bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A002: Discovery of bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine derivatives as orally bioavailable antitumor agents with anti-angiogenic and DNA cross-linking activities
Authors: Chen Tai-Lin , Jain Vicky , Patel Anilkumar S. , Lin Yi-Wen , Su Tsann-Long , Lee Te-Chang 
Published: March 2020

Abstract
Angiogenesis plays a critical role in sustaining the microenvironment, growth, and metastatic potential of a variety of tumors, such as lung cancer, colorectal cancer, and renal cancer. However, the rapid development of resistance to anti-angiogenesis agents has limited the clinical benefits. To improve the therapeutic efficacy, the designed dual functional inhibitors, composed of benzophthalazine (anti-angiogenesis moiety) and bis(hydroxymethyl)pyrrole (DNA interstrand crosslinking moiety), were synthesized. We first demonstrated that 1,2-bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazines displayed dual functions, inducing DNA crosslinking and inhibiting angiogenesis. By aid of DIVAA, we confirmed the in vivo anti-angiogenetic activity. They were cytotoxic to a panel of cancer cell lines, including leukemia, colorectal, renal, and lung cancer cells. Among them, small cell lung cancer (SCLC) cells were the most susceptible cells with the IC50 values ranged from subnanomolar to micromolar. Significantly, we observed tumor suppression by treatment of compound 8 in a given formulation at the dose of 20 mg/kg (10 times in 2 weeks) in SCLC H526, squamous lung cancer H520 and renal cancer 786-O xenograft models. In addition, orally admission of 60 mg/kg compound 8 daily for 14 days was also more potent than cisplatin in suppression of growth of SCLC H526 xenografts. Importantly, compound 8 at the dose given did not cause body weight lost. In summary, our results indicate that bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine hybrids are potent than anticancer agents against a wide spectrum of cancers. They deserve our further development.
Citation Format: Tai-Lin Chen, Vicky Jain, Anilkumar S. Patel, Yi-Wen Lin, Tsann-Long Su, Te-Chang Lee. Discovery of bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine derivatives as orally bioavailable antitumor agents with anti-angiogenic and DNA cross-linking activities [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A002. doi:10.1158/1535-7163.TARG-19-A002
Abstract A005: Clinicopathological factors associated with establishment of gastric cancer PDXs and cell lines
Authors: Kuwata Takeshi 
Published: March 2020

Abstract
Background: Patient-derived xenograft (PDX) models has been widely accepted as a suitable preclinical model. However, the number of PDX models as well as cell-lines from gastric cancer (GC) are limited. We started our DEF study project on May 2013 for establishing new GC PDX models and cell lines for accelerating the development of new therapeutics for GC. Methods: Two hundred and fifty (250) patients, including 233 patients underwent gastrectomy and 17 patients received cell-free and concentrated ascites reinfusion therapy (CART) in our hospitals, were enrolled. We subcutaneously engrafted 232 surgically resected gastric cancer tissues into immune-deficient NOG mice. Primary or PDX tumor tissues or ascites from CART patients were cultivated for establishing GC cell lines. Results and Discussion: From 233 surgically resected tumor tissues, we have successfully established 35 gastric cancer PDX models. PDX-establishment rate was 15.1%, and differentiated type adenocarcinomas (DAs) were more effectively established than poorly differentiated type adenocarcinomas (PDAs). The histology of PDX resembled their primary tumors, and the concordance of histological differentiation grade between primary tumors and PDXs was significant (28/35, p&lt;0.01). Twenty-three (23) GC cell lines have been established from surgically resected primary or subsequently transplanted PDX tissues. Another 2 GC lines were established by cultivating primary GC tissues directly. Among 25 GC cell lines, 24 lines could develop subcutaneous tumors (CDXs) in SCID mice. In contrast to PDX, the concordance of histological differentiation grade between primary tumors and CDXs was not significant. In addition, we have also established 7 GC cell lines from ascites from 17 patients received CART, and six of them could develop CDXs. All of the CDXs from CART cases showed PD histology. As the results, we have established both PDX and Cell lines simultaneously from 21 patients, which allowed us to invest a direct histological and molecular comparison between primary, PDX, and CDX tumors. We would also like to discuss about lymphoproliferative lesions, most of which showed proliferation of B cell with various cytological atypia, encountered during the PDX establishment process.
Citation Format: Takeshi Kuwata. Clinicopathological factors associated with establishment of gastric cancer PDXs and cell lines [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A005. doi:10.1158/1535-7163.TARG-19-A005
Abstract A007: A Rag2/Il2rg double-knockout rat supports engraftment of human immune system for immunotherapy-based cancer efficacy studies
Authors: Noto Fallon K , Adedeji Bisoye Towobola , Agarwal Yash , Beatty Cole , Ho Sara , Das Antu , Salunke Rajeev , Bility Moses , Jamling Tseten Yeshi 
Published: March 2020

