tbuckley/cabot-search huggingface dataset:
Abstract 2794: A novel HNSCC organoid-on-a-chip platform for preclinical investigation and drug screening
Authors: Silvia Bonilla, Else Driehuis, Henriëtte Lanz, Hans Clevers, Jos Joore, Karla Queiroz, Paul Vulto
Journal: Cancer Research (2020)

Abstract Head and neck squamous cell carcinoma (HNSCC) cancer is a broad category of tumor types arising from the inner lining of various anatomic structures including the oral cavity, pharynx, larynx and salivary glands. Treatment often involves an intensive combination of surgery, radiotherapy and chemotherapy. Despite this, tumor recurrence rates remain high and survival rates are relatively poor. Here, we describe a novel high throughput drug screening platform combining the OrganoPlate®, a microfluidic based 3D-culture system, and HN cancer-derived organoids. MIMETAS develops Organ-on-a-Chip-based models for evaluation of new medicines. Our unique microfluidic technology enables testing of compounds on miniaturized 3D organ models in high-throughput. Hereby we show the establishment of HNSCC cancer-derived organoids in 2-lane OrganoPlate®, and its usefulness for phenotypic drug screenings. The aim of the study is to capture differential sensitivity of HN organoid lines to either a common platinum-based chemotherapy or to a targeted drug still not used in the clinic. Organoid lines (T1, T3 and T5) were embedded in the 2-lane OrganoPlate® as single cells in an extracellular matrix gel. At day 2, cultures were treated with cisplatin or PARP-inhibitor niraparib for 120 hours. Additionally, cultures exposed to high doses of cisplatin were evaluated after one week of recovery in order to determine treatment failure and recapitulate potential patient relapse. Drug response was evaluated by assessment of morphology (phase contrast), cell viability (total nuclei count, alamar blue assay), proliferation (EdU incorporation) and DNA damage (phosphorylated histone H2AX). Organoid cultures grow well under medium perfusion in the 2-lane OrganoPlate® and selective sensitivity to cisplatin and niraparib is revealed by the used readouts. The high-throughput, microfluidic 2-lane OrganoPlate® platform offers an attractive method for growing HNSCC cancer-derived organoids, supporting development of individualized tumour models for phenotypic drug screenings. Citation Format: Silvia Bonilla, Else Driehuis, Henriëtte Lanz, Hans Clevers, Jos Joore, Karla Queiroz, Paul Vulto. A novel HNSCC organoid-on-a-chip platform for preclinical investigation and drug screening [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 2794.
Abstract 6171: High throughput screening identified new radiosensitizers which inhibit DNA damage repair pathway
Authors: Keisuke Tamari, Zhihao Li, Hideki Matsutani, Yuji Seo, Yutaka Takahashi, Kazumasa Minami, Fumiaki Isohashi, Kazuhiko Ogawa
Journal: Cancer Research (2020)

Abstract Radiotherapy (RT) plays a crucial role in the treatment of cervical cancer. However, the efficacy of existing radiosensitizers in clinical applications is limited. The aim of this study was to established an efficient method of identifying new radiosensitizers and to investigated the specific mechanisms when used in combination with RT. An effective platform for radiosensitizers discovery was created based on high-throughput screening (HTS) technology. We established an automated and powerful HTS approach to identify potent radiosensitizers from the LOPAC1280 chemical library. We used the Geldanamycin for validation of our HTS method, which had been known as a radiosensitizer for cervical cancer cells. Z'-score of our HTS platform was 0.6. From 1280 compounds, we identified four hit compounds. Among them, we found Dihydroouabain (DHO) and Ro90-7501 which have not been previously known as radiosensitizers. Clonogenic survival assay showed that DHO and Ro90-7501 significantly enhanced radiosensitivity in cervical cancer cells. Western blot analysis showed that DHO inhibited the phosphorylation of Chk1, and Ro90-7501 inhibited the phosphorylation of ATM. These results indicated that DHO and Ro90-7501 inhibited DNA damage response pathway. In conclusion, we established the HTS method for radiosensitizer screening, and found DHO and Ro90-7501 as new radiosensitizers targeting DNA damage repair pathway. Citation Format: Keisuke Tamari, Zhihao Li, Hideki Matsutani, Yuji Seo, Yutaka Takahashi, Kazumasa Minami, Fumiaki Isohashi, Kazuhiko Ogawa. High throughput screening identified new radiosensitizers which inhibit DNA damage repair 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 6171.
Abstract 1721: Hypoxia penetrating ultra-small nanoparticle for anti-cancer effect in Glioblastoma
Authors: Mohd A. Rauf, Katyayani Tatiparti, Samaresh Sau, Arun K. Iyer
Journal: Cancer Research (2020)

