tbuckley/cabot-search huggingface dataset:
Abstract 216: <i>pro</i>-Pyrrolobenzodiazepine (<i>pro</i>-PBD) bioconjugates, the legacy: Design and synthesis of <i>pro</i>-PBD conjugates containing self-immolative substituted disulfide linkers
Authors: Iontcho Vlahov, Longwu Qi, Hari K. Santhapuram, Garth Parham, Kevin Wang, Jeremy F. Vaughn, Spencer J. Hahn, Marilynn Vetzel, Melissa Nelson, Joseph A. Reddy, Christopher P. Leamon
Journal: Cancer Research (2019)

Abstract Naturally occurring pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of highly potent antitumor antibiotics, isolated from various streptomycin species. PBDs covalently bond and cross-link with discrete sequences of base pairs in the minor groove of DNA. A wide range of synthetic PBDs and PBD dimers have been shown to be highly potent cytotoxic agents, and have been used as payloads in antibody drug conjugates (ADCs). However, all PBDs as stand-alone agents or as delivered via small molecule drug conjugates (SMDCs), cause undesired off-target toxicity. Recently, we designed folate conjugated pro-PBDs, masking the imine moiety with its synthetic precursors: namely, 1,3-oxazolidine carbamate and an aromatic amine. The 1,3-oxazolidine carbamate provided a conjugation site for attachment of pro-PBD to a targeting ligand. After delivery to the targeted cell and internalization, reductive cleavage of the linker system results in the generation of a 1,3-oxazolidine. The oxazolidine reacts with water to form an aldehyde which subsequently reacts intramolecularly to ultimately form the PBD diazepine ring. Herein, we report the design and synthesis of folate conjugates of pro-PBDs and self-immolative sterically hindered disulfide linker systems, which pave the way toward novel, highly-specific therapeutics which have the potential to minimize off-target toxicities. One of the so designed conjugates, EC2629, satisfied all of our criteria for selection for pre-clinical development: • EC2629 shows high affinity towards FR mediated binding. • Cross-links DNA only following self-immolative release of free drug. • Picomolar potency against FR-expressing cells. • Curative activity with no weight loss in animal models. • Active against drug resistant tumor xenograft models in-vivo. • EC2629 is active against patient derived xenograft models in-vivo. • Based on high cytotoxicity and minimal off target toxicity (in-vitro &amp; in-vivo), EC2629 is selected for pre-clinical development. • Biological evaluation of EC2629 was presented at World ADC, Berlin, Germany (March, 2018). Citation Format: Iontcho Vlahov, Longwu Qi, Hari K. Santhapuram, Garth Parham, Kevin Wang, Jeremy F. Vaughn, Spencer J. Hahn, Marilynn Vetzel, Melissa Nelson, Joseph A. Reddy, Christopher P. Leamon. pro-Pyrrolobenzodiazepine (pro-PBD) bioconjugates, the legacy: Design and synthesis of pro-PBD conjugates containing self-immolative substituted disulfide linkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 216.
Abstract 685: Development of a multiscale QSP model to characterize the tumor suppressive effects of a cytokine mRNA immunotherapy in a preclinical melanoma mouse model
Authors: Kamau Pierre, Lin Lin, Lore Gruenbaum, Carissa Young, Joshua Apgar, Christian Hotz, Timothy Wagenaar, Spyros K. Stamatelos
Journal: Cancer Research (2019)

