tbuckley/cabot-search huggingface dataset:
Abstract 3608: Identification of differentially expressed genes in 4T1 mice triple-negative mammary gland cancer during the early phase of combination treatment with indomethacin and radiation
Authors: Robert Yuk Sing Cheng, Lisa Ridnour, Timothy Back, Debashree Basudhar, Stephen Anderson, Daniel McVicar, David Wink
Journal: Cancer Research (2020)

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers. In order to develop the most effective treatment against TNBC, we tested the effects of the combination treatment with indomethacin and radiation on TNBC utilizing a mouse experimental TNBC equivalent model. Seven weeks old BALB/c mice were implanted with 4T1 mice triple-negative mammary gland tumor cells on the right hind leg one week before the treatments started. Mice were divided into four groups treated with vehicle control, 6 Gy radiation, 30 mg/L (in water) indomethacin, or combination regime of 6 Gy radiation and 30 mg/L indomethacin. 6 Gy radiation was given to mice on Day 0 only while indomethacin was given to mice every day. Mice received the combination treatment with radiation and indomethacin showed a significant tumor growth delay at the end of the treatment regime (Day 30). We next elucidated if there are changes in biological pathways during the early phase of combination therapy (Day 3). Total RNAs isolated from the primary tumors were subjected to whole genome transcriptomic analyses (RNAseq). We identified a total of 58 genes with 2-fold changes in expression and p-value &amp;lt;0.05 differentially expressed among the treatment groups. Strikingly, the trend in expression levels of differentially expressed genes identified from the combination treatment group was opposite to that from the other two treatment groups. Results indicate that the effect of combination treatment with indomethacin and radiation is neither additive or synergistic. In addition, pathway core analyses revealed “Cancer” as the top associated disease, and “GABA Receptor Signaling and cAMP-Mediated Signaling” as the top canonical pathways among the treatment groups. In conclusion, our findings provided a detailed snapshot of the early events occur in mice subject to either single or combination treatment with indomethacin and radiation. Data will improve our understanding of the treatment responses of TNBC. We believe further time-course and transcriptomic studies may be beneficial for the new therapeutic strategies for TNBC. Citation Format: Robert Yuk Sing Cheng, Lisa Ridnour, Timothy Back, Debashree Basudhar, Stephen Anderson, Daniel McVicar, David Wink. Identification of differentially expressed genes in 4T1 mice triple-negative mammary gland cancer during the early phase of combination treatment with indomethacin and radiation [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 3608.
Abstract LB-184: A lncRNA-histone acetyltransferase complex induces colorectal oncogenesis through regulation of a metabolic kinase network
Authors: Christos Polytarchou, Maria Hatziapostolou, Marina Koutsioumpa, Niki Christodoulou, Tung On Yau, Eleni Birli, Odette Pomenya, Cristina Montiel-Duarte, Swapna Mahurkar Joshi, Daniel W. Hommes, Hein W. Verspaget, Jun Yu, Dimitrios Iliopoulos
Journal: Cancer Research (2020)

Abstract Long non-coding RNAs (LncRNAs) through interactions with other cellular macromolecules drive cell processes contributing to important cancer phenotypes. Here we show that HOTAIR, a highly up-regulated lncRNA in human colon cancers, induces transformation of human non-transformed colon epithelial cells. An exon 6 HOTAIR region directly binds the histone acetyltransferase PCAF (KAT2B). The HOTAIR/PCAF complex regulates H3K27 acetylation and transcriptional activation preferentially of genes encoding components of the PI3K/AKT/MEK pathways and induces cell metabolic reprogramming. The transcriptional signature of this HOTAIR/PCAF metabolic circuit is active in colon cancer and correlates with overall patient survival. Topological and mechanistic analyses were employed to characterize the HOTAIR/PCAF interface and design a reversible specific inhibitor (CPDI-1). Selective blocking of the HOTAIR-PCAF interaction, suppresses AKT activation and tumor growth. In conclusion, we demonstrate that disruption of a lncRNA-histone modifier complex interferes with the cancer epigenome and represents a novel approach for cancer therapeutics. Citation Format: Christos Polytarchou, Maria Hatziapostolou, Marina Koutsioumpa, Niki Christodoulou, Tung On Yau, Eleni Birli, Odette Pomenya, Cristina Montiel-Duarte, Swapna Mahurkar Joshi, Daniel W. Hommes, Hein W. Verspaget, Jun Yu, Dimitrios Iliopoulos. A lncRNA-histone acetyltransferase complex induces colorectal oncogenesis through regulation of a metabolic kinase network [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-184.
Abstract 6436: A potential treatment for malignant glioblastoma: Silver nanoparticles and low-level laser combination
Authors: Rohini Atluri, Daniel Korir, Nishant Tyagi, Eunyoung Kim, Tae-Youl Choi, Denise P. Simmons
Journal: Cancer Research (2020)

