tbuckley/cabot-search huggingface dataset:
Abstract 1402: Preclinical evaluation of a novel senescence-associated miRNA miR-3140-3p for malignant pleural mesothelioma
Authors: Yuki Yamamoto, Ayaka Nishiura, Kimiyoshi Yano, Noriaki Matsuda, Ryou-u Takahashi, Yasuhiro Tsutani, Morihito Okada, Hidetoshi Tahara
Journal: Cancer Research (2020)

Abstract Cellular senescence acts as a natural barrier against tumor progression Our previous study showed that selective induction of senescence using miR-22, one of senescence-associated microRNAs (SA-miRNAs), suppressed tumor progression (JCB 2011) In this study, we developed functional screening system using miRNA library to identify a potent SA-miRNA that suppress malignant tumor such as anti-cancer drug resistant and cancer stem cells. We focused on microRNA inducing the senescent phenotype in normal human fibroblast cell After transfection of 2028 miRNA mimics library in normal human fibroblast TIG-3, we evaluate the senescence phenotypes such as cell growth arrest and size enlargement using high content analyzer, and found that 349 miRNAs induced cellular senescence More importantly, we identified miR-3140-3p as potent SA-miRNA that significantly suppressed tumor cell proliferation in several types of cancer cells including cancer stem cells and anti-cancer drug resistant cells. We focused on malignant pleural mesothelioma (MPM) which is an aggressive tumor developed from the mesothelial lining cells of the pleura MPM is caused by direct asbestos exposure and is an incurable tumor type for the lack of effective treatment In addition, as Japan is one of the world's highest importers and users of asbestos, the cases of mesothelioma are expected to increase in the near future Therefore, we investigated the possibility of whether SA-miRNAs showed tumor suppressive effects against MPM cell lines Moreover, we tried to develop a new treatment or medicine for the MPM patients using SA-miRNA In vitro and in vivo analysis revealed that several SA-miRNAs drastically suppressed the tumor cell proliferation Based on these findings, the modulation of SA-miRNA is a promising approach to improve the treatment of MPM patients In addition, we performed and completed pre-clinical trials and design first-in-human study in Japan. Citation Format: Yuki Yamamoto, Ayaka Nishiura, Kimiyoshi Yano, Noriaki Matsuda, Ryou-u Takahashi, Yasuhiro Tsutani, Morihito Okada, Hidetoshi Tahara. Preclinical evaluation of a novel senescence-associated miRNA miR-3140-3p for malignant pleural 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 1402.
Abstract 1330: Scalable single-day workflows for variant calling with the Genexus Integrated Sequencer
Authors: Jason Gioia, Iris R. Casuga, Frances Chan, James Commins, David Conners, Marla Kratzer, Collyn Seeger, David Yaccarino
Journal: Cancer Research (2020)

Abstract The purpose of this study is to test the speed, scalability, and flexibility of variant detection with the Genexus Integrated Sequencer. This research use only instrument uses nucleic acid input and executes the steps of library preparation, sequencing, analysis, and variant calling. Taking advantage of the instrument's flexibility in sample plexy, the authors used the Oncomine™ Comprehensive Assay v3 and commercially available control samples to detect SNPs, InDels, and fusions reliably at up to 6-plex paired DNA and RNA samples. The instrument can accommodate 1, 2, 4, or 6 paired DNA and RNA samples when using 1, 2, 3, or 4 lanes of the GX5 chip. Regardless of the number of samples analyzed, the system achieved at least 98% sensitivity, 98% positive predictive value, 95% agreement to known truth for de novo variants, and 98% agreement to known truth for hotspot variants in the Acrometrix™ Oncomine Hotspot Control. Also regardless of sample plexy, the system achieved at least 97% agreement to known truth for Fusions within the SeraSeq® Fusion RNA Mix v3. The flexible workflows allow for fast turn-around times of as little as 18 hours for a single sample pair and less than 30 hours for 6 paired DNA and RNA samples. Stability of system initialization is an important feature for flexible use of an NGS system, and read length is a limiting performance metric for evaluating stability. In order to test the Genexus system's read length and stability features the Oncomine™ TCR Beta-LR Assay GX was used. Instruments were initialized with sequencing consumables and tested for performance on day 1 and day 15. There was no statistically significant difference in total reads (3.5 ± 1.0 M at day 1 vs. 3.1 ± 1.0 M at day 15), the fraction of reads that are low quality reads (13% ± 2% vs. 14% ± 2%), or mean read length (301 ± 6 bases vs. 296 ± 6 bases) between the two time points. In conclusion, the Genexus integrated sequencer is a robust NGS system that facilitates rapid turn-around time, flexibility in sample plexy, and stability in system consumables use. Citation Format: Jason Gioia, Iris R. Casuga, Frances Chan, James Commins, David Conners, Marla Kratzer, Collyn Seeger, David Yaccarino. Scalable single-day workflows for variant calling with the Genexus Integrated Sequencer [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 1330.
COVID-19 vaccine trials in Africa
Authors: Munyaradzi Makoni
Journal: The Lancet Respiratory Medicine (2020)

