tbuckley/cabot-search huggingface dataset:
Abstract 648: Optimization of a PEGylated glucuronide-auristatin linker for antibody-drug conjugates
Authors: Patrick J. Burke, Joseph Z. Hamilton, Scott C. Jeffrey, Joshua H. Hunter, Svetlana O. Doronina, Nicole M. Okeley, Martha E. Anderson, Peter D. Senter, Robert P. Lyon
Journal: Cancer Research (2015)

Abstract The clinical success of antibody-drug conjugates (ADCs) brentuximab vedotin and ado-trastuzumab emtansine has led to an increased effort to identify new antibody payloads and develop improved linker technologies. Most antibody payloads impart significant hydrophobicity to the ADC resulting in accelerated plasma clearance and diminished in vivo activity, particularly for conjugates with high drug to antibody ratios (DAR). Consequently, drug-linkers have been designed to minimize or mask hydrophobicity, enabling a higher DAR and improved pharmacokinetic properties, translating to enhanced in vivo potency. We recently reported on the incorporation of a discrete PEG polymer as a side chain in the β-glucuronide-monomethylauristatin E (MMAE) linker to provide homogeneous DAR 8 conjugates with decreased plasma clearance and increased antitumor activity in xenograft models relative to a non-PEGylated control. The PEG-glucuronide-MMAE lead has now been optimized by minimizing the size of the PEG side chain and incorporating a self-stabilizing maleimide to prevent payload de-conjugation in vivo. Multiple PEG-glucuronide-MMAE linker constructs were prepared with PEG size varying from 0 to 24 ethylene oxide units, and uniform DAR 8 ADCs were evaluated. PEG size had small but variable effects in vitro, with diminished activity observed in some cell lines. In contrast, a clear relationship was observed between PEG length and plasma pharmacokinetics. Longer PEG chains resulted in slower clearance, with a ‘threshold’ length beyond which clearance was not impacted. Conjugates bearing PEG of sufficient length to minimize ADC plasma clearance provided a wider therapeutic window relative to conjugates bearing shorter PEGs. Thus, sufficient masking of drug hydrophobicity is a viable strategy to provide uniform DAR 8 ADCs that preserve ADC pharmacokinetics and increase potency through higher drug loading. Citation Format: Patrick J. Burke, Joseph Z. Hamilton, Scott C. Jeffrey, Joshua H. Hunter, Svetlana O. Doronina, Nicole M. Okeley, Martha E. Anderson, Peter D. Senter, Robert P. Lyon. Optimization of a PEGylated glucuronide-auristatin linker for antibody-drug conjugates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 648. doi:10.1158/1538-7445.AM2015-648
Long-term neurologic health and psychosocial function of adult survivors of childhood medulloblastoma/PNET: a report from the Childhood Cancer Survivor Study
Authors: Allison A. King, Kristy Seidel, Chongzhi Di, Wendy M. Leisenring, Stephanie Mabry Perkins, Kevin R. Krull, Charles A. Sklar, Daniel M. Green, Gregory T. Armstrong, Lonnie K. Zeltzer, Elizabeth Wells, Marilyn Stovall, Nicole J. Ullrich, Kevin C. Oeffinger, Leslie L. Robison, Roger J. Packer
Journal: Neuro-Oncology (2016)