Abstract Despite the success of checkpoint blockade immunotherapy, most patients do not respond adequately to treatment and tumors effectively evade T lymphocyte and Natural Killer (NK) cell immune surveillance. Within the tumor microenvironment, the activities of immune cells are regulated by a multitude of signals including the local cytokine milieu. Intratumoral administration of our cytokine mRNA cocktail therapy, consisting of transcripts encoding for IL-12sc, IFNα2b, IL-15sushi and GM-CSF, has induced regression in tumor-bearing mice. Leveraging in vitro, in vivo and in silico data, we have developed a QSP platform that captures the observed preclinical tumor responses and allows for systemic predictions under a variety of conditions. A 5-compartment model was employed to account for the pharmacokinetics, cellular interactions and signaling within the tumor, lymph node, peritoneum, blood and periphery. We model the intratumoral (i.t.) injection of the mRNA mixture and its subsequent uptake, translation and secretion of activated cytokines that induce an immune response. Specifically, when released into the tumor, these cytokines promote tumor killing and trigger the activation and proliferation of CD4+/CD8+ T lymphocytes and NK cells. The model’s simulation results are well aligned with our preclinical data; indicating increased tumor regression with escalating doses of the mRNA monotherapy. The wealth of data and the intertwined information derived from the interaction of receptors and ligands defining the T cell phenotype necessitate a systems approach in order to identify suitable targets and mechanisms of drug action. Our murine immuno-oncology QSP model could be translated across species and be used as part of a computational platform to test various assets with similar MoA. Citation Format: Kamau Pierre, Lin Lin, Lore Gruenbaum, Carissa Young, Joshua Apgar, Christian Hotz, Timothy Wagenaar, Spyros K. Stamatelos. Development of a multiscale QSP model to characterize the tumor suppressive effects of a cytokine mRNA immunotherapy in a preclinical melanoma mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 685.
Bullying: Sydney hospital unit is third to be banned from training junior doctors amid concerns
Authors: Paul Smith
Journal: BMJ (2019)

A third hospital unit in Sydney has been banned from training junior doctors amid concerns over alleged bullying among senior staff.

St George Hospital’s ICU had its accreditation to train junior doctors withdrawn by the College of Intensive Care Medicine of Australia and New Zealand after a routine inspection by a visiting team from the college.

The decision was “effective immediately,” said the college. It sent a letter detailing its reasons to the hospital’s management but said that the contents were “confidential.”

However, local media reports said that the move was the result of “protracted allegations of bullying and dysfunction” in the hospital’s ICU.

St George is the third major hospital in the city to be stripped of training accreditation by a medical college in the past 12 months. The intensive care college stripped Westmead Hospital of its …
Abstract 1309: Targeting GluN2C ion channels as a promising approach in the treatment of melanoma
Authors: Hessam Tabatabaee, Yuchen Feng, Hamed Yari, Ting La, Simonne Sherwin, Lei Jin, Rebecca Lim, Alan Brichta, Xu Dong Zhang
Journal: Cancer Research (2019)

Abstract Ion channels are pore-forming integral membrane proteins that are known to have an impact on all hallmarks of cancer. Due to their expression on the surface of the cells, ion channels provide a distinct therapeutic target with more facilitated access from the extracellular milieu. NMDA receptors are a subtype of ligand-gated ion channels that express unique features including high calcium permeability as well as the requirement for binding of glutamate and the co-agonist glycine in order to be activated. Here we show that a glutamate ionotropic NMDA (N-methyl-D-aspartate) type ion channel, GluN2C is critically required for survival of human melanoma cells. Publicly available microarray data from Gene Expression Omnibus (GEO) were acquired in order to identify the differentially expressed ion channel genes in 127 melanoma patient samples relative to benign nevi or human epidermal melanocytes. Data exists into two major cohorts: First cohort consisted of 18 benign nevi and 45 melanoma (GSE3189), while second cohort contained 8 melanocytes and 82 melanoma (GSE29377). A bioinformatics approach was undertaken to determine commonly upregulated ion channels between the two cohorts. Subsequently, functional enrichment analysis along with pathway evaluation of these genes revealed GluN2C as a novel candidate for further investigation in this study. Upregulation of GluN2C was confirmed in a panel of melanoma cell lines and fresh melanoma isolates. Strikingly, silencing of GluN2C markedly reduced viability and clonogenicity in melanoma cells. Consistently, a pharmacological inhibitor of GluN2C potently killed melanoma cells with minimal effects on melanocytes and fibroblasts. Killing of melanoma cells by inhibition of GluN2C was not due to induction of apoptosis, since a general caspase inhibitor Z-VAD-FMK failed to rescue cells from dying. In contrast, the late stage autophagy inhibitor Bafilomycin A1 blocked the GluN2C induced cell death suggesting that killing of melanoma cells following inhibition of GluN2C is in part associated with induction of autophagy. Collectively, these results uncover a potential role for GluN2C ion channels in the pathogenesis of melanoma and suggest that these ion channels may constitute a promising target for melanoma treatment. Citation Format: Hessam Tabatabaee, Yuchen Feng, Hamed Yari, Ting La, Simonne Sherwin, Lei Jin, Rebecca Lim, Alan Brichta, Xu Dong Zhang. Targeting GluN2C ion channels as a promising approach in the treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1309.
Abstract 2029: Identification of cancer-associated fibroblasts that suppress pancreatic cancer progression
Authors: Atsushi Enomoto, Yasuyuki Mizutani, Hiroki Kobayashi, Tadashi Iida, Susan L. Woods, Daniel L. Worthley, Masahide Takahashi
Journal: Cancer Research (2019)

