bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2856: An intelligent boosting to amplify signal with isobaric labeling (iBASIL) strategy for precise quantitative single-cell proteomics analysis
Authors: Tsai Chia-Feng , Zhao Rui , Moore Ronald , Williams Sarah , Schultz Kendall , Piehowski Paul , Pasa-Tolic Ljiljana , Rodland Karin , Smith Richard , Shi Tujin , Zhu Ying , Zhu Ying , Liu Tao 
Published: September 2020

Abstract
Mass spectrometry (MS)-based proteomics has great potential for overcoming the limitations of antibody-based immunoassays for antibody-independent, comprehensive, and quantitative proteomic analysis of single cells. Indeed, recent advances in nanoscale sample preparation have enabled effective processing of single cells. In particular, the concept of using boosting/carrier channels in isobaric labeling to increase the sensitivity in MS detection (e.g., our recent boosting to amplify signal with isobaric labeling (BASIL) approach) has also been increasingly used for quantitative proteomic analysis of small-sized samples including single cells. However, the full potential of such boosting/carrier approaches has not been significantly explored, nor has the resulting quantitation quality been carefully evaluated. Herein, we have systematically evaluated and optimized the BASIL approach, originally developed for quantifying phosphorylation in small number of cells, for highly effective analysis of single cells. This improved, intelligent BASIL (iBASIL) approach enables comprehensive and quantitative single-cell proteomics analysis by carefully controlling the boosting-to-sample ratio and optimizing MS automatic gain control and ion injection time settings. Using standard LC-MS platforms, iBASIL enabled precise quantification of 800-1,200 proteins from single FACS-isolated cells (depending on the cell type). Moreover, coupling iBASIL to nanoscale fractionation enabled identification of &gt;3,000 proteins and reliable quantification of &gt;2,000 proteins while readily separating single cells from 3 different acute myeloid leukemia cell lines. We believe iBASIL has broad utility for comprehensive and precise quantitative single-cell proteomics for systems biology and biomedical research, as well as for comprehensive proteomic analysis of size-limited clinical specimens that cannot be readily accessed by regular proteomics platforms. It also has the potential to be adapted for phosphoproteome analysis of as few as 100 cells.
Citation Format: Chia-Feng Tsai, Rui Zhao, Ronald Moore, Sarah Williams, Kendall Schultz, Paul Piehowski, Ljiljana Pasa-Tolic, Karin Rodland, Richard Smith, Tujin Shi, Ying Zhu, Ying Zhu, Tao Liu. An intelligent boosting to amplify signal with isobaric labeling (iBASIL) strategy for precise quantitative single-cell proteomics analysis [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 2856.
Abstract 2885: Discovery of a tripeptide-based camptothecin drug-linker for antibody-drug conjugates with potent antitumor activity and a broad therapeutic window
Authors: Lyski Ryan , Bou Lauren , Zaval Margo , Emmerton Kim , Okeley Nicole , Simmons Jessica , Zapata Francisco , Ortiz David , McKinney Erica , Meyer David , Ryan Maureen , Senter Peter , Jeffrey Scott 
Published: September 2020

Abstract
In efforts to bring forward antibody-drug conjugate (ADC) technologies that complement vedotin and enable new clinical-stage ADCs, we have investigated compounds that interact with topoisomerase 1, an enzyme involved in the unwinding of DNA. In connection with this, we developed a highly active and well-tolerated camptothecin drug-linker technology, in which the lead molecule consists of 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT) attached to a protease-cleavable valine-lysine-glycine (VKG) tripeptide linker unit. A hydrophilic and discrete polyethylene glycol unit was included to improve the properties of the drug-linker, enabling high ADC drug-loading, and reducing the propensity for aggregation. A VKG-AMDCPT ADC, with 8 drug-linkers/mAb (DAR8), displayed a pharmacokinetic profile coincident with parental unconjugated antibody, with a high degree of stability against retro-Michael reaction deconjugation. ADCs based on the VKG-AMDCPT were broadly active against cancer cells in vitro, and in mouse xenograft models, giving tumor regressions and complete responses with a single ≤3 mg/kg dose. These included both solid and hematologic tumor models, and models of bystander killing activity and multidrug resistance. A non-binding DAR8 ADC was well-tolerated in rats at 60 mg/kg, q7dx4. The VKG-AMDCPT drug-linker can be prepared from available materials in eight high-yielding steps, and this drug-linker is being employed in the anti-CD30 ADC, SGN-CD30C; an investigational new drug application is planned for 2020.
