tbuckley/cabot-search huggingface dataset:
Abstract 1011: Disulfiram superior to ALDH1A1 inhibitor analogs in targeting ovarian cancer stem cells
Authors: Michael Caminear, Brittney Harrington, Christina Annunziata
Journal: Cancer Research (2021)

Abstract Epithelial ovarian cancer (EOC) is a global health burden and remains the fifth leading cause of cancer related death in women worldwide with the poorest five-year survival rate of the gynecological malignancies. Disease recurrence is the major cause of morbidity and mortality of EOC, considered to be driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs). TIC populations in EOC can be identified by the expression of molecular markers such as aldehyde dehydrogenase (ALDH), CD133, Nanog and Sox2. Although the TICs have been characterized, little progress has been made in finding drugs to specifically target this population, which has driven the research and development of novel therapies to prevent relapse. We previously showed that disulfiram, an ALDH inhibitor, effectively targeted TICs in terms of viability, spheroid formation, oxidative stress and also prevented relapse in an in vivo model of EOC. In this study we sought to determine whether specific targeting of ALDH isoenzyme ALDH1A1 would provide similar benefit as the broader pathway inhibition by disulfiram. NCTs 505 and 506 are isoenzyme specific ALDH1A1 inhibitors whose activity was compared to the effects of disulfiram. Following treatment with either the NCTs or disulfiram, the viability of TICs versus adherent cells, sphere formation, oxidative stress and cell death in our in vitro relapse model were measured and compared in OC cell lines. We found that disulfiram decreased the viability of TICs significantly more effectively versus non-TIC cells, while no trend was observed when the cells were treated with the NCTs. Disulfiram also induced greater amounts of ROS than the NCTs and affected the expression of proteins associated with the NFkB and JNK signaling pathways. Comparison of disulfiram to the direct targeting of ALDH1A1 with the NCTs suggests that disulfiram's broader cellular effects are more suitable as a therapeutic to eradicate TICs from tumors and prevent OC relapse. In addition to providing insight into a fitting treatment for TICs, the comparison of disulfiram to NCTs 505 and 506 has increased our understanding of disulfiram's mechanism of action. Further elucidation of disulfiram's mechanism has the potential to reveal additional targets to treat OC TICs and prevent disease recurrence. Citation Format: Michael Caminear, Brittney Harrington, Christina Annunziata. Disulfiram superior to ALDH1A1 inhibitor analogs in targeting ovarian cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1011.
Pan-caspase inhibition as a potential host-directed immunotherapy against MRSA and other bacterial skin infections
Authors: Martin P. Alphonse, Jessica H. Rubens, Roger V. Ortines, Nicholas A. Orlando, Aman M. Patel, Dustin Dikeman, Yu Wang, Ivan Vuong, Daniel P. Joyce, Jeffrey Zhang, Mohammed Mumtaz, Haiyun Liu, Qi Liu, Christine Youn, Garrett J. Patrick, Advaitaa Ravipati, Robert J. Miller, Nathan K. Archer, Lloyd S. Miller
Journal: Science Translational Medicine (2021)

A pan-caspase inhibitor, Q-VD-OPH, has therapeutic efficacy against preclinical methicillin-resistant Staphylococcus aureus skin infection.
Abstract LB064: Long-term application of TTFields in anaplastic astrocytoma - a case study
Authors: Darko Markovic
Journal: Cancer Research (2021)