Abstract Glioblastomamultiforme (GBM) is a dreadful primary brain tumor characterized with extremely poor prognosis and survival rate, despite available treatments. The failure of current therapies to eliminate specific subpopulations within heterogeneous GBM has been considered a key factor contributing to the inevitable recurrence after treatments. To address this concern, it is necessary to develop novel treatments, which can kill all the GBM cells or at least convert the heterogeneous GBM population to homogeneous populations, which can be easily targeted. In this study, we investigated the effects of Ag-PMMA-PAA nanoparticles (Silver np's) on human malignant glioma(U251) cells and Silver np's role in combinational use with low-level He-Ne laser (632.8nm) against U251 cells.The Silver np's were synthesized using a green chemistry approach and were then characterized using spectroscopic methods. Dose and time dependent studies revealed that the maximum killing (81%) of U251 cells occurred at 225μM Silver np's over 6 hours. Moreover, combined HeNe laser exposure resulted in overall cell death of 92%. Western analysis suggests caspase family members, other than caspase 9, are involved in killing Silver np treated U251 cells or the combination treatment. Thus, our Silver np and low-level laser combination treatment could have a potential application in enhancing chemotherapy for malignant glioma. Citation Format: Rohini Atluri, Daniel Korir, Nishant Tyagi, Eunyoung Kim, Tae-Youl Choi, Denise P. Simmons. A potential treatment for malignant glioblastoma: Silver nanoparticles and low-level laser combination [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 6436.
Abstract 4893: Multi-modality sequencing of multiple HPV mediated oropharyngeal squamous cell carcinomas from single patients reveals synchrony in viral genomes yet discordant mutational profiles and signatures
Authors: Daniel L. Faden, Adam Langenbucher, Krystle Kuhs, James S. Lewis, Michael S. Lawrence, Lisa Mirabello, Robert L. Ferris
Journal: Cancer Research (2020)