Citation Format: Ryan Lyski, Lauren Bou, Margo Zaval, Kim Emmerton, Nicole Okeley, Jessica Simmons, Francisco Zapata, David Ortiz, Erica McKinney, David Meyer, Maureen Ryan, Peter Senter, Scott Jeffrey. Discovery of a tripeptide-based camptothecin drug-linker for antibody-drug conjugates with potent antitumor activity and a broad therapeutic window [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 2885.
Abstract 2895: Characterization of payload release from a novel camptothecin drug-linker
Authors: Cochran Julia H. , Farr Lauren , Lyski Ryan , Senter Peter D. , Jeffrey Scott C. , Hengel Shawna M. , Okeley Nicole M. 
Published: September 2020

Abstract
Camptothecins (CPT) are an important class of molecules that have been employed in cancer therapy for the past 20 years. These molecules interact with the DNA-topoisomerase I complex leading to double-strand breaks and cell death. While these molecules are important cancer therapies, they also induce toxicities including diarrhea and myelosuppression. Antibody-drug conjugates (ADCs) have emerged as a method to help mitigate small molecule toxicities by targeting them to tumors via conjugation to tumor-specific antibodies. Recently, encouraging clinical results have been observed with ADCs bearing CPT payloads, demonstrating a potential new utility for this class. The linker that is used to conjugate a payload to an ADC influences its activity, by controlling the identity of the molecular species that can be released, as well as efficiency of drug release. When employed as an ADC, maleimidopropionyl-PEG7-valine-lysine-glycine-7-aminomethyl-10,11-methylenedioxycamptothecin (VKG-AMDCPT), a novel, highly active and enzyme-cleavable tripeptide CPT drug-linker, releases two CPT payloads in cancer cells, as demonstrated both in vitro and in vivo. Using tandem mass spectrometry (LC-MS/MS), the two CPTs have been identified as 7-amino methyl 10,11-methylenedioxy CPT (AMDCPT) and the corresponding glycine adduct of AMDCPT (G-AMDCPT). We have characterized the efficiency of drug release and intracellular retention of the small molecules released from VKG-AMDCPT-conjugated ADCs. This was accomplished through quantification of each species released in vitro and in vivo using multiple cancer cell lines and xenografts. We report here characterization of the biochemical, cellular and bystander killing potencies of each released drug species to further understand their contributions to ADC activity.
Citation Format: Julia H. Cochran, Lauren Farr, Ryan Lyski, Peter D. Senter, Scott C. Jeffrey, Shawna M. Hengel, Nicole M. Okeley. Characterization of payload release from a novel camptothecin drug-linker [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 2895.
