tbuckley/cabot-search huggingface dataset:
Abstract 2862: Cetuximab-Triptolide conjugate suppresses growth of EGFR-overexpressing lung cancers through targeting RNA polymerase II
Authors: Keqiang Zhang, Yuelong Ma, Yuming Guo, Ting Sun, Jun Wu, David Horne, Dan Raz
Journal: Cancer Research (2020)

Abstract Triptolide (TPL), a natural compound isolated from a traditional Chinese medicine Thunder God Vine, exhibits strong anticancer activities; however, its clinical use is limited by low water-solubility and high systemic toxicity. To overcome these disadvantages, we developed a novel antibody drug conjugate (ADC) to specifically delivered TPL to cancer cells overexpressing EGFR which is frequently found in many types of human cancers including 70% of non-small cell lung cancers (NSCLC). The ADC is made by conjugation of TPL to Cetuximab, a clinically available anti-EGFR monoclonal antibody, via lysine residues of the antibody. Biochemical analysis showed that the average of drug-to-antibody ratio (DAR) of Cet-TPL is about 5, and the conjugation has little effect on the solubility and binding affinity of Cetuximab. The antitumor efficacy and toxicity of Cet-TPL were assessed and compared to that of TPL, Cetuximab, and a combination of these two. And the results demonstrated that Cet-TPL drastically suppresses in vitro proliferation and in vivo growth of these EGFR-overexpressing cancers including A549 and H1299 NSCLC cell lines, and two NSCLC patient-derived xenografts (PDXs); and SCC6 head-neck cancer cell line, while it did not significantly inhibit the proliferation and growth of NSCLC H520 that barely expresses EGFR. Furthermore, immunofluorescent analysis revealed that Cet-TPL is effectively transported into lysosomes of cancer cells that overexpress EGFR proteins, spared cells that don't express EGFR. Similar to TPL, which inhibits RNA polymerase II (Pol II) mediated transcription, Cet-TPL can also effectively target Pol II and significantly induce apoptosis in these EGFR-overexpressing cancers. Compared to Triptolide, Cetuximab, or their combinations, Cet-TPL displays higher target-specific cytotoxicity against EGFR-expressed cancers and much lower in vivo systematic toxicity. In addition, Cet-TPL efficiently suppresses activated EGFR pathway in SCC6 cancer cells. Taken together, Cet-TPL represents a potent targeted therapeutic agent against EGFR-overexpressing NSCLC and other cancers. Citation Format: Keqiang Zhang, Yuelong Ma, Yuming Guo, Ting Sun, Jun Wu, David Horne, Dan Raz. Cetuximab-Triptolide conjugate suppresses growth of EGFR-overexpressing lung cancers through targeting RNA polymerase II [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 2862.
Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis
Authors: James D. Chalmers, Charles S. Haworth, Mark L. Metersky, Michael R. Loebinger, Francesco Blasi, Oriol Sibila, Anne E. O’Donnell, Eugene J. Sullivan, Kevin C. Mange, Carlos Fernandez, Jun Zou, Charles L. Daley
Journal: New England Journal of Medicine (2020)

Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases.In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed.Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo.In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).
Abstract 1840: NUC-1031 causes release of DAMPs and upregulates PD-L1 expression in lung cancer cells
Authors: Jennifer Bré, Oliver J. Read, David J. Harrison
Journal: Cancer Research (2020)