Abstract Background: Anaplastic astrocytomas WHO III° (AA) represent diffusely infiltrating, high grade gliomas (HGG). Despite advancements in the molecular characterization of HGG treatment options are limited and are often in analogy to grade IV glioblastoma treatment. Tumor Treating Fields therapy (TTF) is an established modality for newly diagnosed and recurrent glioblastoma (GBM) shown to significantly improve progression-free and overall survival. While TTF is under investigation in grade III gliomas in several clinical trials, we present an exemplary case of an AA undergoing mid-term TTF therapy and adjuvant chemotherapy to explore treatment adherence, feasibility and safety. Methods: We present case details of a patient from our specialized neurosurgical oncology center, with an anaplastic astrocytoma (WHO grade III) who began TTF treatment at first diagnosis while being in the adjuvant chemotherapy phase at the time of TTF commencement. We describe treatment details and the course of disease under continuous and ongoing TTF therapy. Results: In December 2016 a 43year-old male patient was diagnosed with an anaplastic astrocytomaIDH 1/2 mutant, MGMT promoter-hypermethylation without 1p/19q codeletion. After biopsy and consequent partial tumor resection, he received concomitant radiochemotherapy and adjuvant chemotherapy with temozolomide. TTF was started six months after initial diagnosis. He has now completed 1328 days of treatment with an average daily usage of 90% and has survived 48 months from first diagnosis (cutoff January, 8th, 2021). Since beginning TTF, he has undergone temozolomide treatment for 6 cycles. He continues TTF without further adjuvant therapy. The patient is symptomatically stable and his quality of life is maintained. Significant adverse events or longer treatment interruptions have not occurred. Conclusion: The treatment with TTFields was well tolerated and seems to be feasible in this patient with an anaplastic astrocytoma. Considering the long treatment duration and favorable average daily usage, this treatment might be suitable for a long-term treatment in high grade gliomas. Ongoing clinical trials will provide more information on safety and efficacy for the use of TTFields in patients with grade III gliomas. Citation Format: Darko Markovic. Long-term application of TTFields in anaplastic astrocytoma - a case study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB064.
Artificial intelligence for polyp characterization: a challenging road ahead
Authors: Emanuele Rondonotti
Journal: Endoscopy (2021)

Replacing histology with optical biopsy is one of the most challenging tasks in gastrointestinal endoscopy. We all agree that histology represents one of the most expensive items in colonoscopy. In that case, we need to question how productive or cost effective it is to send an innocent-looking lesion, such as a hyperplastic polyp, for further evaluation, wasting valuable resources without any clinical benefit.
Abstract 558: Muti-gene ARMS PCR using both cfDNA and cfRNAin the supernatant of pleural effusion achieves rapid and accuracy driver gene mutations detection
Authors: Xuejing Chen, Kun Li, Zichen Liu, Fei Gai, Guanshan Zhu, Shun Lu, Nanying Che
Journal: Cancer Research (2021)

Abstract Background Pleural effusion from patients with advanced non-small cell lung cancer has been proved valuable for molecular analysis, especially when the tissue sample not available. However, simultaneous detection of multiple driver gene alterations especially the fusions is still challenging. Methods In this study, 77 patients with advanced NSCLC and pleural effusion were enrolled, 49 of whom had matched tumor tissues. Supernatants, cell sediments, and FFPE cell blocks were prepared from pleural effusion samples for detection of driver alterations by a PCR-based 9-gene mutation detection kit. Results In addition to mutations in EGFR, KRAS and HER2 detected in genomic DNA from cell sediments, FFPE cell blocks, and in cfDNA from supernatants, and fusions in ALK detected in RNA from cell sediments and FFPE cell blocks, fusions in ALK were also successfully detected in cfRNA from supernatants. Compared with matched tumor tissue, the supernatant showed the highest overall sensitivity (81.3%), with 81.5% for SNV/Indels by cfDNA and 80% for fusions by cfRNA, followed by FFPE cell blocks (71.0%) and the cell sediments (66.7%). Within the group of treatment-naïve patients or malignant cells observed in the cell sediments, supernatant showed higher overall sensitivity (89.5%, 92.3%) with both 100% for fusions. Based on the results, an optimized driver gene mutations detection procedure of pleural effusion is proposed. With the proposed procedure, an overall sensitivity 85.3% was achieved, with 82.1% for SNV/Indels and 100% for fusions. Conclusions CfDNA and cfRNA derived from pleural effusion supernatant (PES) have been successfully tested with a PCR-based multi-gene detection kit. An optimized procedure could maximize clinical value of testing pleural effusion samples and has good potential for routine clinical application. Citation Format: Xuejing Chen, Kun Li, Zichen Liu, Fei Gai, Guanshan Zhu, Shun Lu, Nanying Che. Muti-gene ARMS PCR using both cfDNA and cfRNAin the supernatant of pleural effusion achieves rapid and accuracy driver gene mutations detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 558.
Abstract LB252: Evaluation of the pan-class I phosphoinositide 3-kinase (PI3K) inhibitor copanlisib in the Pediatric Preclinical Testing Consortium osteosarcoma <i>in vivo</i> models
Authors: Douglas Harrison, Jonathan Gill, Pooja Hingorani, Michael Roth, Wendong Zhang, Beverly Teicher, Eric J. Earley, Stephen W. Erickson, Gregory Gatto, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Edward A. Kolb, Richard Gorlick
Journal: Cancer Research (2021)