Abstract Glioblastoma multiforme (GBM) is a lethal brain tumor currently without successful treatment options. Chemotherapeutic agents are the frontline in the management of GBM. Nonetheless, accessibility of the brain tumor is greatly impeded by the poor blood-brain barrier (BBB) penetration of drugs, which needs immediate attention. Ultra-small multifunctional nanoparticle offers a great promise in overcoming the delivery barriers to GBM. The primary goal of our research is to develop BBB targeted nanoparticle that can selectively deliver drugs to GBM and trigger cell death. We developed Anti-GBM drug, such as temozolomide (TMZ) encapsulated biocompatible, ultra-small nanoparticle using Lactoferrin (LAC) protein. Further, we chemically conjugated LAC with tumor hypoxia biomarker homing molecule, Acetazolamide (ATZ) to obtain LAC-ATZ nanoparticle. To validate our hypothesis of hypoxia targeting, we evaluated the carbonic anhydrase-IX (CAIX) receptor expression in human brain tumor section. The IHC data demonstrated significant overexpression of CAIX in tumor tissue compared to healthy human brain tissue section. Literatures have reported overexpression of LRP-1 in endothelial blood vessel of GBM tumor. Thus, use of LAC-ATZ will enhance its penetration across the BBB and delivery of TMZ in hypoxic core of GBM. To achieve the effective BBB penetration, we engineered LAC-ATZ@TMZ nanoparticle that demonstrated homogenous ultra-small particle size of average diameter of 20-30 nm using TEM analysis. The SDS-PAGE analysis demonstrated the conjugation of LAC with ATZ. Our preliminary data in GBM cells, U87MG suggested the dose dependent cell uptake of DiD-fluorescence labeled LAC-ATZ nanoparticle. The nanoparticles are selective in targeting the U87MG cell when compared to healthy microglial BV2 cells. Thus, it is supporting the potential of LAC-ATZ nanoparticle for targeting the GBM tumor with limited effect in healthy brain tissue. We developed conditioned BBB cell culture model to demonstrate the penetration of LAC-ATZ across the BBB. Based on the exciting preliminary outcome in this study builds a strong rational of using LAC-ATZ nanoparticle for overcoming the bottle neck barrier of BBB with improved anti-GBM response. Keywords: Glioblastoma multiforme (GBM), blood-brain barrier (BBB), Lactoferrin (LAC), Acetazolamide (ATZ) Citation Format: Mohd A. Rauf, Katyayani Tatiparti, Samaresh Sau, Arun K. Iyer. Hypoxia penetrating ultra-small nanoparticle for anti-cancer effect in 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 1721.
Abstract 3480: Potential impact of voluntary exercise on patterns of metastasis in a colorectal cancer model
Authors: Liza A. Wijler, Daniëlle A. Raats, Miriam van Dijk, Anne M. May, Onno Kranenburg
Journal: Cancer Research (2020)

