary culture model. Methods: Using POU5F1 promoter-containing sequence, POU5F1-EGFP-positive cells were established by the construct with lentiviral vector, and we examined their sub-populations. The capacity to form distant metastasis in vivo was examined using the primary culture models. Results: We obtained clinical samples from surgically resected gastrointestinal cancers. They were mechanically and enzymatically digested and collected using customized filters. Obtained cells were cultured on a matrix-coated plate with chemically defined stem-cell culture medium. All these primary cultured cells grew and about 90% of them were successfully passaged. The morphology and gene expressions were similar to each parental clinical tumor. Using these primary tumors, POU5F1 expressing cells were examined. The POU5F1-EGFP-positive cells highly expressed stem cell-associated markers and they had self-renewal and differentiation abilities. POU5F1-high cells actively formed liver metastasis. Conclusion: POU5F1-positive cells have the self-renewal and differentiation abilities as cancer stem cells. The positive cells produce tumor heterogeneity. POU5F1 contributes to the ability forming liver metastasis in CRC. Keywords: colorectal cancer, tumor heterogeneity, metastasis, POU5F1. Citation Format: Norikatsu Miyoshi, Shiki Fujino, Masaru Sasaki, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Chu Matsuda, Tsunekazu Mizushima, Hidetoshi Eguchi, Yuichiro Doki. Tumor heterogeneity driven by cancer stem cell expressing POU5F1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4962.
Abstract 4871: The roles of E3/E4 ubiquitin ligase UBE4B and its targets p53 and Ku70 in neuroblastoma cell death and differentiation
Authors: Christophe Le Clorennec, Jacqueline Lesperance, Yuchen Huo, Peter E. Zage
Journal: Cancer Research (2020)

Abstract Children with high-risk neuroblastoma have poor survival rates and need novel treatment strategies. UBE4B is an E3/E4 ubiquitin ligase whose gene is found in the chromosome 1p36 region commonly deleted in high-risk neuroblastoma tumors and whose expression is associated with neuroblastoma patient outcomes. However, the functional roles of UBE4B in neuroblastoma pathogenesis are not known. We hypothesized that UBE4B would interact with mediators of DNA damage and repair pathways, leading to the observed associations between UBE4B and patient outcomes. Using cell lines with stable UBE4B depletion and over-expression, we evaluated the interaction of UBE4B with the E3 ubiquitin ligase ITCH/AIP4 and the effects of UBE4B expression levels on p53 and Ku70 ubiquitination and proteasomal degradation by co-immunoprecipitation and Western blots. We also evaluated the role of UBE4B in neuroblastoma differentiation, cell death, and responses to chemotherapy and HDAC inhibition using continuous live cell imaging and Western blots. We determined that UBE4B directly interacts with ITCH/AIP4 in the last WW domain of ITCH and we also determined that Ku70 directly interacts with ITCH in the three first WW domain of ITCH. We also determined that UBE4B depletion leads to reduced polyubiquitination and degradation of both p53 and Ku70 in neuroblastoma cells. UBE4B depletion also led to reduced apoptosis induced by both HDAC inhibition with vorinostat and chemotherapy treatment with carboplatin and doxorubicin via stabilizaton of the ITCH target protein c-FLIPL leading inhibition of caspase 8 activation. Our results have identified novel interactions and novel targets for UBE4B ubiquitin ligase activity and a direct role of the UBE4B-ITCH complex in HDAC inhibitor and DNA-damage induced cell death, and suggest that the association of UBE4B expression with neuroblastoma patient outcomes may be mediated by effects on responses of patient tumors to chemotherapy. Citation Format: Christophe Le Clorennec, Jacqueline Lesperance, Yuchen Huo, Peter E. Zage. The roles of E3/E4 ubiquitin ligase UBE4B and its targets p53 and Ku70 in neuroblastoma cell death and differentiation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4871.