Abstract Background: The nucleoside analog gemcitabine is used for the treatment of patients with lung cancer. Its cytotoxic effect is largely attributed to generation of the active metabolite dFdCTP, which causes DNA damage. NUC-1031, a ProTide transformation of gemcitabine, is specifically designed to overcome the key cancer resistance mechanisms associated with poor survival following gemcitabine treatment. NUC-1031 has shown high response rates in clinical studies, and efficacy in patients who were refractory to or had relapsed on gemcitabine. Certain cytotoxic agents are known to promote the release of damage-associated molecular patterns (DAMPs) from cancer cells, including cell surface exposure of calreticulin (CRT) and re-localization of nuclear high mobility group box protein 1 (HMGB1). DAMPs enhance cancer cell recognition by the immune system, promoting immunogenic cell death (ICD). Conversely, studies have shown that cancer cells can upregulate programmed death-ligand 1 (PD-L1) as an adaptive, protective response to cell stress resulting from drug exposure, potentially leading to evasion from immune cell-mediated cytotoxicity. This study investigates the effect of NUC-1031 on the release of DAMPs and modulation of PD-L1 in lung cancer cells. Methods: Non-small cell lung cancer (NSCLC) cell lines were treated with NUC-1031 for 24h and cytotoxicity was assessed at 96h post-treatment to determine half-maximal inhibitory concentrations (IC50). Cells were treated with increasing concentrations of NUC-1031 and cell surface expression of CRT and PD-L1 were analyzed by flow cytometry and complemented with RT-qPCR. IFN-γ was used as a positive control for PD-L1 induction. Localization of HMGB1 was assessed by immunofluorescence microscopy. Results: NUC-1031 induced the release of HMGB1 from the nucleus and increased cell surface expression of CRT in a dose-dependent manner. We confirmed that IFN-γ strongly and uniformly induced cell surface PD-L1 (270% increase). By comparison, NUC-1031-induced cell surface expression of PD-L1 was modest (67% increase). This effect was dose-dependent, with no further increase in PD-L1 expression above 1 μM. Conclusions: NUC-1031 is a potent cytotoxic agent that directly causes DNA damage through generation of dFdCTP. In addition, these data demonstrate the NUC-1031 promotes adaptive changes that alter the recognition of cancer cells by the immune system. The release of DAMPs by NUC-1031 and increase in PD-L1 is predicted to engender an immune response, which might be further potentiated by immune checkpoint inhibition. Citation Format: Jennifer Bré, Oliver J. Read, David J. Harrison. NUC-1031 causes release of DAMPs and upregulates PD-L1 expression in lung cancer cells [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 1840.
Abstract 3761: HSK26784: An oral PROTAC-BTK degrader for multiple B lymphocyte derived malignancies
Authors: Meilin Qian, Fei Ye, Chen Zhang, Jianming Wang, Yuanli Zhang, Yangyang Cui, Linli Li, Xiaoli Gou, Jia Ni
Journal: Cancer Research (2020)

Abstract PROteolysis TArgeting Chimeras (PROTACs) have emerged as a new and promising modality utilizing an event-driven MOA, whereby protein levels could be modulated by PROTAC-induced degradation by hijacking the ubiquitin-proteasome system. Starting from 2001, many target proteins have been studied, such as BET and kinase families as well as nuclear receptors. Bruton's tyrosine kinase (BTK) is an essential component of BCR pathway, which plays an important role in development, activation, proliferation, and survival of B lymphocytes. Ibrutinib is an irreversible inhibitor of BTK, and shows promising activity against multiple B lymphocyte derived malignancies. However, there remains a big concern about the development of Ibrutinib induced resistance by BTK C481S mutant. In our study, HSK26784 was found as a novel orally available BTK-PROTAC molecule, which could selectively degrade the BTK proteins. HSK26784 selectively degraded BTK proteins in Mino cell lines, with a half degradation concentration (DC50) of 22.9 nM. HSK26784 also effectively induced BTK degradation in mouse spleen, with a DC50 of 3.8 mg/kg. In addition, HSK26784 significantly inhibit the expression of CD69 on human PBMC cells after ex vivo BCR stimulation. HSK26784 could inhibit cell proliferation in many malignant B cell lines. In Ibrutinib sensitive cell lines, the inhibitory activity of HSK26784 is similar to that of Ibrutinib. While in the Ibrutinib non-sensitive cell lines, HSK26784 was more potent than Ibrutinib. Importantly, in the xenograft models, HSK26784 could also inhibit the tumor growth in a dose dependent manner. And HSK26784 achieved much better therapeutic effects than Ibrutinib. HSK26784 could inhibit the kinase activity of BTK wt and BTK C481S mutant, with IC50 of 11 nM and 14 nM respectively. It indicated that the efficacy of HSK26784 in BTK wt and BTK C481S mutant was comparable. HSK26784 showed good orally bioavailability in different species. The oral bio availabilities in mice, rats and dogs were 15.4 %, 11.8 % and 12.8 % respectively. In conclusion, HSK26784 is a promising BTK PROTAC degrader with better efficacy than Ibrutinib in multiple B lymphocytes. Citation Format: Meilin Qian, Fei Ye, Chen Zhang, Jianming Wang, Yuanli Zhang, Yangyang Cui, Linli Li, Xiaoli Gou, Jia Ni. HSK26784: An oral PROTAC-BTK degrader for multiple B lymphocyte derived malignancies [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 3761.
Abstract 2778: Mapping the extracellular pH gradient of colorectal cancer after immuno-thermal ablation
Authors: Ryan J. Slovak, Daniel Coman, Johannes M. Ludwig, Hyun S. Kim
Journal: Cancer Research (2020)