Abstract Background: Physical activity (PA) is associated with a lower risk of colorectal cancer (CRC) initiation and death from CRC. However, evidence for a causal link between PA and disease progression is lacking. This study assesses the effect of voluntary exercise on metastases formation in a novel pre-clinical mouse model for late-stage metastatic CRC. Methods: Murine colorectal tumor organoids were transplanted into the livers of immunocompetent C57Bl/6 mice using microsurgery. Animals were fed ad libitum. Voluntary exercise in tumor-bearing (TB) mice was modeled by offering running wheels for 0h/day (n=12), 3h/day (n=12) or 24h/day (n=12). Running wheel revolutions were cumulatively measured every 30min. PA was monitored by infrared cameras. Tumor progression was monitored using in vivo Bioluminescent Imaging. Food intake was measured by weighing. Body composition was monitored by echoMRI. All animals were sacrificed 12 weeks after tumor initiation. Results: We have developed a novel model for exploring the effects of exercise on metastatic tumor progression in CRC. The model combines micro-surgical transplantation of tumor organoids, yielding spontaneously metastasizing CRC, with voluntary exercise. Voluntary exercise in both exercise groups led to an on average running distances of 2,3±0,3 km/night (total 221±29 km) in TB-3h animals and 6,6±3,0km/night (total 600±290km) in TB-24h animals. TB-3h and TB-24h animals developed more lean mass and lower fat mass compared to sedentary animals. Intermittent exercise had no effect on primary tumor growth and reduced metastasis. Vigorous exercise increased primary tumor growth (229606±186012) compared to TB-3h (152821±125902) and sedentary animals (165171±250993). Moreover, vigorous exercise non-significantly increased lung metastasis formation (2382±3539) compared to intermittent exercise (753±852) and to sedentary (1333±2902), while reducing metastatic spread to the liver and the peritoneal cavity was found. Conclusions: These results suggest that exercise has the potential to influence the patterns and extent of metastasis in CRC, and that the degree of exercise is likely to be an important variable. Confirmation of these results in additional models, for instance using patient-derived organoids, is now warranted. Citation Format: Liza A. Wijler, Daniëlle A. Raats, Miriam van Dijk, Anne M. May, Onno Kranenburg. Potential impact of voluntary exercise on patterns of metastasis in a colorectal cancer model [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 3480.
Two Tales of Single-Cell RNA Sequencing: Gene Expression and Alternative Splicing in Mouse Kidney Development
Authors: Lihe Chen
Journal: Journal of the American Society of Nephrology (2020)

Mammalian nephrogenesis is a process of cell fate acquisition and segregation driven by the reciprocal interactions between the ureteric bud (UB) and adjacent metanephric mesenchyme (MM).[1][1] In response to signals released from MM, the UB branches extensively, forming the collecting duct system.
Abstract 2986: NR2F1 underlies persistence of residual disease in melanoma
Authors: Manoela Tiago, Jessica L. Teh, Timothy J. Purwin, Weijia Cai, Connor Hollingworth, Melisa Lopez-Anton, Julio A. Aguirre-Ghiso, Andrew E. Aplin
Journal: Cancer Research (2020)