Abstract
Immune humanized mice have been valuable in the development of novel cancer immunotherapies and have demonstrated stronger efficacy when combined with standard of care chemotherapy. An immune humanized rat could provide several advantages over the currently available humanized mouse models, including supporting the growth of larger tumors for serial fine needle biopsies to assess immune infiltration and serial blood draws for assessing human immune development and tumor biomarkers in real-time throughout an efficacy study. We developed a novel autologous human skin and immune cells-humanized rat model by co-engrafting full-thickness human-fetal skin and autologous fetal lymphoid organoids under the kidney capsule along with intravenous injection of autologous fetal-liver derived hematopoietic stem cells, thus termed, human skin-immune system humanized rat model (hSIS-humanized rat). hSIS-humanized rat support development of adult-like, full-thickness human skin and human lymphoid organoids along with human immune cells. Methicillin-resistant Staphylococcus aureus inoculation in the human skin results in infection and skin pathology, thus recapitulating clinical outcomes. This model will enable in vivo mechanistic studies for development and evaluation of novel therapeutics for skin infectious disease and may also provide a model for establishing skin grafts of patient-derived melanoma tumors to investigate melanoma metastasis and response to therapies. In addition, engrafting the rat with human lymphoid organs and human immune cells may provide a similar platform to the BLT mouse for immunotherapy studies. Finally, we have demonstrated humanization of the rat immune system using human PBMCs. Human CD45+, CD3+, and CD20+ cells can be found in the peripheral blood, spleen, and bone marrow of engrafted rats. These immune humanized rat models may be beneficial for evaluating immunotherapies in human cancer models, including assessment of immune cell infiltration through fine needle biopsies.
Citation Format: Fallon K Noto, Bisoye Towobola Adedeji, Yash Agarwal, Cole Beatty, Sara Ho, Antu Das, Rajeev Salunke, Moses Bility, Tseten Yeshi Jamling. A Rag2/Il2rg double-knockout rat supports engraftment of human immune system for immunotherapy-based cancer efficacy studies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A007. doi:10.1158/1535-7163.TARG-19-A007
Abstract A014: Gastric cancer PDX models for predictive preclinical studies: Establishment, drug sensitivity, and genomic characterization
Authors: Becker Michael , Brzezicha Bernadette , Conrad Theresia , Rolff Jana , Linnebacher Michael , Treese Christoph , Rau Beate , Walther Wolfgang , Hoffmann Jens 
Published: March 2020