Abstract 2932: CD59 facilitates tumor progression through activating TGF-β/Smad signaling pathway in hepatocellular carcinoma
Authors: Lan Tian , Wu Hong 
Published: September 2020

Abstract
Little success has been achieved in the exploitation of effective interventions against hepatocellular carcinoma (HCC) pathogenesis. To determine the crucial regulators in this process, CD59 was identified from the lung metastasis screening mice models that we previously reported. It is well known that CD59, belonging to membrane-bound complement regulatory proteins (mCRPs), acts as a suppressor of the formation of the membrane attack complex to enable tumor cells to escape from complement surveillance. Apart from that, our work identified CD59 as a potential oncogenic driver in hepatocarcinogenesis and metastasis. Specifically, CD59 was considerably upregulated in HCC tissues. High expression of CD59 was associated with poor overall survival and disease-free survival. Functional studies demonstrated that CD59 knockdown inhibited proliferation, cell cycle and apoptosis resistance of HCC cells, impaired their tumorigenic and metastasis capacities in vitro and in vivo, whereas overexpression of CD59 exhibited opposite cell phenotypes. Mechanistically, CD59 competitively binds to aminoacyl tRNA synthetase complex interacting multifunctional protein 1 (AIMP1), resulting in the disassociation of AIMP1 from Smad-specific E3 ubiquitin protein ligase 2 (Smurf2) and the continuous interaction between Smurf2 and Smad7, thus accelerating the ubiquitin-mediated degradation of Smad7. By contrast, loss of CD59 promoted excessive Smad7 formation, leading to the abolishment of Smad2/3 phosphorylation and subsequent nuclear translocation, therefore inhibiting hepatocarcinogenesis and metastasis. Overall, our findings indicated that CD59 facilitated HCC pathogenesis via modulating TGF-β signaling, apart from disturbing the complement-dependent cytotoxicity. CD59 may be an effective prognostic biomarker and potential therapeutic target for HCC.
Citation Format: Tian Lan, Hong Wu. CD59 facilitates tumor progression through activating TGF-β/Smad signaling pathway in hepatocellular carcinoma [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 2932.
Abstract 3042: Anti-cancer efficacy of an anti-ErbB3 antibody, ISU104, against the cancers with NRG1-overexpression, NRG1-fusion, or oncogenic ErbB3 mutations
Authors: Hong Seung-Beom , Hong Mirim , Kim Tae-Eun , Kim Ju Yeon , Kim Jung Won , Cho Jeongin , Shin Bongseok , Bae Donggoo 
Published: September 2020

Abstract
ErbB3, a heterodimeric partner of EGFR or ErbB2, plays important roles in the survival and growth of cancer cells through activation of PI3K/AKT pathway. ErbB3 can be activated by NRG1 expressed either by cancer cells or adjacent mesenchymal cells, or NRG1-fusion proteins produced by genetic alterations in cancer cells. Oncogenic driver mutations in ErbB3 also induce its activation. Previously, we have demonstrated preclinical anti-cancer efficacy of a monoclonal anti-ErbB3 antibody, ISU104 as a monotherapy or in combination with anti-EGFR antibody in various preclinical models. Biomarker analysis of the models demonstrated that there is a significant positive correlation between tumor growth inhibition by ISU104 and NRG1 mRNA/pERBB3 protein expression levels. Based on this analysis, anti-cancer efficacy of ISU104 was further explored in cancer cells and cell line- or patient-derived xenograft cancer models with high NRG1 expression, NRG1-fusion or oncogenic ErbB3 mutations. ISU104 potently inhibited phosphorylation of ERBB3 and AKT, cell proliferation and tumor growth of such models. Potential impacts of other genetic alterations on the anti-cancer efficacy of ISU104 were also investigated. Overall, the presented data suggest that ISU104, an anti-ErbB3 agent in the early stage of clinical development, can be applied for the treatment of the solid tumors expressing high level of NRG1 or harboring genetic alterations such as NRG1-fusion or oncogenic ErbB3 mutations.
Citation Format: Seung-Beom Hong, Mirim Hong, Tae-Eun Kim, Ju Yeon Kim, Jung Won Kim, Jeongin Cho, Bongseok Shin, Donggoo Bae. Anti-cancer efficacy of an anti-ErbB3 antibody, ISU104, against the cancers with NRG1-overexpression, NRG1-fusion, or oncogenic ErbB3 mutations [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 3042.
Abstract 309: Mapping oncogenic signal transduction in PKA-driven cancers
Authors: Chan Gary Kwan Leung , Maisel Samantha M. , Hwang Y. Christina , Wolber Rebecca , Swaney Danielle L. , Bardeesy Nabeel , Gordan John D. 