Abstract Despite the clinical success of targeted therapy and checkpoint inhibitors in melanoma, therapeutic responses are transient, followed by relapse that may be driven by a small subpopulation of residual or drug-tolerant cells. Understanding residual disease and metastasis mechanisms can provide clues both for developing improved versions of a drug and for guiding the selection of appropriate drug combinations for melanoma therapy. Here, we found that the well-known marker of tumor dormancy, Nuclear Receptor Subfamily 2 Group F Member 1 (NR2F1), was overexpressed in minimal disease residual cells following CDK4/6 and MEK inhibitors (CDK4/6i+MEKi) treatment in vivo. Furthermore, melanoma cells overexpressing NR2F1 were less sensitive to (CDK4/6i+MEKi) or BRAF and MEK inhibitors (BRAFi+MEKi) treatment in vitro and in vivo models, inhibiting apoptosis. Surprisingly, we did not find any evidence of decreased cell growth in our model. Using a three-dimensional tumor spheroid assay in vitro, we found the NR2F1 expression enhanced melanoma invasion following CDK4/6i+MEKi or BRAFi+MEKi treatments. The use of published RNA Seq data sets that were gathered from the GEO database and Single Cell Seq data sets from PDX melanoma samples showed that high expression of NR2F1 is enriched in the undifferentiated cell state and invasive cells, respectively. Furthermore, BRAF mutant patient sample with an acquired mutation in NRAS Q61R following BRAFi+MEKi+CDKi presented a high expression of NR2F1. Altogether, these findings suggest that NR2F1 may play a role in residual disease persistence besides known features of tumor dormancy, especially important in determining responses to dramatic changes in the environment, such as changes induced by anti-cancer therapy. Citation Format: Manoela Tiago, Jessica L. Teh, Timothy J. Purwin, Weijia Cai, Connor Hollingworth, Melisa Lopez-Anton, Julio A. Aguirre-Ghiso, Andrew E. Aplin. NR2F1 underlies persistence of residual disease 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 2986.
Modulatory capacities and possible implications of soluble Fc-epsilon RI in the IgE-mediated immune response
Authors: S. Monino-Romero, C. Bannert, K. Schmidthaler, S.C. Diesner, T. Eiwegger, E. Dehlink, A. Fiocchi, S. Amoah, M. Yazdanbakhsh, B. Bohle, E. Fiebiger, Z. Szepfalusi
Journal: Allergy (2016)
Abstract 606: Cisplatin disrupts MDM2-DAXX-HAUSP complex, &amp; induces apoptosis in acute leukemia cells
Authors: Paul B. Tchounwou, Sanjay Kumar
Journal: Cancer Research (2020)

Abstract Cisplatin (CDDP) is an antitumor drug successfully used in the treatment of various types of human malignancies. It enhances toxicity of arsenic trioxide (ATO) in head and neck squamous cell carcinoma cell, small cell lung cancer, ovarian cancer cells, and oral squamous cell carcinoma cells (, and chronic myelogenous leukemia cells. CDDP induces cytotoxicity, DNA damage, oxidative stress, and apoptosis in acute promyelocytes leukemia (APL) cells. However, the molecular mechanisms of CDDP-induced P53 activation, cell cycle arrest, and apoptosis in APL cells remain poorly understood. We hypothesized that CDDP inhibits proliferation of APL cells through MDM2-DAXX-HAUSP complex disruption, p53 activation leading to cell cycle arrest and apoptosis. To test hypothesis, we used three APL cell lines and a mice model of APL and investigated CDDP effects on cells growth, complex disruption, cell cycle progression, and apoptosis by applying western blotting, immunoprecipitation(IP), gene knockdown techniques, immune/histocytochemistry, and confocal imaging. We found that CDDP induced stress signal transmitted by protein kinase (ATM, ATR) and its downstream targets (CHK1 &amp; CHK2) phosphorylation leading to down-regulation of complex molecules expression and accumulation of p53. CDDP-induced p53 expression modulated cell cycle progression and apoptosis in APL cells, and stimulated the formation of more promyelocytes with dense granules through reduction of MDM2 expression in bone marrow cells. CDDP also activated p53 in APL mice liver tissues. This novel mechanism of action of CDDP in APL cells may help in the design of new anti-leukemic drugs for treatment of APL patients. Citation Format: Paul B. Tchounwou, Sanjay Kumar. Cisplatin disrupts MDM2-DAXX-HAUSP complex, &amp; induces apoptosis in acute leukemia 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 606.
Abstract 6395: <i>VHL</i> deficiency sensitizes CC-RCC to inhibition of small GTPases by statins
Authors: Olga V. Razorenova, Jordan M. Thompson, Alejandro Alvarez, Monika K. Singha, Matthew W. Pavesic MW, Quy H. Nguyen, Luke J. Nelson, David A. Fruman
Journal: Cancer Research (2020)