Abstract Cancer-associated fibroblasts (CAFs) constitute a major component of the cancer stroma. They can promote cancer progression through a variety of mechanisms including the production of growth factors, chemo/cytokines, and extracellular matrix (ECM). Recent observations from genetically engineered mouse models and clinical studies have suggested that there may exist at least two subpopulations of CAFs, i.e., cancer-promoting CAFs (pCAFs) and cancer-restraining CAFs (rCAFs). Although various pCAF markers have been identified, the identity of rCAFs is unknown due to a lack of specific rCAF marker(s). Here, we show that Meflin, a glycosylphosphatidylinositol (GPI)-anchored protein that maintains the undifferentiated state of mesenchymal stromal/stem cells (MSCs) (Maeda et al., Sci Rep, 6:22288, 2016), is a marker of pancreatic stellate cells (PSCs). We find that Meflin-positive CAFs represent rCAFs in pancreatic ductal adenocarcinoma (PDAC). Infiltration of Meflin-positive CAFs correlated with favourable prognosis in patients with PDAC, consistent with our observation that Meflin deficiency led to tumour progression with poorly differentiated histology in a PDAC mouse model. Notably, Meflin-positive cells gave rise to α-smooth muscle actin (SMA)-positive CAFs during cancer progression. Both genetic ablation of Meflin-positive CAFs and delivery of a Meflin-expressing lentivirus into the stroma suppressed xenografted tumour differentiation and growth, respectively. Mechanistically, Meflin interacts with lysyl oxidase (Lox) to inhibit collagen crosslinking activity, and Meflin deficiency led to straightened and wide stromal collagen fibers as demonstrated by a second harmonic generation microscopy. These data demonstrate the presence of rCAFs in the cancer stroma and the significance of their differentiation to pCAFs in cancer progression, which may be exploited for the development of therapeutic strategies to specifically target pCAFs or reprogram them into rCAFs. Citation Format: Atsushi Enomoto, Yasuyuki Mizutani, Hiroki Kobayashi, Tadashi Iida, Susan L. Woods, Daniel L. Worthley, Masahide Takahashi. Identification of cancer-associated fibroblasts that suppress pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2029.
Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial
Authors: Jeffrey E. Rubnitz, Norman J. Lacayo, Hiroto Inaba, Kenneth Heym, Raul C. Ribeiro, Jeffrey Taub, Jennifer McNeer, Barbara Degar, Deborah Schiff, Allen Eng-Juh Yeoh, Elaine Coustan-Smith, Lei Wang, Brandon Triplett, Susana C. Raimondi, Jeffery Klco, John Choi, Stanley Pounds, Ching-Hon Pui
Journal: Journal of Clinical Oncology (2019)