Abstract Human Papilloma Virus (HPV) mediated oropharyngeal squamous cell carcinoma (HPVmOPSCC) is increasing in prevalence in the United States, as are cases of patients with multiple, spatially distinct, HPVmOPSCCs (mHPVmOPSCC). Patients with mHPVmOPSCCs present a unique opportunity to study the biology of HPV mediated tumorigenesis in the oropharynx, which currently is poorly understood. We performed whole exome sequencing and RNA-Seq on 16 paired HPVmOPSCCs (eight patients) and whole genome sequencing of the viral genome using a HPV16 NGS assay described previously. Viral sequencing revealed considerable diversity between patients, across multiple viral sublineages. However, all tumor pairs from a given patient contained the same viral genome, with at most 2 clonal SNPs distinguishing the viruses within a pair. In contrast, tumor DNA sequencing revealed striking dissimilarity between tumors from a given patient. Seven of eight tumor pairs shared no overlapping somatic mutations with one pair sharing only six variants out of 277 (2%). Mutational signature analysis demonstrated a dominant APOBEC signature in six tumors. Tumor pairs showed striking discordance of mutational signatures. In 3/8 pairs, one tumor exhibited a nearly 100% pure APOBEC+ mutational profile, while the other was totally devoid of APOBEC-signature mutations. Here, we have demonstrated that spatially independent tumors, originating within the same individual, in the same tissue type, are caused by the same virus. Interesting, despite this shared etiology, the pair of tumors within a patient develop with vastly different mutational profiles and have different mutational processes driving tumorigenesis. This suggests that despite infection by a single oncogenic virus, HPVmOPSCCs may develop via multiple, disparate pathways. Of particular interest is the tumor pairs' clear discordance in APOBEC mutational burden, which challenges existing hypotheses on the role of APOBEC mutagenesis in this disease. Citation Format: Daniel L. Faden, Adam Langenbucher, Krystle Kuhs, James S. Lewis, Michael S. Lawrence, Lisa Mirabello, Robert L. Ferris. Multi-modality sequencing of multiple HPV mediated oropharyngeal squamous cell carcinomas from single patients reveals synchrony in viral genomes yet discordant mutational profiles and signatures [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 4893.
Abstract 4244: The efficacy and safety of anti-PD-1 therapy in metastatic sarcomas
Authors: Jilong Yang
Journal: Cancer Research (2020)

Abstract Sarcomas are a group of rare and malignant tumors originating from mesenchymal tissue with a variety of cellular subtypes. Although several major standard treatments, including neo-adjuvant and adjuvant chemotherapy, surgery and radiation, have made breakthroughs to improve overall survival, there are few additional effective treatments for metastatic sarcomas that have failed traditional therapy. With the encouraging efficacy of PD-1 monoclonal antibodies in nonresectable or metastatic malignant melanomas and lung cancers, immunosuppressive agents provide new hope for the treatment of sarcomas. We retrospectively collected information from 15 patients with stage IV sarcomas who were treated with a PD-1 inhibitor with or without angiogenesis inhibitor after the failure of traditional treatments, from June 15, 2016 to September 30, 2019. The primary observation endpoint was median progression-free survival (mPFS), and the objective response rate (ORR) and the disease control rate (DCR) were secondary endpoints. Treatment-related adverse events (AEs) were evaluated. Patients were observed until death, loss to follow-up, or the end of the PD-1 inhibitor therapy. The average follow-uptime was 8.47 months (1.97-28.12 months). At 12 weeks, the ORR was 23.1% (3/13) and the DCR was 84.6% (11/13). Finally the overall median PFS was 5.06 months, the ORR was 15.4% (2/13) and the DCR was 61.5% (8/13). Common AEs (occurring with 15 patients) included grade 4 hypertension (n=1, 2.6%), grade 3 leukopenia (n=1,2.6%), grade 2 hand and foot syndrome(HFSR) (n=2, 5.1%), grade 1 reactive capillary hyperplasia (RCCEP) (n=7,17.9%), fatigue and weakness (n=5, 12.8%), digestive dysfunction (n=3,7.7%) and fever (n=3,7.7%). The results indicate that PD-1 inhibitors based therapies are effective, safe and well tolerated in patients with advanced sarcomas. The PD-1 inhibitor combined with anti-angiogenesis agents might provide a new and effective strategy to treat metastatic sarcomas. Citation Format: Jilong Yang. The efficacy and safety of anti-PD-1 therapy in metastatic sarcomas [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 4244.
Abstract 4858: Oncogenic HIPPO-YAP1: <i>in vivo</i> target validation of YAP1 in malignant mesothelioma
Authors: Loreley Calvet, Odette Dos Santos, Véronique Jean-Baptiste, Emmanuel Spanakis, Yvette Ruffin, Isabelle Sanchez, Jessica Mestadier, Stéphane Soubigou, Sylvie Feteanu, Pascale Picard, Chagri Boumaya, Jack Pollard, Colette Dib, Sukhvinder Sidhu, Laurent Debussche, Iris Valtingojer
Journal: Cancer Research (2020)