Abstract
Gastric cancer is a common malignant disease representing the fifth common cancer worldwide. Its prognosis is determined by the stage and localization (distal vs. proximal), making gastric cancer the third most lethal cancer type. In early and localized stages, the therapeutic aim is curative, in metastatic stages however, palliative treatment is the only option. Despite some progress in the last 10 years, mortality for late stage gastric cancer is still high due to late diagnosis of the disease. Therefore, we have established patient-derived xenograft models (PDX) of gastric cancer to determine their potential as a preclinical tool to improve diagnosis and therapies of this cancer. For PDX generation, tumor tissue specimens were collected from the gastric cancers immediately after surgery and transplanted subcutaneously into immunodeficient mice. Each PDX was serially passaged for at least three times. Established PDX models were treated in monotherapy with standard of care drugs, inter alia, from the European FLOT standard (5-FU, leucovorine, oxaliplatin and docetaxel). PDX tumor tissue was collected for immunohistochemistry as well as for next generation RNA sequencing and a comprehensive transcriptome analysis was performed. We established 7 new PDX models of gastric cancer and stably expanded them for further analyses. The histology of the primary tumor was preserved in the PDX model proven by histopathological evaluation. Treatment with standard of care drugs such as 5-FU, docetaxel, or oxaliplatin showed an individual response towards these drugs. The mutational and gene expression landscape of the PDX models resembles the pattern known from public gastric cancer data sets. In conclusion, the newly established gastric cancer PDX panel represents a tool for preclinical analyses of molecular mechanisms of drug sensitivity and resistance. They further provide a clinically relevant platform to identify new biomarkers and to develop novel therapies.
Citation Format: Michael Becker, Bernadette Brzezicha, Theresia Conrad, Jana Rolff, Michael Linnebacher, Christoph Treese, Beate Rau, Wolfgang Walther, Jens Hoffmann. Gastric cancer PDX models for predictive preclinical studies: Establishment, drug sensitivity, and genomic characterization [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A014. doi:10.1158/1535-7163.TARG-19-A014
Abstract A026: An automated biomarker discovery platform based on in vitro pharmacology raw data
Authors: Xue Jia , Li Henry QX , Guo Sheng 
Published: March 2020

Abstract
In vitro pharmacology studies using cultures of biological models, such as cancer cell lines or lately organoids in the oncology field, are commonly used to assess drug efficacy. The baseline genetic or epigenetic features, including those reflective of the original patient tissue, can be characterized by genomic profiling of the respective models, and correlated to the efficacy observed during pharmacology studies to discover potential predictive biomarkers. On the other hand, the changes of these features following specific treatment (pharmacodynamic changes) can be used to explore the drug mechanism of action (MOA) or potential drug targets. Discovery and/or validation of relevant biomarkers using these in vitro preclinical pharmacology studies are obviously critical in drug discovery/development. Although important, the biomarker discovery and validation process can be complex and labor intensive, and currently there are few robust tools that can be used readily to take on the task of automated computation discovery. To this end, we have established an automated biomarker discovery platform for in vitro preclinical pharmacology studies by implementing a variety of machine learning algorithms and statistical methods, combining them with Shiny package in R, an integrated suite of software facilities for data manipulation, calculation and graphical display. This platform is user-friendly and efficiently manages raw data uploads, data conversions, drug efficacy overview, biomarker discovery analysis as well as data report generation. In conclusion, our platform provides a new solution for precision biomarker discovery in preclinical, especially immune-oncology studies.
Citation Format: Jia Xue, Henry QX Li, Sheng Guo. An automated biomarker discovery platform based on in vitro pharmacology raw data [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A026. doi:10.1158/1535-7163.TARG-19-A026
Abstract A034: The use of biomarkers and ctDNA in a phase 1 trial of ARQ 751
Authors: Pant Shubham , Lamar Maria , Kazakin Julia , Savage Ronald , Schwartz Brian , hall terence 
Published: March 2020