Abstract Background: Biosensor imaging of redundant deviation in shifts (BIRDS) is a non-invasive MR imaging modality that maps extracellular pH (pHe) by directly detecting paramagenetically shifted non-exchangeable protons of exogeneous agents. Previously it has been used to characterize various tumors in the rat brain and to monitor the response to loco-regional treatment of liver cancer. The purpose of this study was to investigate the feasibility of utilizing pHe mapping with BIRDS to differentiate ablated and non-ablated tumors in the setting of systemic immunotherapy of murine colorectal cancer (CRC). Materials and Methods: Eight BALB/c mice (Charles River Laboratories, Wilmington, MA, USA) were implanted with bilateral flank injections of 0.5 × 106 CT26.WT colorectal cancer cells (CRL- 2638; ATCC, Manassas, VA). Mice were randomly assigned into 3 treatment groups; group 1 received injections of sham antibodies (InVivoMAb IgG controls), group 2 was treated with dual anti-PD-1 and anti-CTLA-4 antibodies (Clone J43 &amp; Clone 9D9; BioXcell, West Lebanon, NH, USA), III). Group 3 received cryoablation in combination with systemic injections of dual checkpoint inhibitors. Mapping of pHe was performed between 3-10 days after the initiation of treatment and was immediately followed by sacrifice. Results: The mean pHe of untreated, control tumors was significantly lower than the average pHe of tumors treated with immuno-thermal ablations (6.6 vs 6.96; p&amp;lt;0.05). Among the mice in the ablation groups, the targeted tumors demonstrated significantly less acidity on average than the distal, off-target tumors (6.96 vs 6.63; p&amp;lt;0.05). The average pHe of tumors in the DICB group was not significantly different than any other group (6.75 vs 6.6, 6.96 &amp; 6.63; p&amp;gt;0.05). Conclusions: BIRDS MR quantification was feasible for imaging murine CRC model. BIRDS quantification of pHe could serve as an imaging non-invasive biomarker for metabolic changes of the tumor microenvironment in a murine CRC model with Immuno-Thermal Ablation Therapy. Significance at a GlanceTreatment GroupMean Extracellular pHSignificant DifferencesControl6.6Vs Target Ablated Tumors (p&amp;lt;0.05)Dual Immune Checkpoint Blockade (DICB)6.75NoneTargeted tumors in Ablated group6.96Vs Control (p&amp;lt;0.05) Vs Off-target Tumors (p&amp;lt;0.05)Off-target tumors in Ablated Group6.63Vs Ablated Tumors (p&amp;lt;0.05) Citation Format: Ryan J. Slovak, Daniel Coman, Johannes M. Ludwig, Hyun S. Kim. Mapping the extracellular pH gradient of colorectal cancer after immuno-thermal ablation [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 2778.
Abstract 174: Genomic cytometry characterization of preclinical models for development of immune-oncology therapeutics
Authors: Joon Sang Lee, Shannon McGrath, Emma Wang, Maximilian Rogers-Grazado, Yu-an Zhang, Natalia Malkova, Jack Pollard, Alexei Protopopov
Journal: Cancer Research (2020)