On Aug 17, 2020, screening began for participants to enrol in the mid-stage study of an experimental COVID-19 vaccine by Novavax, a US drug developer of next-generation vaccines for serious infectious diseases, at Witwatersrand University (Wits) in Johannesburg, South Africa. A US$15 million grant towards the trial was awarded to Novavax by the Bill & Melinda Gates Foundation. 2665 healthy adults and nearly 240 medically stable, HIV-positive adults will be enrolled.
Abstract CT205: Phase 2 study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K / mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status
Authors: Patrick Y. Wen, John de Groot, James D. Battiste, Samuel A. Goldlust, James S. Garner, Jeremy A. Simpson, Jelle Kijlstra, Alan Olivero, Timothy Cloughesy
Journal: Cancer Research (2020)

Abstract Introduction: Paxalisib (previously GDC-0084) is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. The PI3K pathway is upregulated in ~85% of GBM cases and paxalisib has shown efficacy in preclinical models. A phase I study (NCT01547546) investigated paxalisib dosed once daily in 47 patients with recurrent high-grade gliomas and established a maximum tolerated dose (MTD) of 45mg once daily. The current phase II study (NCT03522298) aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Methods: This study has a 2-part design: an open-label, dose-escalation phase to assess the safety, tolerability and MTD (Part 1), followed by an expansion cohort (Part 2) at the MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 recruits 20 patients who are randomised to administration in fed or fasted states. Results: Part 1 is complete. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis, with toxicity and patterns of AEs consistent with prior experience and other PI3K-targeting agents. For eight response-evaluable patients in Part 1, the median progression-free survival (PFS) was 8.4 months, and 25% of patients remained progression free after 15 months of follow-up. Part 2 is ongoing. Citation Format: Patrick Y. Wen, John de Groot, James D. Battiste, Samuel A. Goldlust, James S. Garner, Jeremy A. Simpson, Jelle Kijlstra, Alan Olivero, Timothy Cloughesy. Phase 2 study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K / mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status [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 CT205.
Abstract 2961: Olaparib mediated DNA damage response and its resistant mechanism in cervical cancer cells
Authors: Ka Yu Tse, Stephanie Si Liu, Horace Hok Yeung Lee, Philip Pun Ching Ip, Kin Tak Chan
Journal: Cancer Research (2020)