Abstract Yes associated protein YAP1 (YAP1) is a cofactor of gene transcription and exerts its action through association with transcription factors from the TEAD family. Activity of YAP1-TEAD is tightly regulated by the HIPPO pathway and upon activation the expression of pro-survival and anti-apoptotic genes is induced. The HIPPO pathway consists of a series of Ser/Thr kinases, which lead to the phosphorylation of YAP1, and hence to its inactivation by either sequestration in the cytoplasm, or degradation. HIPPO pathway deletions and YAP1 activation are particularly prevalent (&amp;gt; 60 %) in patients with malignant pleural mesothelioma. We use a malignant mesothelioma tumor cell line with a HIPPO deleted genetic background (MSTO-211H, LATS1 loss) to demonstrate, that downregulation of YAP1 leads to the inhibition of YAP1-dependent gene expression, the induction of apoptosis and the inhibition of cell growth in vitro. When these cell lines are grown as an in vivo subcutaneous xenograft in mice, downregulation of YAP1 leads to the inhibition of YAP1-dependent gene expression and eventually results in the regression of established tumors. This effect is specific to YAP1 activated mesothelioma models and is not observed in the HIPPO pathway independent HCT116 colon cancer model. We show here, that YAP1 activity alone is required for tumor maintenance in vivo in the context of HIPPO pathway genetic alterations, and thus confirm the relevance of this target for a drug discovery approach. Citation Format: Loreley Calvet, Odette Dos Santos, Véronique Jean-Baptiste, Emmanuel Spanakis, Yvette Ruffin, Isabelle Sanchez, Jessica Mestadier, Stéphane Soubigou, Sylvie Feteanu, Pascale Picard, Chagri Boumaya, Jack Pollard, Colette Dib, Sukhvinder Sidhu, Laurent Debussche, Iris Valtingojer. Oncogenic HIPPO-YAP1: in vivo target validation of YAP1 in malignant mesothelioma [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 4858.
Abstract LB-383: An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors
Authors: Katharina Reinhard, Benjamin Rengstl, Petra Oehm, Özlem Türeci, Ugur Sahin
Journal: Cancer Research (2020)

Abstract Chimeric antigen receptor (CAR)-T cells have shown efficacy in patients with B cell malignancies. Yet, their application for solid tumors has challenges that include limited cancer-specific targets and nonpersistence of adoptively transferred CAR-T cells. Here, we introduce the developmentally regulated tight junction protein claudin 6 (CLDN6) as a CAR target in solid tumors and a strategy to overcome inefficient CAR-T cell stimulation in vivo. We demonstrate that a nanoparticulate RNA vaccine, designed for body-wide delivery of the CAR antigen into lymphoid compartments, stimulates adoptively transferred CAR-T cells. Presentation of the natively folded target on resident antigen-presenting cells promotes cognate and selective expansion of CAR-T cells. Improved engraftment of CAR-T cells and regression of large tumors in difficult-to-treat mouse models was achieved at subtherapeutic CAR-T cell doses. Citation Format: Katharina Reinhard, Benjamin Rengstl, Petra Oehm, Özlem Türeci, Ugur Sahin. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against 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 LB-383.
Abstract 2187: Kinetics and potency of T Cell-mediated cytolysis of glioblastoma
Authors: Stacie A. Chvatal, Meghan T. Logun, Heather B. Hayes, Daniel C. Millard, Lohitash Karumbaiah
Journal: Cancer Research (2020)