Medulloblastoma is the most common malignant childhood brain tumor, although long-term risks for chronic neurologic health and psychosocial functioning in aging adult survivors are incompletely characterized. The Childhood Cancer Survivor Study (CCSS) includes 380 five-year survivors of medulloblastoma/primitive neuroectodermal tumor (PNET; median age at follow-up: 30 y, interquartile range 24–36) and sibling comparison (n = 4031). Cumulative incidence of neurologic health conditions was reported. Cox regression models provided hazard ratios (HRs) and 95% CIs. Cross-sectional outcomes were assessed using generalized linear models. Compared with siblings, survivors were at increased risk of late-onset hearing loss (HR: 36.0, 95% CI: 23.6–54.9), stroke (HR: 33.9, 95% CI: 17.8–64.7), seizure (HR: 12.8, 95% CI: 9.0–18.1), poor balance (HR: 10.4, 95% CI: 6.7–15.9), tinnitus (HR: 4.8, 95% CI: 3.5–6.8), and cataracts (HR: 31.8, 95% CI: 16.7–60.5). Temporal/frontal lobe radiotherapy of 50 Gy or more increased risk for hearing loss (HR: 1.9, 95% CI: 1.1–1.3), seizure (HR: 2.1, 95% CI: 1.1–3.9), stroke (HR: 3.5, 95% CI: 1.3–9.1), and tinnitus (HR: 2.0, 95% CI: 1.0–3.9). Survivors were less likely than siblings to earn a college degree (relative risk [RR]: 0.49, 95% CI: 0.39–0.60), marry (RR: 0.35, 95% CI: 0.29–0.42), and live independently (RR: 0.58, 95% CI: 0.52–0.66). Adult survivors of childhood medulloblastoma/PNET demonstrate pronounced risk for hearing impairment, stroke, lower educational attainment, and social independence. Interventions to support survivors should be a high priority.
Activation of Monocytes by Aspergillus Fumigatus Hyphae and Conidia.
Authors: Ziad Haddad, Juergen Loeffler, Michael Bonin, Ulrike Schumacher, Marija Markulin, Friederike Frank, Markus Kapp, Hermann Einsele, Holger Hebart
Journal: Blood (2004)
Abstract 3222: Biomarker discovery through bioinformatic analysis of genomic profiles of PDX models with different responses to cancer therapies
Authors: Jingjing Jiang, Tengfei Yu, Ying Yan, Wei Du, Tingting Tan, Xuqin Yang, Jiali Gu, Liang Hua, Katherine Xin Ye, Zhenyu Gu
Journal: Cancer Research (2015)

Abstract Patient derived xenograft (PDX) tumor models have been proved to recapitulate the complexity and heterogeneity of their corresponding human tumors by phenotypic and genomic characterization, and thus become to be widely used in recent years in preclinical setting to facilitate drug discovery, translational studies and clinical trials support. Results from increasing number of preclinical studies, especially mouse trials, with PDX models in the past several years, have also demonstrated close correlation between drug response profiles with PDX models and clinical outcomes. GenenDesign has established over 800 PDX tumor models and derived around 100 resistance models to drugs of interest. Genomic profiling data of PDX models are acquired at hot-spot mutation, gene expression, gene copy number and RNA/Exome sequence levels. Through our in-house efforts, PDX models of different tumor types were tested with related SOCs and clinical candidates in biomarker-driven multi-drug multi-arm clinical trial settings. So far, more than 1200 data sets have been generated, including responses to targeted inhibitors against HER2, EGFR, FGFRs, c-Met/ALK, cell cycle regulators, Ras/Raf pathway, PI3K/Akt pathway, epigenetic targets, as well as chemotherapy drugs. In this study, we use bioinformatic tools to compare the genomic profiles of NSCLC PDX models based on their response profiles to multiple chemotherapy drugs. Biomarker signatures associated with SOC treatment sensitivity or resistance are revealed from bioinformatic analysis and being tested with both new NSCLC PDX models and clinical cohorts. The combination of genomic profiles and drug response information to multiple chemo/targeted therapies of over 800 PDX models at GenenDesign would help biomarker discovery for companion diagnosis to meet the increasing needs for precision medicine. Citation Format: Jingjing Jiang, Tengfei Yu, Ying Yan, Wei Du, Tingting Tan, Xuqin Yang, Jiali Gu, Liang Hua, Katherine Xin Ye, Zhenyu Gu. Biomarker discovery through bioinformatic analysis of genomic profiles of PDX models with different responses to cancer therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3222. doi:10.1158/1538-7445.AM2015-3222
721. Safety of Multiple Doses of CAR T Cells
Authors: Kristen Fousek, Rayne Rouce, Nabil Ahmed, Stephen Gottschalk, Barbara Savoldo, Gianpietro Dotti, Carlos Ramos, Chrystal Louis, Cliona Rooney, Malcolm Brenner, Helen Heslop
Journal: Molecular Therapy (2015)