Abstract Cervical cancer is still the most common gynecologic cancer in developing countries. Olaparib is a poly-(ADR-ribose)-polymerase 1 (PARP1) inhibitor targeting at DNA strand break repair. However its efficacy in cervical cancer is unclear. This study aimed to evaluate the therapeutic potential of olaparib in cervical cancer. Olaparib remarkably reduced the PARylation activity and arrested cervical cancer cells at G2/M phase, and was associated with reduced level of a mitosis marker, phosphor-histone H3 as indicated by propidium iodide DNA staining and immunofluorescence. Cytotoxicity of olaparib against cervical cancer cells was determined by XTT assay with IC50 ranged from 35.49µM in C4I to 87.17µM in SiHa. The difference in olaparib sensitivity between C4I and SiHa was consistently demonstrated in annexin V based apoptotic assay, where a higher level of apoptotic response was found in C4I (21.12%) compared to SiHa (6.37%). Immunofluorescent staining and western blot for gH2AX clearly showed DNA double-strand break accumulation in both cell lines upon PARP1 blockade. Lower expression level of RAD51, a homologous recombination (HR) repair factor, was also observed in C4I, when compared to SiHa. Besides, gH2AX/RAD51 foci co-immunofluorescent line scan image analysis showed that there was reduced level of DNA damage recognition by RAD51 (26.80%), compared to SiHa (65.31%). These findings suggested that there was a reduced HR activity in C4I and might explain the higher sensitivity to olaparib compared to SiHa. We also demonstrated the therapeutic potential of olaparib in cervical cancer, and the rationale of using RAD51 as a predictive biomarker for olaparib sensitivity. Citation Format: Ka Yu Tse, Stephanie Si Liu, Horace Hok Yeung Lee, Philip Pun Ching Ip, Kin Tak Chan. Olaparib mediated DNA damage response and its resistant mechanism in cervical 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 2961.
Abstract 3127: To investigate the role of BRAF V600E co-occurring mutations in Langerhans cell histiocytosis (LCH)
Authors: Subhradip Karmakar, R Dhar, K Purkayastha, R Seth, S Karmakar
Journal: Cancer Research (2020)

Abstract a. Introduction : Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia caused by alterations of several genes in the MAPKinase pathway. The cell of origin is a white blood cell known as a dendritic cell priviously called as histiocyte characterized by a unique cytoplasmic organelle, the Birbeck granule, and the expression of CD1a and class II major histocompatibility complex molecules . The mutations cause these dendritic cells to attract other white blood cells and cause a “lesion” in any organ of the body. LCH has multi-orgnan involvement affecting skin bones, lymph nodes, brain etc. Systemic symptoms may include fever, bone pain, weight loss, jaundice, diabetes insipidus. b. Description: LCH is a rare sporadic, non-hereditary and non-malignant disease with unknown etiology characterized with a clonal proliferation of pathologic cells.Recent discovery of recurrent somatic mutations, BRAFV600E in MAPK pathway genes at critical stages of myeloid hematopoietic differentiation in LCH patients supports redefinition of the disease as a myeloproliferative disorder and provides opportunities to develop novel approaches to diagnosis and therapy. In the present proposal, we intend to analyze the BRAFV600E status along with other co-occurring mutations in a cohort of pediatric LCH patients by DNA sequencing in bone marrow samples or Peripheral Blood. Additionally we approach the above unanswered questions by applying an improved machine learning approach for classification and defining an algorithm for disease into different clusters for immediate clinical implication and to address its clinical heterogeneity. c. Results : We screened about 5 LCH patients and performed tageted exome seq to asertain the mutational profile of these patients. Sequencing detected BRAF V600E mutation in 3 of 5 samples for a mutation frequency of 60%. IHC based immunofloroscence shows that the intensity of phospho-MEK and phospho-ERK staining shows no significant alterations samples with mutation in BRAF. We are currently investigating mutations in other members of MAK pathways d. Conclusion : BRAF-V600E mutations were detected in few of our LCH patients. Neverless seeing the disease heterogeneity, we expect additionall mutations. More studies are needed to investigate mutations in the MAPK pathways that could efffect the course of disease management.We further plan to integrate the clinical and genomic findings to design a predictive model for the disease outcome. Citation Format: Subhradip Karmakar, R Dhar, K Purkayastha, R Seth, S Karmakar. To investigate the role of BRAF V600E co-occurring mutations in Langerhans cell histiocytosis (LCH) [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 3127.
Abstract 5331: Targeted protein degradation for the treatment of TRK fusion-driven cancers
Authors: Xiaoran Han, Liqun Chen, Chengwei Zhang, Bingyang Jiao, Yanke Chen, Jing Liu, Michael Plewe, Jialiang Wang
Journal: Cancer Research (2020)