Published: September 2020

Abstract
Protein Kinase A (PKA) is a major effector of cyclic-AMP (cAMP) signaling and has recently been appreciated to play a role in multiple malignancies. Mutations of its catalytic subunit (PRKACA) have been identified in a substantial proportion of adrenocortical tumors, and are also detected in a wide spectrum of tumor types in the TCGA dataset, although at a low frequency. A unique fusion protein of PRKACA and DNAJB1 is seen in the majority of fibrolamellar liver cancers (FLC), a rare malignancy of young adults, where it is suspected to be the primary oncogenic driver. However, the key effectors of oncogenic signaling in FLC and other PRKACA driven cancers remain unknown. To understand PKA's downstream targets, we generated genetic cell models with doxycycline-inducible PRKACA or its dominant negative counterpart, a mutant form of the PRKAR1A regulatory subunit. These cell models were then subjected to mass spectrometry for kinome profiling in order to detect kinases with significant altered activity following PKA modulation. This was integrated with small molecule inhibition and siRNA knockdown to identify PKA-regulated kinases that impact cell proliferation. Our analysis revealed activation of the aurora-family kinase AURKA, with preferential sensitivity to the confirmation-disrupting AURKA inhibitor (CD-AURKAi) CD532 compared to other AURKA inhibitors. CD-AURKAi not only selectively inhibit AURKA's kinase activity, but also disrupt its interaction with MYC-family transcription factors. These key oncogenic mediators are necessary to drive the proliferation of multiple tumor types, although they have not yet been connected with oncogenic PKA signaling. Our follow up quantitative PCR experiments confirm that CD-532 treatment results in reduced expression of MYC family members and their transcriptional targets. We next confirmed that MYC family members support the proliferation of PKA-driven cell models with live cell imaging. Finally, we have begun to investigate other kinases identified in our siRNA screen for potential effects on MYC, and have identified several potential combination partners to augment the activity of CD-532 and other CD-AURKAi. These data suggest that CD-AURKAi, either alone or in combination, have the potential to serve as therapeutic agents for PKA-driven cancers.
Citation Format: Gary Kwan Leung Chan, Samantha M. Maisel, Y. Christina Hwang, Rebecca Wolber, Danielle L. Swaney, Nabeel Bardeesy, John D. Gordan. Mapping oncogenic signal transduction in PKA-driven cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 309.
Abstract 3432: Zinc metallochaperones for mutant p53 reactivation in cancer therapeutics
Authors: Yu Xin , Na Bing , Zaman Saif , Withers Tracy , Gilleran John , Blayney Alan J. , Bencivenga Anthony F. , Blanden Adam R. , Liu Yue , Boothman David A. , Loh Stewart N. , Kimball S. David , Ganesan Shridar , Carpizo Darren R. 
Published: September 2020

Abstract
The p53 transcription factor functions as one of cancer's most potent tumor suppressors and is the most frequently mutated gene in human cancer. Restoration of wild type structure and function (so-called reactivation) of the high levels of the deficient mutant p53 protein with a small molecule is a highly sought after goal in anti-cancer drug development. We discovered a new class of small molecule zinc chelators named zinc metallochaperones (ZMCs) that reactivate zinc deficient mutant p53 through a novel mechanism by refolding p53 protein and inducing a p53 mediated apoptotic program. We identified the role of cellular zinc homeostasis as the OFF switch in ZMC pharmacodynamics indicating that a brief period of p53 mutant reactivation is sufficient for on-target efficacy. We conducted pre-clinical pharmacokinetic (PK), pharmacodymanic (PD) and efficacy studies in the murine pancreatic cancer (KPC) and BRCA1-deficient breast cancer models and found that ZMC1 and its new formulation of the drug in complex with zinc improved survival and inhibited tumor growth specifically for the zinc deficient allele. Using the BRCA1-deficient breast cancer model, we observed a highly synergistic effect of ZMC1 and the PARP inhibitor olaparib. Olaparib is now approved for the treatment of advanced BRCA1/2 mutant ovarian cancers, and recent clinical data also support its efficacy in BRCA1/2 mutant breast cancers. However acquired resistance to PARP inhibitors is inevitable in most advanced cancers. We investigated the ZMC therapeutic efficacy and found that the cell lines derived from olaparib resistant tumors are still sensitive to ZMC1 treatment. We are currently investigating the mechanism and testing the combination in vivo. In addition, we explored synergistic combinations of ZMC1 and other chemotherapy drugs based on its mechanism of action including ZMC1 with MDM2 antagonists and BCL2 antagonists. Overall, our findings indicate that the mutant p53 reactivational activity of ZMCs is governed by a unique ON/OFF switch mechanism that allows the compounds to be effective with a brief exposure to avoid the off target toxicities. The targeted and synergistic combinatorial treatments represent a significant departure from the traditional paradigm for developing a targeted molecular therapeutic in cancer.