Abstract Single cell characterization of protein epitopes is usually associated with fluorescent Flow Cytometry, which can be both costly and time consuming to optimize for multiple epitopes. To overcome the limitations of this method, we introduce Genomic Cytometry that utilizes cellular indexing of transcriptomes and protein epitopes by next-generation sequencing (CITE-seq) technology instead of flow. Genomic Cytometry is based on staining cells with antibodies conjugated to unique 15-bp DNA barcodes instead of fluorophores. After sequencing and data analysis the barcode read number can be linked to protein abundance. We utilized Genomic Cytometry to simultaneously analyze over 50 different protein biomarkers in a single scalable workflow. The application is ideal for characterization of heterogeneous cell populations such as tumors including their immune content. In addition to profiling a number cell surface protein markers that exceeds capabilities of traditional flow cytometry the technology allows for assessment of single cell gene expression data to link protein and genomic data sets. Corresponding pre-analytical and 10X Genomics-based analytical workflows were established for human PBMC samples, as well as for solid tissue including tumor specimens derived from mouse syngeneic tumor models. Data analysis pipelines were developed and validated that includes custom scripts. We ran a number of cross-platform validation studies (mouse and human cells) and found that the Genomic Cytometry is highly correlative to fluorescent flow. Multiplex methods were implemented to allow pooling of samples to reduce biases related to sample manipulation. The method enables large-scale single-cell sequencing experiments. In proof of concept experiments, a number of preclinical models, such as MC38 and H22, were deeply analyzed using CITE-seq approach. Genomic Cytometry enables rapid and cost effective characterization of both immune-oncology (I-O) models and modes of action of new I-O molecules in order to develop more differentiated therapeutics. Citation Format: Joon Sang Lee, Shannon McGrath, Emma Wang, Maximilian Rogers-Grazado, Yu-an Zhang, Natalia Malkova, Jack Pollard, Alexei Protopopov. Genomic cytometry characterization of preclinical models for development of immune-oncology therapeutics [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 174.
Abstract 1485: E7011, a novel anti-angiogenesis inhibitor targeting Notch4 receptor signal pathway
Authors: Yusuke Adachi, Yoshimasa Sakamoto, Youya Nakazawa, Sho Tachino, Ken Ito, Takanori Abe, Yukinori Minoshima, Kana Hoshino-Negishi, Hideaki Ogasawara, Tomomi Kawakatsu, Miyuki Nishimura, Masashi Shimizu, Kazuhiro Tahara, Toshitaka Sato, Katsuhisa Suzuki, Kishan Agarwala, Masao Iwata, Yasuhiro Funahashi, Kenichi Nomoto, Yoichi Ozawa, Junji Matsui, Toshio Imai, Yu Kato
Journal: Cancer Research (2020)

Abstract Notch4 is selectively expressed on tumor endothelial cells and hypothesized to contribute to cancer malignancy through mechanisms including tumor angiogenesis regulation and promoting drug resistance. We developed E7011, a humanized IgG2κ antibody targeting Notch4 receptor signaling. To obtain anti-human Notch4 monoclonal antibody, human Notch4 3EGFR (epidermal growth factor repeat) domain - NRR (negative regulatory region) - SEAP (secreted alkaline phosphatase) - His protein was immunized to mice and 6698 hybridomas were obtained. By screening these clones with the Notch4 binding assay and Notch4-specific gal4-fusion luciferase reporter assay, mouse anti-human Notch4 mAb clone (6-3-A6) was selected. The CDRs (complementarity determining regions) of 6-3-A6 were grafted into the variable regions of human IgG2κ, and E7011, novel humanized anti-human Notch4 monoclonal antibody, was developed by screening in assays above. The biomolecular interaction analysis showed that E7011 is able to bind to human and mouse Notch4-NRR domain-SEAP-His, and inhibit human Notch4 receptor signaling in an antibody-dose dependent manner as well as 6-3-A6. IHC analysis showed that Notch4 was expressed on CD31 positive endothelial cells in Calu6 human non-small cell lung carcinoma xenograft tumor. Intravenous administration of E7011 at 1, 3, 10 mg/kg in twice a week significantly decreased tumor growth compared with control IgG treatment without severe body weight loss. We also investigated the functional tumor angiogenesis by hoechest dye-perfusion and staining with anti-CD31 antibody in the Calu6 xenograft model. E7011 treatment significantly decreased hoechst-positive perfusion area compared with vehicle treatment. In conclusion, E7011 is a novel antitumor agent that is a specific signal inhibitor targeting the Notch4 receptor and suppresses tumor growth through decreasing tumor vessel function in based on preclinical studies. Citation Format: Yusuke Adachi, Yoshimasa Sakamoto, Youya Nakazawa, Sho Tachino, Ken Ito, Takanori Abe, Yukinori Minoshima, Kana Hoshino-Negishi, Hideaki Ogasawara, Tomomi Kawakatsu, Miyuki Nishimura, Masashi Shimizu, Kazuhiro Tahara, Toshitaka Sato, Katsuhisa Suzuki, Kishan Agarwala, Masao Iwata, Yasuhiro Funahashi, Kenichi Nomoto, Yoichi Ozawa, Junji Matsui, Toshio Imai, Yu Kato. E7011, a novel anti-angiogenesis inhibitor targeting Notch4 receptor signal pathway [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 1485.
Abstract 3717: LncRNA RNF157-AS1 inhibits autophagy in ovarian cancer cells by downregulating ARHI: The different role in proliferation and drug resistance
Authors: Sujuan Xu, Pengfei Xu
Journal: Cancer Research (2020)