Abstract Background. Copanlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor with activity against all four PI3K class I isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ). Copanlisib was approved for use by the FDA in the treatment of refractory follicular lymphoma in 2017. Preclinical data have suggested that deregulation of the PI3K pathway is a key driver of multiple malignancies. The relevance of this pathway in osteosarcoma tumorigenesis remains a subject of debate, however, whole genome and RNA sequencing data have revealed several PI3K aberrations in osteosarcoma tumor samples. The in vivo effects of copanlisib were studied in the Pediatric Preclinical Testing Consortium osteosarcoma xenograft models. Methods. The in vivo anticancer effects of copanlisib were assessed in a panel of 6 osteosarcoma models (OS-2, OS-9, OS-31, OS-33, OS-36, and OS-60). Copanlisib was administered by oral gavage at a dose of 10 mg/kg/day, two days on and five days off, repeated weekly for 4 weeks. Time to event and tumor volume responses were defined and analyzed utilizing standard PPTC statistical methods. Results. Copanlisib was well tolerated in the models with minimal weight loss and no treatment related mortality as compared to controls. Copanlisib induced prolonged event-free survival (EFS) in 5/6 osteosarcoma models (p&amp;lt;0.05, Gehan-Wilcoxon). Tumor regression (mean minimum attained relative tumor volume (minRTV) &amp;lt; 1.0) was not observed for any of the tested models. 3/6 models exhibited lower min RTV compared to untreated controls (p &amp;lt; 0.05, Wilcoxon rank sum). All osteosarcoma models showed progressive disease as their objective response measure. Conclusions. While copanlisib induced prolonged EFS in 5/6 osteosarcoma models, no tumor regression was seen, with all models developing progressive disease suggesting minimal activity. While copanlisib did not result in tumor regression, further study is needed to fully explore the role of the PI3K pathway in the pathogenesis of osteosarcoma. Citation Format: Douglas Harrison, Jonathan Gill, Pooja Hingorani, Michael Roth, Wendong Zhang, Beverly Teicher, Eric J. Earley, Stephen W. Erickson, Gregory Gatto, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Edward A. Kolb, Richard Gorlick. Evaluation of the pan-class I phosphoinositide 3-kinase (PI3K) inhibitor copanlisib in the Pediatric Preclinical Testing Consortium osteosarcoma in vivo models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB252.
The role of angiogenic signatures in advanced urothelial carcinoma (aUC) treated with VEGF-targeted therapy
Authors: F.E. Jackson-Spence, C. Ackerman, M. Khan, M. Grant, G. Soosaipillai, E. Nally, J. Choy, T.B Powles, B.E. Szabados
Journal: European Urology (2021)
PDCD1 methylation predicts response to anti–PD-1 based immunotherapy in advanced and metastatic renal cell carcinoma
Authors: N. Klümper, D.J. Ralser, R. Zarbl, K. Schlack, A.J. Schrader, M. Rehlinghaus, M.J. Hoffmann, G. Niegisch, A. Uhlig, L. Trojan, J. Steinestel, K. Steinestel, R.M. Wirtz, G. Kristiansen, M. Toma, M. Hölzel, M. Ritter, S. Strieth, J. Ellinger, D. Dietrich
Journal: European Urology (2021)
Abstract 1160: SAM competitive PRMT5 inhibitor PF06939999 demonstrates antitumor activity in splicing dysregulated NSCLC with decreased liability of drug resistance
Authors: Kristen Jensen-Pergakes, John Tatlock, Karen Maegley, Indrawan McAlpine, Michele McTigue, Tao Xie, Christopher Dillon, Yuli Wang, Shinji Yamazaki, Noah Spiegel, Manli Shi, Amy Nemeth, Natalie Miller, Eleanore Hendrickson, Hieu Lam, John Sherrill, Wei Liu, Ya-Li Deng, Chi-Yeh Chung, Elizabeth A. McMillan, Prakash Palde, Alexei Brooun, John Braganza, Susan E. Kephart, Robert Kumpf, Ryan Patman, Eugene Rui, Stephanie Scales, Michelle Tran-Dube, Fen Wang, Martin Wythes, Thomas Paul
Journal: Cancer Research (2021)