Citation Format: Xin Yu, Bing Na, Saif Zaman, Tracy Withers, John Gilleran, Alan J. Blayney, Anthony F. Bencivenga, Adam R. Blanden, Yue Liu, David A. Boothman, Stewart N. Loh, S. David Kimball, Shridar Ganesan, Darren R. Carpizo. Zinc metallochaperones for mutant p53 reactivation in cancer therapeutics [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 3432.
Abstract 3466: Can grape powder supplemented diet prevent prostate cancer progression
Authors: Joshi Tanvi , Patel Ishani , Kumar Avinash , Donovan Virginia , Levenson Anait S. 
Published: September 2020

Abstract
Epidemiological and experimental studies suggest a correlation between diet, particularly fat consumption and the risk of developing prostate cancer (PCa). In previous studies, we reported that stilbenes, namely resveratrol and pterostilbene, restrained prostatic intraepithelial neoplasia (PIN) formation and reduced tumor development and progression in mice models of PCa with high expression of metastasis-associated protein 1 (MTA1), an epigenetic modifier involved in the regulation of prostate cancer progression and metastasis. In this report, we evaluated three major aspects: 1) whether altering diet [low fat diet (LFD) versus high fat diet (HFD)] affects PCa progression; 2) whether grape powder (GP) supplementation to the diets protects against PCa progression, and 3) whether MTA1 targeting is the main mechanism of action. We addressed these questions by utilizing the prostate-specific (PB-Cre4) Pten heterozygous transgenic mice (Pten+/f), which mimic slow-growing PCa progression in humans. Upon accumulating 56 mice of desired genotype, we randomized mice in two major groups and fed them ad libitum with either LFD or HFD. Each of these diets contained either 0% GP or 10% GP supplementation. The same groups were assigned for control wild-type (WT) mice (Pten+/f; Cre-). After 33 weeks on corresponding diets, mice were sacrificed and urogenital system was collected for histological and immunochemical analysis. In addition, protein and RNA was isolated from the prostate tissues for molecular analysis. Blood was also collected for cytokines evaluation and pharmacokinetic analysis. The results demonstrated the following beneficial effects of GP supplementation: LFD and HFD - fed Pten+/f mice showed added favorable histopathology (H&E), intact basal layer (SMA) and luminal cells (CK-8); significant reduction of the proliferative rate of prostate epithelial cells (Ki67); non-significant trend for reducing HFD-induced MTA1 expression in Pten+/f and WT mice; protective effects against “bad” genotype and HFD-induced activation of Akt pathway; attenuation of HFD-associated increase in AR levels in both Pten+/f and WT mice; reduction of HFD-provoked increased inflammation marker IL-1β levels; non-significant trend for reducing angiogenesis (CD31; VEGF-C) in Pten+/f mice; and trend towards decreasing inflammatory TGFβ1 expression in Pten+/f mice. Curious results were obtained concerning the effect of GP on apoptosis. There were no significant changes in body weight, food intake or fat intake in GP supplemented diets groups.
Citation Format: Tanvi Joshi, Ishani Patel, Avinash Kumar, Virginia Donovan, Anait S. Levenson. Can grape powder supplemented diet prevent prostate cancer progression [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 3466.