Chimeric antigen receptor (CAR) T cells have demonstrated promising results for cancers in pre-clinical models and early phase trials. However, some groups have observed serious adverse events (SAEs) and toxicities attributable to the administration of CART cells, the most clinically significant being cytokine release syndrome (CRS). In addition, a recent case report described a patient who developed an anaphylaxis reaction to CART cells, ultimately attributed to receipt of multiple doses of cells. As there are a number of ongoing clinical trials at our institution utilizing CAR T cells to treat various hematologic and solid malignancies and several patients have received multiple doses, we performed a retrospective review to assess whether early or late infusion toxicities were observed with subsequent infusions. We identified 45 of over 200 patients who received more than one dose of CAR T cells between January 2009 and December 2014. We assessed patient characteristics including type of malignancy, disease status at the time of subsequent infusions, cell product (autologous vs. allogeneic), presence or absence of prior lymphodepletion, number of infusions, dosing schedule, and the relationship to development of CRS. Each characteristic was examined for any correlation to developing a SAE. Our results indicate that at our institution, repeated CAR T cell infusions are well tolerated, with the majority of grade 3-4 adverse events being hematologic and electrolyte abnormalities. Furthermore, the majority of SAEs reported after repeated CAR T cell infusions were attributed as unrelated to the infusion itself. However, further evaluation of a larger cohort is necessary to determine whether an association between the timing of repeated infusions and CRS and other SAEs exists. These findings and our continued evaluation of patients receiving multiple infusions will help us to ensure the safety of administering multiple doses of CAR T cells in the future.
Genetic Polymorphisms In Oxidative Stress-Related Genes Correlated with Outcome Following Anthracycline-Based Therapy for Aggressive B-Cell Non-Hodgkin Lymphomas
Authors: Heather L. Tardif, Song Yao, Bryan H. Goldman, Catherine M. Spier, Michael L. LeBlanc, Lisa M. Rimsza, Daniel O. Persky, Thomas P. Miller, Richard I Fisher, Christine B. Ambrosone, Margaret M. Briehl
Journal: Blood (2010)
Abstract 4618: The risk prediction for esophageal cancer by drinking, smoking, and the polymorphisms of ALDH2 and ADH1B
Authors: Hidemi Ito, Isao Oze, Satoyo Hosono, Miki Watanabe, Hideo Tanaka, Keitaro Matsuo
Journal: Cancer Research (2015)

Abstract Background: The impact of drinking and smoking on the risk of esophageal cancer has been established worldwide (IACR, 2012 updated). In our previous study, we found that the polymorphisms ofalcohol dehydrogenases 1B (ADH1B - rs1229984) and aldehyde dehydrogenases 2 (ALDH2 - rs671) were associated with esophageal cancer risk in a Japanese population (Matsuo K, 2001 &amp; Oze I, 2009). However, the extent to which these environmental and genetic risk factors contribute as predictors of esophageal cancer among Japanese is unknown. The objective of our study was to evaluate the performance of a risk assessment model that incorporates both environmental and genetic risk factors in a Japanese population. Methods: We conducted a case-control study with 265 cases and age- and sex- matched 530 controls within the framework of the Hospital-based Epidemiological Research Program at Aichi Cancer Center (HERPACC). We fit regression models with the risk factors. For discrimination assessment, we compared the area under the curves (AUC) in the receiver - operating curve (ROC) analysis of Environmental model (E-model), Genetic model (G-model), and Inclusive model. In addition, we evaluated contribution to risk prediction for each risk factor by calculating the integrated discrimination improvement (IDI) index. Results: We created a risk prediction model for esophageal cancer by polymorphisms of ADH1B and ALDH2, drinking and smoking. The AUCs were 0.873 (0.847-0.898) for E-model and 0.747 (0.711-0.782) for G-model. The Inclusive model including all risk factors, with an AUC of 0.931 (0.912-0.949), showed promise for stratifying people into different risk groups. We found that each risk factor statistically significantly contributed to risk prediction for esophageal cancer (p&amp;lt; 0.001, the IDI indexes of 0.064 for rs1229984, 0.066 for rs671, 0.220 for drinking and 0.101 for smoking). Conclusion: The risk prediction model that includes these environmental and genetic factors could be useful to classify Japanese into relevant risk groups of esophageal cancer for personalized prevention programs. Citation Format: Hidemi Ito, Isao Oze, Satoyo Hosono, Miki Watanabe, Hideo Tanaka, Keitaro Matsuo. The risk prediction for esophageal cancer by drinking, smoking, and the polymorphisms of ALDH2 and ADH1B. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4618. doi:10.1158/1538-7445.AM2015-4618
Role of CD3ζ expression and arginase activity in predicting response and survival in metastatic renal cell carcinoma (mRCC) patients receiving IL-2
Authors: A. H. Zea, M. B. Atkins, D. McDermont, A. O'Neil, M. Regan, C. Hernandez, A. Youmans, J. Desalvo, A. Ochoa
Journal: Journal of Clinical Oncology (2004)