Abstract Ovarian cancer(OC) is the commonest cause of female cancer death. Long noncoding RNAs (lncRNAs) has been shown to have regulatory roles in the procession of many cancers, including OC. Here, in our previous study, we reported that lncRNA RNF157-AS1 was overexpression in OC tissues, which is confirmed by GSE144077 and TCGA matched GTEx normal data. Further experiments revealed that RNF157-AS1 knockdown significantly repressed the proliferation both in vitro and in vivo and overexpressed RNF157-AS1 promoted the proliferation of OC cells. However, the higher expression of RNF157-AS1 predicted a better prognosis for OC patients in TCGA database. RNA-seq analysis revealed that ARHI was significant overexpressed after RNF157-AS1 silencing and it is negative correlated with RNF157-AS1 in TCGA and matched GTEx normal data. ARHI, a autophagy-related gene, could induced autophagy in OC cells. Because of 70% of OC patients were diagnosed with advanced tumors and need to chemotherapy. Overexpression of RNF157-AS1 could inhibit autophagy-associated cell death and promote rapid proliferation of OC cells, while overexpressed RNF157-AS1 decrease autophagy and induced cells apoptosis under adverse environment. To test our hypothesis, CCK8 assay suggested overexpression of RNF157-AS1 significantly decreased the chemoresistance to cisplatin (DDP) and silencing of RNF157-AS1 increased the DDP-resistance of OC cells, which are confirmed by clone formation assay and apoptosis experiments. Western blot assay also suggested that RNF157-AS1 silencing promote ARHI, LC3II/I and beclin1 expression. To our knowledge, this is the first report revealed that the different roles of RNF157-AS1 in OC cells' proliferation and chemoresistance and our study also can provide guidance for clinical treatment of OC patients. Citation Format: Sujuan Xu, Pengfei Xu. LncRNA RNF157-AS1 inhibits autophagy in ovarian cancer cells by downregulating ARHI: The different role in proliferation and drug resistance [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 3717.
The Complement System of Man
Authors: Shaun Ruddy, Irma Gigli, K. Frank Austen
Journal: New England Journal of Medicine (1972)

Inherited AbnormalitiesThe diagnosis of a selective deficiency of a complement component or inhibitor requires the demonstration, by functional or immunochemical technics, of a reduced serum level. A normal total hemolytic complement (CH50) does not exclude heterozygous deficiency states or absence of the C1̄ inhibitor. Stoichiometric hemolytic_ titrations, which have been described for C1,113 C1̄ inhibitor,12 C4,114 C2,113 C314 and C9,115 provide sensitive measurements of the activities of individual complement components in normal human serum. Immunochemical determinations, which use monospecific antibody against complement proteins to quantitate serum levels by radial or electroimmunodiffusion, are available for C1q,116 C1s,117 C1̄ inhibitor,12 C4, . . .
A prospective, blinded study of a PF4-dependent assay for HIT diagnosis
Authors: Bethany Samuelson Bannow, Deepti M. Warad, Curtis G. Jones, Shannon M. Pechauer, Brian R. Curtis, Daniel W. Bougie, Ruchika Sharma, Diane E. Grill, Mary W. Redman, Parisa R. Khalighi, Rachel R. Leger, Rajiv K. Pruthi, Dong Chen, Daniel E. Sabath, Richard H. Aster, David A. Garcia, Anand Padmanabhan
Journal: Blood (2020)