Abstract Clear cell renal cell carcinoma (CC-RCC) type of kidney cancer has limited therapeutic options available for advanced stages. The objective of this study was to investigate statins as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. Treatment with statins causes a profound cytostatic effect at nanomolar concentrations and becomes cytotoxic at low micromolar concentrations in VHL-deficient CC-RCC. The synthetic lethal effect can be fully rescued by both mevalonate and geranylgeranylpyrophosphate, but not by squalene, indicating that the effect is due to disruption of small GTPase isoprenylation and not the inhibition of cholesterol synthesis. Rho and Rho kinase (ROCK) inhibition by siRNAs, as well as C3-toxin (for Rho) and Y27637 (for ROCK) mimic the statin-mediated synthetic lethality effect, suggesting the involvement of Rho/ROCK pathway in the mechanism. Overactivation of hypoxia-inducible factor signaling resulting from VHL loss is required for statin-mediated toxicity. Since both VHL and ROCK were previously reported to control mitosis fidelity, we show that mitotic catastrophe is one of the mechanisms of action of compounds targeting the Rho/ROCK pathway in VHL-deficient CC-RCC. Finally, statin treatment is able to inhibit both tumor initiation and progression of subcutaneous 786-OT1-based CC-RCC tumors in mice. Thus, statins represent potential therapeutics for the treatment of VHL-deficient CC-RCC. Citation Format: Olga V. Razorenova, Jordan M. Thompson, Alejandro Alvarez, Monika K. Singha, Matthew W. Pavesic MW, Quy H. Nguyen, Luke J. Nelson, David A. Fruman. VHL deficiency sensitizes CC-RCC to inhibition of small GTPases by statins [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 6395.
Abstract 2845: Role of neutrophil associated a2 isoform of V-ATPase in cancer
Authors: Safaa A. Ibrahim, Valerie Riehl, Sylvia Schneiderman, Kenneth D. Beaman
Journal: Cancer Research (2020)

Abstract Tumors associated neutrophils (TAN) regulate the tumor microenvironment by directly promoting tumor progression and represent a potential therapeutic target for cancer treatment. Identifying neutrophil associated proteins that promotes neutrophil pro-tumorigenic properties will provide new specific targets for cancer therapy. The a2 isoform of V-ATPase (a2V) is multisubunit enzyme that is expressed on the intravesicular membranes as well as the plasma membrane of activated immune cells. Immuno-histochemical analysis shows that TAN in human cancer tissues express a2V. Isolated neutrophils from healthy donors were primed with tumor conditioned media collected from MDA MB-231 and MCF-7. Primed neutrophils showed increased gene expression of a2V while a1 and a3 isoform expression were not changed. Increased a2V in neutrophils was confirmed in the protein level by western blot and immunofluorescence staining. Flow cytometric analysis showed increased a2V surface staining on live primed neutrophils. Multiplex Luminex assay showed increased secreted protein levels of multiple pro-, anti-inflammatory cytokines and protumorigenic factors such as IL-8, VEGF and MMP-9 from primed neutrophils. Currently we are characterizing a method to knock down the a2V in human neutrophils isolated from peripheral blood and investigating its effect on neutrophil phenotypes. Together these data suggest that neutrophil associated a2V can play an important role in regulating the neutrophil phenotype. This makes it a potential candidate to target for cancer therapy. Citation Format: Safaa A. Ibrahim, Valerie Riehl, Sylvia Schneiderman, Kenneth D. Beaman. Role of neutrophil associated a2 isoform of V-ATPase in 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 2845.
Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis
Authors: Bruce C. Trapnell, Yoshikazu Inoue, Francesco Bonella, Cliff Morgan, Stéphane Jouneau, Elisabeth Bendstrup, Ilaria Campo, Spyros A. Papiris, Etsuro Yamaguchi, Erdogan Cetinkaya, Mikhail M. Ilkovich, Mordechai R. Kramer, Marcel Veltkamp, Michael Kreuter, Tomohisa Baba, Cecilia Ganslandt, Inge Tarnow, Grant Waterer, Taneli Jouhikainen
Journal: New England Journal of Medicine (2020)

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP. In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24. In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group. In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).