Abstract
Background: AKT, a critical node in the PI3K/AKT/mTOR pathway, is one of the most frequently activated protein kinases in human cancers. ARQ 751 is a potent and highly selective pan-AKT inhibitor against AKT1, AKT2, and AKT3, and is currently in a phase 1b clinical trial as a single agent, or combination with paclitaxel or fluvestrant. Inhibition of the PI3K/AKT pathway is known to cause increases in serum glucose and insulin in patients. Recent advances in next generation sequencing technologies are providing physicians and researchers with access to tumor genomic data, including circulating tumor DNA (ctDNA), to support and evaluate treatment strategies. Methods: Samples were collected for pharmacokinetic, pharmacodynamic, and genetic analysis. PK samples were collected on Days 1 and 22 to generate PK profiles. Samples were analyzed, and PK parameters generated, including Cmax, AUC, and t1/2 (where possible). Biomarkers evaluated for target engagement were serum glucose and insulin. Finally, whole blood was collected and mutational status of ctDNA was analyzed using Guardant360. Results: The Recommended Phase 2 Dose (RP2D) of ARQ 751 was determined to be 75 mg QD, with a mean Cmax of 263 ng/mL and an AUClast 2240 h*ng/mL on Day 22. Changes in both serum insulin and glucose were observed, and these increases correlated with ARQ 751 exposure. In patients with detectable levels of ctDNA (matching tumor); 6 (1PR, 4SD, 1PD) showed a decrease between Cycle 1, Day 1 and Cycle, 2 Day 1, and 3 showed an increase (1PR, 1SD, 1 PD). Conclusions: Preliminary PK, PD, and ctDNA data support the selection of 75 mg QD as the RP2D for ARQ 751. ARQ 751 plasma levels at this dose produced increases in both serum insulin and glucose, confirming target engagement. Additionally, an evaluation of a limited set of pre and post treatment ctDNA data provides interesting new insights on patient’s responses to therapy. Additional data to be presented at the meeting.
Citation Format: Shubham Pant, Maria Lamar, Julia Kazakin, Ronald Savage, Brian Schwartz, terence hall. The use of biomarkers and ctDNA in a phase 1 trial of ARQ 751 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A034. doi:10.1158/1535-7163.TARG-19-A034
Abstract A097: Tubulysin ADC payloads: An antimitotic drug class that retains activity in multidrug resistant models
Authors: Burke Patrick J , Hamilton Joseph Z , Pires Thomas A , Emmerton Kim K , Senter Peter D , Jeffrey Scott C 
Published: March 2020

Abstract
As antibody-drug conjugates (ADCs) find increasing clinical application, treatment-related resistance mechanisms may eventually impact efficacy. One resistance mechanism that emerges following prolonged exposure to auristatin-based ADCs such as brentuximab vedotin and polatuzumab vedotin involves upregulation of efflux pumps that confer the multidrug resistance positive (MDR+) phenotype. New payload technologies that retain activity in this context may be important for next-generation anti-tubulin ADCs. The tubulysins are a potent class of tubulin binders consisting of natural products and designed analogues which have become a compelling cytotoxic payload for drug targeting applications. This is due in large part to their high cytotoxic potency on cancer cells, including those that express MDR-conferring transporters. Recently, we developed the quaternary ammonium linker system to conjugate tertiary amine-containing payloads and applied it to the tubulysins. In this work, β-glucuronidase-cleavable quaternary ammonium linkers of tubulysin M were evaluated as ADC payloads for activity in MDR+ models. The resulting conjugates displayed high potency in multiple MDR+ models at well-tolerated doses, including those resistant to MMAE-based ADCs. In addition to potency in resistant models, the tubulysin conjugates also retained bystander activity - a property in common with vedotin-based conjugates and important for indications characterized by heterogeneous antigen expression. Thus, the glucuronide-tubulysin M linker could enable future ADC programs designed for the treatment of resistant tumors due to emergence of MDR transporters.
Citation Format: Patrick J Burke, Joseph Z Hamilton, Thomas A Pires, Kim K Emmerton, Peter D Senter, Scott C Jeffrey. Tubulysin ADC payloads: An antimitotic drug class that retains activity in multidrug resistant models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A097. doi:10.1158/1535-7163.TARG-19-A097
Abstract A112: Drug discovery efforts on the RNA protein methyltransferase METTL3/METTL14
Authors: Boriack-Sjodin P. Ann , Gardino Alexandra K. , Wynn Thomas A. , Buker Shane M. , Laidlaw Monique , Sickmier E. Allen , Hodous Brian L. , Case April W. , Greene-Colozzi April E. , Copeland Robert A. , Ribich Scott 
Published: March 2020