Abstract Protein arginine methyltransferase 5 (PRMT5) overexpression in hematological and solid tumors promotes symmetrical di-methyl arginine (SDMA) on cellular proteins involved in important cancer functions including cell cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, including the clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the co-factor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of NSCLC cancer cells, with dose-dependent decreases in SDMA levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity associates with cancer pathways including MYC, cell cycle and splicing. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 for treatment of splicing dysregulated NSCLC. Citation Format: Kristen Jensen-Pergakes, John Tatlock, Karen Maegley, Indrawan McAlpine, Michele McTigue, Tao Xie, Christopher Dillon, Yuli Wang, Shinji Yamazaki, Noah Spiegel, Manli Shi, Amy Nemeth, Natalie Miller, Eleanore Hendrickson, Hieu Lam, John Sherrill, Wei Liu, Ya-Li Deng, Chi-Yeh Chung, Elizabeth A. McMillan, Prakash Palde, Alexei Brooun, John Braganza, Susan E. Kephart, Robert Kumpf, Ryan Patman, Eugene Rui, Stephanie Scales, Michelle Tran-Dube, Fen Wang, Martin Wythes, Thomas Paul. SAM competitive PRMT5 inhibitor PF06939999 demonstrates antitumor activity in splicing dysregulated NSCLC with decreased liability of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1160.
Addressing the real trajectory of COVID-19 in the Eastern Mediterranean region
Authors: Khuloud Alsaba
Journal: The Lancet (2021)

others, are dependent on daily wages in the informal labour markets, that many social gatherings in these countries are, in fact, queues for food and medication.Such omissions highlight the real dangers inherent to organisations adopting a narrowly epidemiological approach in a region in which the trajectory of the pandemic is so strikingly shaped by the social and political determinants of health.
Multi-aspect analysis of ureteral access sheath usage in retrograde intrarenal surgery: Results of propensity score matching study
Authors: O. Ozman, H.M. Akgül, C. Başataç, Ö. Çınar, E.B. Sancak, C.M. Yazıcı, B. Önal, H. Akpınar
Journal: European Urology (2021)
Clinical study of VERU-111, an oral cytoskeletal disruptor in men with metastatic Castration Resistant Prostate Cancer (mCRPC) who failed an androgen receptor targeting agent
Authors: R. Getzenberg, M.C. Markowski, R. Tutrone, M.A. Eisenberger, C. Pieczonka, D. Rodriguez, K.G. Barnette, M.S. Steiner, D.R. Saltzstein, E.S. Antonarakis
Journal: European Urology (2021)
Biology and Models of the Blood–Brain Barrier
Authors: Cynthia Hajal, Baptiste Le Roi, Roger D. Kamm, Ben M. Maoz
Journal: Annual Review of Biomedical Engineering (2021)

The blood–brain barrier (BBB) is one of the most selective endothelial barriers. An understanding of its cellular, morphological, and biological properties in health and disease is necessary to develop therapeutics that can be transported from blood to brain. In vivo models have provided some insight into these features and transport mechanisms adopted at the brain, yet they have failed as a robust platform for the translation of results into clinical outcomes. In this article, we provide a general overview of major BBB features and describe various models that have been designed to replicate this barrier and neurological pathologies linked with the BBB. We propose several key parameters and design characteristics that can be employed to engineer physiologically relevant models of the blood–brain interface and highlight the need for a consensus in the measurement of fundamental properties of this barrier.
Abstract LB207: Glutamine transporter SLC38A3 promotes breast cancer migration via GSK3beta/beta-catenin/EMT pathway
Authors: Zheqiong Tan, Caitlin M. Tressler, Kanchan Sonkar, Kristine Glunde
Journal: Cancer Research (2021)