Abstract Small molecule-mediated targeted protein degradation offers a systemic approach to deplete disease-causing proteins. The tropomyosin receptor kinase (TRK) family kinases are receptors for neurotrophic factors and primarily function in the central nervous system. As results of chromosomal rearrangement events, TRK kinases are re-expressed as fusion proteins and implicated in a wide diversity of human malignancies. These fusion proteins universally retain the kinase domain and function as key oncodrivers. Two TRK kinase inhibitors, entrectinib and larotrectinib, have been approved to treat TRK fusion-expressing cancers with compelling clinical evidence, highlighting the significance of TRK fusion kinases as oncology targets. In the current study, we report the development of selective TRK degraders. Lead compounds induced rapid degradation of different TRK fusion variants identified in patients at subnanomolar concentrations. Degradation of the fusion kinases significantly compromised TRK-dependent cancer cell growth with low nanomolar IC50. The lead compound exhibited approximately 16% oral bioavailability in mouse and effectively controlled TRK-driven xenograft tumor growth. Pharmacodynamic analysis demonstrated sustained degradation of the TRK fusion in xenograft tumors. Collectively, these findings provide the framework to develop a novel approach that modulates oncogenic TRK fusion kinases for cancer treatment. Citation Format: Xiaoran Han, Liqun Chen, Chengwei Zhang, Bingyang Jiao, Yanke Chen, Jing Liu, Michael Plewe, Jialiang Wang. Targeted protein degradation for the treatment of TRK fusion-driven cancers [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 5331.
Abstract 3241: Targeting the tumor stroma using CAR T-cells
Authors: Sarah Ash, Frances Turrell, Clare Isacke, Steven Lee
Journal: Cancer Research (2020)

Abstract The majority of breast cancer deaths are due to metastatic disease, thus developing new strategies to target the metastatic cascade is clinically relevant and of scientific importance. Breast cancer metastasis is a multi-step process influenced by many factors, including the tumor microenvironment (TME). Key interactions between the TME and tumor cells have been identified as promoting metastasis, thus presenting novel clinical targets. One such target is endosialin (CD248), a transmembrane glycoprotein which has limited expression in the healthy adult but is strongly upregulated on tumor-associated pericytes and fibroblasts in most solid cancers, including breast cancer. Using endosialin knockout mice, our laboratory has demonstrated that expression of endosialin in the tumor stroma promotes tumor cell intravasation, thereby promoting metastatic dissemination. Endosialin-expressing cells present an interesting target for CAR T-cell therapy, an emerging approach within cancer immunotherapy. Thus far, targeting tumor cells with CAR T-cells has proven challenging in solid neoplasms owing to the harsh, immunosuppressive environment that CAR T-cells encounter. Here, we describe an alternative approach of targeting cells of the microenvironment, which are more accessible to the infiltrating CAR T-cells, to limit breast cancer metastasis. Experiments comparing the effects of endosialin-directed CAR T-cells (Endo3 CARs) and mock- transduced T-cells (mock T-cells) in a spontaneously metastatic BALB/c breast cancer model reveal that Endo3 CAR treatment significantly reduces the number of metastatic deposits in the lungs. Endo3 CARs expand by at least 2-fold in tumor-bearing mice and endosialin staining confirms that Endo3 CAR treatment results in the depletion of endosialin-positive cells in the tumor stroma, without affecting normal tissue. Strikingly, Endo3 CAR treatment also results in significant growth inhibition and necrosis of the primary tumor. However, some evidence of Endo3 CAR T-cell associated toxicity is observed in treated mice, and we are currently testing therapeutic options to minimize these side effects. No off- target activity is observed in parallel experiments with tumor-bearing endosialin knockout mice. In conclusion, these promising results demonstrate that Endo3 CAR T-cell therapy presents a novel approach to limiting breast cancer metastasis via the targeting of activated stromal cells in the tumor microenvironment. Citation Format: Sarah Ash, Frances Turrell, Clare Isacke, Steven Lee. Targeting the tumor stroma using CAR T-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 3241.
In Vivo HSC Gene Therapy Using a Bi-modular HDAd5/35++ Vector Cures Sickle Cell Disease in a Mouse Model
Authors: Chang Li, Hongjie Wang, Aphrodite Georgakopoulou, Sucheol Gil, Evangelia Yannaki, André Lieber
Journal: Molecular Therapy (2020)