Abstract
A variety of covalent modifications of and structural changes to RNA have been identified and demonstrated to affect RNA processing, stability and translation. The enzymes that catalyze these changes, RNA modifying proteins or RMPs, represent a large class of novel targets for oncology and other disease indications that can be targeted with small molecule inhibitors. Methylation of adenosine at the N6 position (m6A) in mRNA is currently the most well-studied covalent RNA modification and is catalyzed by the RNA methyltransferase enzyme complex METTL3/METTL14. Once generated, m6A can modulate mRNA splicing, export, localization, degradation and translation and is implicated in AML and multiple solid tumor indications Although potent and selective inhibitors exist for several members of the Type I S-adenosylmethionine (SAM)-dependent methyltransferase family, no inhibitors have been published for METTL3/METTL14 to date. Accent Therapeutics has prioritized drug discovery efforts on METTL3/METTL14 and potent and selective inhibitors have been identified. Enzymatic assays using multiple methodologies have been developed to facilitate inhibitor identification and characterize mechanism of inhibition for compounds; select assays are capable of measuring compounds in the picomolar range of enzyme activity. Biophysical tools have been established to validate compound binding and measure inhibitor residence time. Cellular assays that measure m6A depletion in mRNA show good correlation with biochemical assay results. Anti-proliferative activity is seen for potent compounds.
Citation Format: P. Ann Boriack-Sjodin, Alexandra K. Gardino, Thomas A. Wynn, Shane M. Buker, Monique Laidlaw, E. Allen Sickmier, Brian L. Hodous, April W. Case, April E. Greene-Colozzi, Robert A. Copeland, Scott Ribich. Drug discovery efforts on the RNA protein methyltransferase METTL3/METTL14 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A112. doi:10.1158/1535-7163.TARG-19-A112
Abstract A122: Molecular barcoding and single cell approaches to investigate drug tolerance in EGFRmut NSCLC
Authors: Cotton Jennifer L. , KrishnamurthyRadhakrishna Viveksagar , Chen Julie , Piquet Michelle , Wagner Joel , Boulay Gaylor , Sprouffske Kathleen , Song Youngchul , Li Xiaoyan , Schumacher Katja , Thierry Raphael , Kirkpatrick Nathaniel D. , Ruddy David A. , Korn Joshua , Morris Erick J. , Hammerman Peter S. , Engelman Jeffrey A. , Niederst Matthew J. 
Published: March 2020

Abstract
Patients with non-small cell lung cancer (NSCLC) that is driven by an activating mutation in the epidermal growth factor receptor (EGFR) are routinely treated with tyrosine kinase inhibitors (TKI) to specifically target the activated EGFR signaling pathway. EGFR-mutant NSCLC tumors initially respond well to EGFR inhibitors, however a subset of drug-tolerant persister cells remain at minimal residual disease (MRD) and represent a cell reservoir from which acquired genetic mutations, such as EGFRT790M or MET amplification, can emerge to render the tumor fully drug-resistant. Prior to the emergence of genetic mutations, little is known about how drug-tolerant persister cells are able to survive EGFR targeted therapy at MRD. To better understand this cell population, we investigated drug-tolerance using single cell cloning and scRNAseq in NSCLC cell lines. Using ClonTracer barcoding, we found that the same barcodes emerged after EGFR-inhibitor treatment across multiple replicates, indicating that drug-tolerance is both pre-defined and stable over many generations. Within each individual cell line, we observed multiple distinct heterogeneous subpopulations of drug-tolerant persister cells with unique gene expression signatures and proliferation rates. Additionally, we observed evidence of putative mechanisms of drug tolerance that were shared by persister cells across cells lines and used a drug combination treatment approach to target these distinct subpopulations of drug-tolerant persister cells. Taken together, our findings provide evidence that drug-tolerant persister cell subpopulations are both predefined and heterogeneous, as well as suggesting that drug-combination treatment approaches in the clinic would be more effective at targeting multiple persister cell survival mechanisms.
Citation Format: Jennifer L. Cotton, Viveksagar KrishnamurthyRadhakrishna, Julie Chen, Michelle Piquet, Joel Wagner, Gaylor Boulay, Kathleen Sprouffske, Youngchul Song, Xiaoyan Li, Katja Schumacher, Raphael Thierry, Nathaniel D. Kirkpatrick, David A. Ruddy, Joshua Korn, Erick J. Morris, Peter S. Hammerman, Jeffrey A. Engelman, Matthew J. Niederst. Molecular barcoding and single cell approaches to investigate drug tolerance in EGFRmut NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A122. doi:10.1158/1535-7163.TARG-19-A122