2535 Background: A decrease in the T cell receptor ζ chain expression has been described in malignancy and chronic infections. The association with response to treatment and the mechanisms leading to this diminished expression are unclear. In vitro models suggest that arginase production may decrease CD3ζ expression.Methods: We examined the expression of CD3ζ chain and arginase activity in preRx samples of peripheral blood mononuclear cells from pts with mRCC receiving IL-2 Rx on a CWG Phase III trial, ζ chain expression was studied by florescence intensity (MFI) and serum arginase activity by conversion of arginine to ornithine. Results were compared to blood obtained from 33 healthy normal volunteers (NV). Results: Of 106 with a pre-Rx blood samples 18 pts responded (7 CR, 11 PR). MFI for CD3 ζ was 21.39 +/- 8.15 for the pts vs 35.43 +/- 12.24 for the NV. Mean arginase was 128.55 for pts vs 32.63 for NV. Serum arginase levels and CD3 ζ chain expression were inversely related (r= -0.31, p<0.01 ). Low and extremely low ζ expression was defined as 1 or 2 SD below the mean of the NV's. Median survival was 26, 19 and 14mos and tumor response was 19% (8/42), 18% 10/56 and 0% (0/8) for pts with normal, low and extremely low ζ expression. Arginase was 128.55 for pts vs 32.63 for NV. No correlation of survival or response with arginase expression was observed. . Data on other immune abnormalities including CD14+, CD4/CD25 reg T cells, LCK and Jak-3, and inducible cytokines are still being analyzed. Conclusions: These data suggest that mRCC is associated with decrement in ζ chain and increased arginase expression. Decreased ζ chain is associated with poor response and survival outcome Given the absence of response in pts with low ζ chain in these data, its role as a potential selection factor should be further investigated. The role of arginase in the loss of CD3ζ and in response to immunotherapy requires further study No significant financial relationships to disclose.
Nilotinib Versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-Month (mo) Follow-up
Authors: Giuseppe Saglio, Philipp D. LeCoutre, Ricardo Pasquini, Saengsuree Jootar, Hirohisa Nakamae, Ian W. Flinn, Andreas Hochhaus, Timothy P. Hughes, Richard A. Larson, Albert Hoenekopp, Neil J. Gallagher, Richard Yu, Rick E. Blakesley, Dong-Wook Kim, Hagop M. Kantarjian
Journal: Blood (2011)
133. Highly Efficient Homology-Driven Genome Editing in Human T Cells with Combined Zinc-Finger Nuclease mRNA and AAV6 Donor Delivery and Improved Efficiency Under Serum-Free Conditions
Authors: Jianbin Wang, Joshua J. DeClercq, Samuel B. Hayward, Patrick Wai-Lun Li, David A. Shivak, Gary Lee, Michael C. Holmes
Journal: Molecular Therapy (2016)

Immunotherapy using gene-modified T cells for adoptive cell transfer is a rapidly expanding field that is currently being tested in early- and late-stage clinical studies, with recent successes seen in the treatment of hematologic malignancies using T-cell receptor or chimeric antigen receptor (CAR)-retargeted T cells. Ex vivo T cell modification can potentially further enhance the activity and safety of these cells via the insertion of the desired transgenes at a specific pre-selected site such as a safe harbor locus. We describe the development of a highly efficient method to genome edit both primary human CD8 and CD4 T cells by homology-directed repair at a pre-defined site of the genome. We have identified AAV serotype 6 as a capsid variant with high tropism for both human CD8+ and CD4+ T cells. Two different homology donor templates were evaluated, representing both minor gene editing events (restriction site insertion) to mimic gene correction, or the more significant insertion of a larger gene cassette. By combining this AAV6 donor delivery method with the delivery of ZFNs as mRNA, we could 'gene correct' >40% of CCR5 or 55% of PPP1R12C (AAVS1) alleles in CD8+ T cells. We were also able to achieve targeted insertion of a GFP transgene cassette in >40% of CD8+ and CD4+ T cells at both the CCR5 and AAVS1 safe harbor loci, potentially providing a robust genome editing tool for T cell-based immunotherapy. In addition, we found that transducing T cells with AAV6 donor and ZFN encoding mRNA under serum-free conditions resulted in a marked improvement in HDR-mediated genome editing at significantly lower vector doses (2-log lower doses of AAV6 donor), representing an essential stride in the production of clinical-scale genome edited T cells for use in adoptive T cell therapy.
Abstract 1447: Functional genomics identifying a TIS1-HIF-NOTCH signaling orchestrating epithelial-mesenchymal transition for tumor invasion
Authors: Sen-Yung Hsieh
Journal: Cancer Research (2015)