We have recently reported that, after in vivo hematopoietic stem cell/progenitor (HSPC) transduction with HDAd5/35++ vectors, SB100x transposase-mediated γ-globin gene addition achieved 10%-15% γ-globin of adult mouse globin, resulting in significant but incomplete phenotypic correction in a thalassemia intermedia mouse model. Furthermore, genome editing of a γ-globin repressor binding site within the γ-globin promoter by CRISPR-Cas9 results in efficient reactivation of endogenous γ-globin. Here, we aimed to combine these two mechanisms to obtain curative levels of γ-globin after in vivo HSPC transduction. We generated a HDAd5/35++ adenovirus vector (HDAd-combo) containing both modules and tested it in vitro and after in vivo HSPC transduction in healthy CD46/β-YAC mice and in a sickle cell disease mouse model (CD46/Townes). Compared to HDAd vectors containing either the γ-globin addition or the CRISPR-Cas9 reactivation units alone, in vivo HSC transduction of CD46/Townes mice with the HDAd-combo resulted in significantly higher γ-globin in red blood cells, reaching 30% of that of adult human α and β
Bone Morphogenetic Protein 9 Protects Against Neonatal Hyperoxia-Induced Lung Injury By Improving Alveolarization And Reducing Pulmonary Inflammation
Authors: X. Chen, M. Orriols, E. Laghmani, A. Hoogeboom, A. Hogen-Esch, P. Hiemstra, G. Folkerts, M.J. Goumans, P. Dijke, N. Morrell, F. Walther, G. Wagenaar
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Abstract 1805: The therapeutic potential of 5-Azacitidine plus various BH3 mimetics in melanoma
Authors: Chiara Dart, Nabanita Mukherjee, Carol Amato, Robert J. Van Gulick, Morgan MacBeth, Kasey Couts, Jacqueline Turner, Stacey Bagby, Mayumi Fujita, William Robinson, Yiqun Shellman
Journal: Cancer Research (2020)

Abstract Treatment options for melanoma have progressed in recent years, with the rise of targeted therapy and immunotherapy. Options are still limited for patients that are BRAF wildtype, treatment refractory, and patients with non-sun exposed melanoma subtypes that typically do not respond to standard therapies. Therefore, it is necessary to explore other biological processes that may provide new therapeutic approaches. One of most appealing is the BCL-2 family of apoptotic/anti-apoptotic system that is effective in leukemias, with BH3 mimetics venetoclax alone or in combination with the hypomethylating agent 5-azacitidine. We examined similar combinations on the group of eleven patient-derived and commercially available melanoma cell lines. The BH3 mimetics we tested include MCL1 inhibitors (S63845, AMG 176, AZD5991), an inhibitor of BCL2, BCLXL, and BCLW (navitoclax/ABT-263), a BCL2 inhibitor (venotoclax/ABT-199), and a BCLXL inhibitor (A1331852). Our data showed that treatments with MCL1 inhibitors plus 5-azacitidine are effective in reducing melanoma cell viability. S63845 was the most potent compound when combined with 5-azacitidine, with nine out of eleven (~80%) melanoma cell lines achieving less than 50% viability at the highest dose. There was an overall weaker response to treatment with 5-azacitidine in combination with ABT-263 or A1331852, with only 54% and 45% of cell lines responding at the highest dose, respectively. Response to ABT-199 with 5-Azacitidine was highly limited, 18% of cell lines responded at the highest concentration. Our data demonstrate that treatment with S63845 in combination with 5-azacitidine is highly effective in cell lines from a variety of melanoma subtypes, including the rare uveal and mucosal subtypes. In vivo and mechanistic experiments are planned. The novel combination of the MCL1 inhibitor S63845 and 5-azacitidine may be a promising alternative therapeutic target in melanoma. Citation Format: Chiara Dart, Nabanita Mukherjee, Carol Amato, Robert J. Van Gulick, Morgan MacBeth, Kasey Couts, Jacqueline Turner, Stacey Bagby, Mayumi Fujita, William Robinson, Yiqun Shellman. The therapeutic potential of 5-Azacitidine plus various BH3 mimetics in melanoma [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 1805.