Abstract Glioblastoma (GBM) is an aggressive form of brain cancer that has no effective treatments and a prognosis of only 12-15 months. Immune system effector T cells are a promising therapy due to their high specificity and innate cytotoxicity. The ability to assess the efficacy and potency of T cell therapies in vitro and with high throughput is vital for the further development of this promising therapy. Cellular impedance-based assays offer a sensitive, label-free, and nondestructive method to continuously monitor cancer cell proliferation and immune cell-mediated cytotoxicity in real-time and at high throughputs, revealing not only the potency but also the kinetics of T cell therapies. Here, we investigated the targeting potency of activated human T cells on human U87MG glioma cell monolayers across multiple cell densities. U87MG cells were plated at 10k, 25k, and 50k cells per well on a PDL-coated CytoView-Z 96-well plate (n=12 wells per density), and their impedance was continuously monitored on the Maestro Z impedance platform. After 24 hours, activated patient-derived T Cells (ImmunoCult CD3/CD28 activation media) were added in a 10:1 effector:target ratio. Impedance and cytolysis were subsequently monitored for another 120 hours. As expected, higher densities proliferated faster and reached a higher impedance level at 24 hours. The addition of activated human T cells resulted in a decrease of the impedance signal consistent with T cell-mediated lysis of the glioma cells. The highest density of T cells (500k) exhibited the fastest rate of U87 cytolysis, with a Kill Time 50 of 35 hours. All densities reached 100% cytolysis by 100 hours. Overall, activated human T cells were highly effective for cytolysis of U87MG glioma cell monolayers of varying densities. The cellular impedance assay revealed high potency, with kinetics that varied across cell densities despite the same effector:target ratios. Citation Format: Stacie A. Chvatal, Meghan T. Logun, Heather B. Hayes, Daniel C. Millard, Lohitash Karumbaiah. Kinetics and potency of T Cell-mediated cytolysis of glioblastoma [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 2187.
Abstract 3826: The zinc transporters, ZnT5 and ZnT6, in breast cancer
Authors: Erina Iwabuchi, Yasuhiro Miki, Takanori Ishida, Hironobu Sasano
Journal: Cancer Research (2020)

Abstract The zinc levels in breast cancer tissue were reported to be higher than those in normal tissue. In addition, the expression levels of zinc transporters, including ZnT5 and ZnT6, in breast cancer were reported to be higher than those in normal breast tissue. ZnT5 and ZnT6 have been also reported to contribute to the formation of heterodimers and be involved in several different biological functions. Among those, autotaxin, matrix metalloproteinase 9, and carbonic anhydrase IX, which have crucial roles in tumor formation, invasion, and metastasis, were reported to require ZnT5–ZnT6 heterodimers for their activation and secretion in the chicken DT40 cells. However, the functions of ZnT5 and ZnT6 heterodimers has remained virtually unknown in breast cancer. Therefore, we first immunolocalized ZnT5 and ZnT6 in pathology specimens of breast cancer. We examined 88 breast cancer specimens in this study. We then analyzed the interaction between ZnT5 and ZnT6 using proximity ligation assay (PLA) in breast cancer tissues and further evaluated cell proliferation and migration in ZnT5 knockdown MCF-7 and T-47D cells using siRNA. Immunohistochemical analysis revealed that the number of ZnT5-positive breast cancer cells was significantly higher in HER2-positive patients and the number of ZnT6-positive breast cancer cells was significantly higher in patients with low histological grade and high ER and PgR expressions. The number of ZnT5 and ZnT6 double-positive breast cancer cells tended to be associated with low stage (p = 0.0577). In addition, ZnT5 and ZnT6 interaction was detected using PLA through high expression of both ZnT5 and ZnT6 in breast cancer tissues. ZnT5 knockdown exerted no effect on cell proliferation in the presence of 100 µM ZnCl2 in MCF-7 and T-47D cells. The 100 µM ZnCl2 treatment inhibited cell migration in MCF-7 and T-47D cells but ZnT5 knockdown promoted cell migration. To the best of our knowledge, this is the first study demonstrating the expressions of ZnT5 and ZnT6 in breast cancer. The results of this study also indicated that both ZnT5 and ZnT6 could be involved in less aggressive subtypes of breast cancer possibly through inhibition of cell migration. Further studies are required to clarify the clinical significance of their interactions in patients with breast cancer. Citation Format: Erina Iwabuchi, Yasuhiro Miki, Takanori Ishida, Hironobu Sasano. The zinc transporters, ZnT5 and ZnT6, in breast 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 3826.