Abstract Human hepatocellular carcinoma (HCC) is characterized by frequent local invasion and recurrence, which are strongly associated with poor overall survival of HCC patients. Epithelial-mesenchymal transition (EMT) is an initiating event driving tumour invasion and metastasis. However, the molecular mechanisms of EMT in HCC remains largely unknown. We have performed a human kinome/phosphatome RNAi screen to identify novel genes that are involved in invasion and metastasis of HCC cells using Hep3B, a low motile HCC cell line, and identified TIS1 (Tumor Invasion Suppressor 1) as a potential cell motility suppressor. Mechanistic studies revealed that TIS1 was a novel actin binding protein that sequestrated globular actins and prevented actin filament (F-actin) formation, thereby suppressing the formation of filopodia, lamillepodia and invadopodia. Silencing of TIS1 enhanced EMT and tumor cell migration and invasion. Notably, F-actin polymerization induced by TIS1 silencing led to activation of the NOTCH signalling via induction of HIF1A, which in turn further supports EMT for sustaining tumor invasion and metastasis. Clinically, TIS1 was frequently downregulated in many human cancers including HCC and strongly associated with tumor recurrence, local invasion, and poor prognosis. In conclusion, a novel TIS1-HIF/NOTCH signaling forms a positive feedback loop sustainingly driving mesenchymal transition of cancer cells for invasion and metastasis. This TIS1-mediated tumor invasion and metastasis signaling may serve as therapeutic targets for prevention and treatment of HCC invasion and metastasis. Citation Format: Sen-Yung Hsieh. Functional genomics identifying a TIS1-HIF-NOTCH signaling orchestrating epithelial-mesenchymal transition for tumor invasion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1447. doi:10.1158/1538-7445.AM2015-1447
Abstract 5427: Small molecule inhibitors of Musashi family of RNA-binding proteins
Authors: Lan Lan, Carl Appelman, Amber Smith, Jia Yu, Sarah Larsen, Rebecca Marquez, Xiaoqing Wu, Hao Liu, Anuradha Roy, Asokan Anbanandam, Ragul Gowthaman, John Karanicolas, Steven Rogers, Jeffrey Aubé, Roberto De Guzman, Kristi Neufeld, Liang Xu
Journal: Cancer Research (2015)

Abstract Musashi family of RNA-binding proteins are key regulators of several stem cell populations and are also involved in tumor proliferation and maintenance. There are two Musashi proteins in humans, Msi1 and Msi2, both of which regulate target mRNAs translation. We aim to identify small molecule inhibitors of Msi activity thus blocking the growth of a broad range of cancer cells. Known mRNA targets of Msi1 include Numb, APC and p21WAF-1, key regulators of Notch, Wnt signaling and cell cycle progression, respectively. Numb is also an mRNA target of Msi2. We confirmed the binding between numb and Msi1/Msi2 by RNA-IP. Using a fluorescence polarization assay, we screened small molecules from several chemical libraries for those that disrupt the binding of Msi1 to its consensus RNA binding site. Hits were validated by surface plasmon resonance, amplified luminescent proximity homogeneous assays and nuclear magnetic resonance. Among the small molecules that we screened, we found several hit compounds that disrupt the Msi1-numb RNA binding potently. Our study supports the hypothesis that Msi1 inhibition is a viable and effective anti-cancer strategy and we identified (-)-gossypol as the first small molecule inhibitor of Msi1 that inhibits tumor xenograft growth in vivo. Citation Format: Lan Lan, Carl Appelman, Amber Smith, Jia Yu, Sarah Larsen, Rebecca Marquez, Xiaoqing Wu, Hao Liu, Anuradha Roy, Asokan Anbanandam, Ragul Gowthaman, John Karanicolas, Steven Rogers, Jeffrey Aubé, Roberto De Guzman, Kristi Neufeld, Liang Xu. Small molecule inhibitors of Musashi family of RNA-binding proteins. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5427. doi:10.1158/1538-7445.AM2015-5427