PURPOSE To identify effective and less toxic therapy for children with acute myeloid leukemia, we introduced clofarabine into the first course of remission induction to reduce exposure to daunorubicin and etoposide. PATIENTS AND METHODS From 2008 through 2017, 285 patients were enrolled at eight centers; 262 were randomly assigned to receive clofarabine and cytarabine (Clo+AraC, n = 129) or high-dose cytarabine, daunorubicin, and etoposide (HD-ADE, n = 133) as induction I. Induction II consisted of low-dose ADE given alone or combined with sorafenib or vorinostat. Consolidation therapy comprised two or three additional courses of chemotherapy or hematopoietic cell transplantation. Genetic abnormalities and the level of minimal residual disease (MRD) at day 22 of initial remission induction determined final risk classification. The primary end point was MRD at day 22. RESULTS Complete remission was induced after two courses of therapy in 263 (92.3%) of the 285 patients; induction failures included four early deaths and 15 cases of resistant leukemia. Day 22 MRD was positive in 57 of 121 randomly assigned evaluable patients (47%) who received Clo+AraC and 42 of 121 patients (35%) who received HD-ADE (odds ratio, 1.86; 95% CI, 1.03 to 3.41; P = .04). Despite this result, the 3-year event-free survival rate (52.9% [44.6% to 62.8%] for Clo+AraC v 52.4% [44.0% to 62.4%] for HD-ADE, P = .94) and overall survival rate (74.8% [67.1% to 83.3%] for Clo+AraC v 64.6% [56.2% to 74.2%] for HD-ADE, P = .1) did not differ significantly across the two arms. CONCLUSION Our findings suggest that the use of clofarabine with cytarabine during remission induction might reduce the need for anthracycline and etoposide in pediatric patients with acute myeloid leukemia and may reduce rates of cardiomyopathy and treatment-related cancer.
Abstract 895: The identification of molecular mechanism underlying the progression of gastric cancer peritoneal dissemination by senescent fibroblasts
Authors: Tadahito Yasuda, Mayu Koiwa, Tomoyuki Uchihara, Atsuko Yonemura
Journal: Cancer Research (2019)

Abstract Background: Secreted factors from cancer associated fibroblast (CAFs) is likely to be implicated in cancer progression, but the precise mechanism is not fully understood. It is reported that senescent cells survive and secrete some cytokines, so called senescence-associated secretory phenotype (SASP). The purpose of current study is to identify the molecular mechanism underlying the progression of gastric cancer (GC) peritoneal dissemination by CAFs showing SASP. Methods: We examined the senescent state of CAFs activated NFkB signaling by inflammatory cytokines (iCAFs) and evaluated the expression of SASP factors. We investigated the growth ability of GC cell lines treated with iCAFs derived condition medium (CM). We transplanted GC cell lines with intraperitoneal administration to generate peritoneal metastasis mouse model and evaluated the influence of SASP factors on cancer progression. Results: We found that the growth ability of iCAFs decreased and their expression of p16 and p15, which was senescent markers increased. And the comprehensive genomic analysis revealed that iCAFs was highly enriched the senescent related genes and SASP factors related genes. Next, we also found that iCAFs derived CM significantly increased the growth ability of GC cells. Moreover, also in peritoneal metastasis mouse model, iCAFs derived CM remarkably enhanced intraperitoneal tumors. Conclusion: These findings suggest that SASP factors from senescent CAFs, which activated by inflammatory cytokines can promote peritoneal dissemination of GC cells. Citation Format: Tadahito Yasuda, Mayu Koiwa, Tomoyuki Uchihara, Atsuko Yonemura. The identification of molecular mechanism underlying the progression of gastric cancer peritoneal dissemination by senescent fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 895.
Abstract 1187: Toward high-throughput, high-multiplex FFPE tumor tissue assays for translational research: 7-color, whole slide imaging
Authors: Amanda J. Bares, Eloise M. Wheeler, Maël Manesse
Journal: Cancer Research (2019)