Abstract Breast cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related death among women. Triple negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor and HER2 expression. TNBC shows a high capacity for early metastasis and leads to worse clinical outcomes than other breast cancer subtypes due to the lack of specific therapeutic targets. We are looking to develop cancer-specific therapeutic targets for TNBC. Many types of cancer cells including TNBC cells rely on glutamine as carbon and nitrogen source to fuel unchecked growth. We screened for key genes in regulating glutamine metabolism in a panel of breast cancer cell lines. This screen identified the mRNA and protein levels of solute carrier family 38 member 3 (SLC38A3), a glutamine transporter, to be upregulated in human breast cancer cell lines, especially in TNBC cell lines. The TCGA breast cancer patient database also showed that SLC38A3 mRNA is overexpressed in invasive ductal breast carcinoma tissues, and it is even higher in TNBC relative to other breast cancer subtypes. To test the biological role of SLC38A3 protein in TNBC cells, we performed loss-of-function experiments in multiple TNBC cell lines. Silencing of SLC38A3 decreased cellular glutamate, glutamine and alanine levels. Silencing of SLC38A3 also activated apoptosis, and suppressed cell viability, migration and invasion in several TNBC cell lines. Interestingly, silencing of SLC38A3 increased the activity of glycogen synthase kinase 3-β (GSK3β) which promoted the degradation of β-catenin, leading to the decrease of the mRNA levels of epithelial-to-mesenchymal-transition (EMT)-associated transcription factors in TNBC cell lines. In summary, we showed that SLC38A3 is overexpressed in TNBC and promotes breast cancer migration and invasion via GSK3β/β-catenin/EMT pathway, which could be a novel therapeutic target for breast cancer. Citation Format: Zheqiong Tan, Caitlin M. Tressler, Kanchan Sonkar, Kristine Glunde. Glutamine transporter SLC38A3 promotes breast cancer migration via GSK3beta/beta-catenin/EMT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB207.
Abstract 1647: CAPTIV-8: A prospective trial of atezolizumab using a multivariate model incorporating whole genome and transcriptome analysis
Authors: Emma Titmuss, Alexandra Pender, Erin Pleasance, Scott Brown, Cameron J. Grisdale, James Topham, Yaoqing Shen, Melika Bonakdar, Gregory A. Taylor, Laura Williamson, Karen Mungall, Eric Chuah, Andrew J. Mungall, Richard A. Moore, Jean-Michel Lavoie, Stephen Yip, Howard Lim, Daniel J. Renouf, Sophie Sun, Steven J. Jones, Robert Holt, Marco A. Marra, Janessa Laskin
Journal: Cancer Research (2021)

Abstract Dramatic and durable responses to immune checkpoint inhibitors (ICIs) have been observed across multiple tumor types, but identifying the patients most likely to respond to these drugs remains challenging, particularly in the context of metastatic and pre-treated disease. Recent clinically approved biomarkers for patient selection are tumor agnostic, but currently all approved markers are evaluated independently. Through the Personalized Onco Genomics (POG) program at BC Cancer, we aimed to study the impact of evaluating multiple biomarkers in a tumor agnostic cohort. We performed whole genome and transcriptome analysis (WGTA) on fresh tumor biopsies from a heterogeneous pan-cancer cohort of 82 patients with advanced metastatic disease subsequently treated with ICIs. Established biomarkers, including tumor mutation burden (TMB) and CD8+ T cell scores, were able to distinguish responders in our advanced and pre-treated cohort. Additionally, we discovered that combining multiple biomarkers provided the best stratification of patients, suggesting a multifaceted approach, such as WGTA, may be suitable for more accurate identification of patients that may benefit from ICIs. As such, we have initiated a Phase II clinical trial, CAPTIV-8 (NCT04273061), which is distinctive in its use of WGTA to evaluate multiple markers including TMB, CD8+ T cell scores, an M1-M2 macrophage score and viral integration to select patients most likely to respond to atezolizumab. Clinical and genomic data prospectively collected from two hundred patients will be evaluated to test the efficacy of combining these biomarkers and identify additional biomarkers of response which can be used to guide treatment with ICIs. Citation Format: Emma Titmuss, Alexandra Pender, Erin Pleasance, Scott Brown, Cameron J. Grisdale, James Topham, Yaoqing Shen, Melika Bonakdar, Gregory A. Taylor, Laura Williamson, Karen Mungall, Eric Chuah, Andrew J. Mungall, Richard A. Moore, Jean-Michel Lavoie, Stephen Yip, Howard Lim, Daniel J. Renouf, Sophie Sun, Steven J. Jones, Robert Holt, Marco A. Marra, Janessa Laskin. CAPTIV-8: A prospective trial of atezolizumab using a multivariate model incorporating whole genome and transcriptome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1647.