Abstract Background: Immuno-oncology research and predictive biomarkers discovery requires the ability to rapidly identify, quantify, and spatially map many cell sub-types of the tumor environment in FFPE tissue sections. Multiplexed immunofluorescence (IF) enables identification of multiple targets within separate spectral, or color, channels, which in turn enables more in-depth analysis of rare tissue material relative to traditional methods. Although many methods for multiplexed IF exist, they are often costly and require time-consuming assay development and long imaging times. The Ultivue® InSituPlex® technology enables rapid, optimized staining of multiple targets utilizing widely-used immunohistochemistry (IHC) staining and fluorescence imaging instrumentation. Here, we demonstrate the application of InSituPlex technology to image 6 targets and a nuclear counterstain in a 7-color single whole-slide scan, without linear unmixing-based image reconstruction. This technique expands the subtyping depth that can be achieved in a single imaging round and on a single section, and also increases sample-to-answer throughput with a streamlined, single-day workflow. Methods: InSituPlex technology was used to perform 6-plex immune profiling of different FFPE tumor sections. Slides were stained with a cocktail of primary antibodies using a Leica® Bond® RX autostainer and imaged on commercially available fluorescent slide scanners. Subsequent image analysis of the whole slide scans was carried out using Indica Labs HALO® software. Results: In this poster, we present an assay for pathology research that enables fast immuno-profiling in tumor tissues, using a streamlined staining workflow and 7-color imaging. Newly selected fluorophores were used with corresponding optical filter pairs, which increased the number of spectral channels available on commercially available slide scanners while limiting channel cross-talk. Analysis led to the identification of key immune cell phenotypes through marker colocalization without significant ambiguity between targets tagged with spectrally adjacent fluorescent labels. Conclusion: The newly-expanded fluorophore configuration of the InSituPlex technology enables high throughput identification of 6 targets and a nuclear counterstain on whole tumor sections, empowering translational and immuno-oncology research. Citation Format: Amanda J. Bares, Eloise M. Wheeler, Maël Manesse. Toward high-throughput, high-multiplex FFPE tumor tissue assays for translational research: 7-color, whole slide imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1187.
Abstract 3994: Genomic characterization of melanoma in the elderly reveals molecular drivers of progression and prognosis associated with immunotherapy response
Authors: Stephen P. Smith, Caroline Gaudy-Marqueste, Rajive Kumar, Richard Marais, Eduardo Nagore, Amaya Viros
Journal: Cancer Research (2019)

Abstract Melanoma incidence and mortality particularly affects elderly patients. 85% of melanoma deaths occur in patients older than 60, and age is a powerful independent predictor of outcome. The genomic characteristics driving melanoma in the aged population have not been previously investigated. We have undertaken a comprehensive genomic analysis of age-specific molecular characteristics in metastatic cutaneous melanoma and discovered a core set of 4 driver genes that when mutated in older patients is a powerful predictor of poor outcome. We validate these findings in international independent primary melanoma replication cohorts. This signature stratifies patient prognosis more accurately than the current staging guidelines from early to late stages, making it relevant to immediate clinical practice. Checkpoint inhibitors are showing promising results in the adjuvant setting to treat early stage melanoma patients, and the cost burden to health care will limit access to these drugs. Importantly, elderly patients benefit from immune checkpoint inhibitor therapies, and there are currently no accepted predictors of response used to prioritize patients for these costly therapies in the adjuvant or advanced disease stages. Previous studies have shown a higher mutation burden and neo-antigen load are indicators of response. Critically, we show elderly melanoma patients are the population subset most likely to present with a higher mutation burden, and our signature strongly correlates with melanomas of higher mutation burden and neo-antigen load. We validate these findings across multiple primary and metastatic melanoma cohorts. Finally, stratifying old patients by our 4-gene outcome signature is also associated with immunotherapy response in the metastatic stage. Our study demonstrates that stratifying patients by age will allow improved discrimination of prognosis and association with response to treatment. Current selection of patients is based on AJCC stage alone, which means more patients have to be enrolled and more time is required to discriminate the effect of novel adjuvant immunotherapy strategies. Our work, validated across multiple cohorts, directly proposes enrolling patients with high genetic risk of poor outcome and improved rate of immunotherapy response using a simple 4-gene DNA signature that can be easily translated into clinical practice. Citation Format: Stephen P. Smith, Caroline Gaudy-Marqueste, Rajive Kumar, Richard Marais, Eduardo Nagore, Amaya Viros. Genomic characterization of melanoma in the elderly reveals molecular drivers of progression and prognosis associated with immunotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3994.
Familial Kidney Cancer: Implications of New Syndromes and Molecular Insights
Authors: Maria I. Carlo, A. Ari Hakimi, Grant D. Stewart, Gennady Bratslavsky, James Brugarolas, Ying-Bei Chen, W. Marston Linehan, Eamonn R. Maher, Maria J. Merino, Kenneth Offit, Victor E. Reuter, Brian Shuch, Jonathan A. Coleman
Journal: European Urology (2019)