bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A092: Multiplexed measurement of DNA repair capacity for tumor heterogeneity
Authors: Hardie Lakotah , Richer Amanda , Hesselberth Jay 
Published: March 2020

Abstract
Purpose of Study: DNA damage has been shown to have a strong link to the origin and propagation of many cancers. Specific damages to different DNA repair pathways within the cell spell accumulations of DNA damaging events and alterations in normal biochemical activities of the cell. More recently, these biochemical differences have begun to be explored and have demonstrated potential evidence supporting a heterogeneous picture of tumor and cancer pathology. The goal of this project focused upon developing a cellular assay to measure the DNA repair capacities of cancer cells and to apply it at the level of an individual cell. Methods Used: Bulk Hap1 cellular lysate was prepared and incubated with the assay and repair activities were recovered from DNA substrates. Amplification and ILLUMINA sequencing was then used to detail repair capacities. Bioinformatic pipelines systematically compared differences in repair profiles across tested conditions in the optimization of the assay with ATP regeneration and chemotherapy pre-treated cells. Future direction will include the combination of a microfluidic platform for single cell analysis. Summary of Results: The use of a creatine phosphokinase (CPK) ATP regeneration system demonstrated increased capture across all repair pathways as compared to a control. Nucleotide Excision Repair (NER) and mismatch repair (MMR) saw significant increases in repair activities not previously seen without the regeneration system. Temozolomide pretreated cells demonstrated increased repair activities in Direct Reversal repair of methylated adducts as compared to Hydrogen Peroxide pretreated cells and positive controls. Conclusions: The addition of an ATP regeneration system significantly increased capture of repair events by increasing local concentrations of ATP to support cellular enzyme activities. Increases in repair activates were seen across all pathways tested, indicating reproducible results. DNA damaging pretreatments indicated predictable up-regulations in certain DNA repair pathways matching the type of DNA damage event generated.
Citation Format: Lakotah Hardie, Amanda Richer, Jay Hesselberth. Multiplexed measurement of DNA repair capacity for tumor heterogeneity [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 A092. doi:10.1158/1535-7163.TARG-19-A092
Abstract A108: Specific and traceless payload release from HER2-ADC containing LBG-linker prodrug by the action of lysosomal β-glucuronidase
Authors: Shin Dong Yeon , Jang Taeik , Song Ho Young , Kim Sung Min , Park Yun-Hee , Park Chang Sik , Oh Hwanhee , Baek Juyuel , Chae Jeiwook , Lee Chang-Sun 
Published: March 2020

Abstract
Many antibody-drug conjugates (ADCs) have actively been evaluated in clinical trials since Mylotarg was approved in 2001, but only 4 more have been approved by the FDA. The main reason for the poor results is yet to overcome worse risk-benefit than the expected from ADC approach. Controlled payload release specifically at cancer cells would significantly reduce systemic toxicity. Herein, we report that LBG000-linker can be selectively cleaved from ADC to release free toxins in a traceless manner by β-glucuronidase. Lysosomal β-glucuronidase is overexpressed in many cancer cell lines, and its enzymatic activity is much higher in acidic condition than neutral pH. As a model reaction, an LBG-linker-MMAE conjugate, LCB14-0302, was incubated with a β-glucuronidase in vitro resulting clean release of free MMAE while other lysosomal enzymes such as cathepsin B or heparanase did not generate the free toxin. We also confirmed that there was no free MMAE found when β-glucuronidase inhibitor, β-D-glucuronic acid, was treated. Also, lysosomal extract incubation with LCB14-0302 clearly demonstrated the traceless toxin release by β-glucuronidase regardless of other enzymatic disturbance. Therefore, these results strongly suggest that LBG-linker is highly stable and specific to β-glucuronidase among hundreds of enzymes in the lysosome.
Citation Format: Dong Yeon Shin, Taeik Jang, Ho Young Song, Sung Min Kim, Yun-Hee Park, Chang Sik Park, Hwanhee Oh, Juyuel Baek, Jeiwook Chae, Chang-Sun Lee. Specific and traceless payload release from HER2-ADC containing LBG-linker prodrug by the action of lysosomal β-glucuronidase [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 A108. doi:10.1158/1535-7163.TARG-19-A108
Abstract A109: Repurposing low dose of quinoline methanol derivatives as a novel treatment for pediatric glioblastoma
Authors: Teng Jian , Carvalho Litia , Tabet Elie , Tannous Bakhos 
Published: March 2020

Abstract
Both primary brain tumors and secondary brain metastases that start in another part of the body and spreads to the brain, such as lung, breast, melanoma, kidney, nasopharynx, and colon cancers have limited or no response to chemotherapy. Through repurposing drug screen using pediatric glioblastoma cells established from newly diagnosed and recurrent patients, we identified that FDA-approved compound mefloquine have significant cancer killing properties. A growing body of evidence suggests that this extensively used anti-malaria drug may cause adverse neurological effects after crossing the blood-brain barrier and accumulates in the brain at relatively high concentration. To the amelioration of this problem, an analog campaign was conducted in selecting compounds lacking penetration but maintaining the anti-malarial properties using mefloquine as the leading compound. We therefore thought to take advantage of this unique characteristic and use low dose of these compounds and target the infiltrative disease reservoir while avoiding the neurological side effects. While this program focuses on high anti-malaria potency, low neurotoxicity (against rat neurons), and low brain absorption, we are interested in high anti-malaria potency, low general toxicity, and high brain/tumor concentration. Among these compounds, we selected TQM due to its promising results in efficacy, potency, and selectivity in killing brain tumor cells at a much lower range compared to mefloquine based on our quantitative structure-activity relationship model. Studies suggested that this group of drugs induce cell apoptosis in host and parasites through increased production of reactive oxygen species (ROS). Even though for a long time ROS is believed to promote cell proliferation; however, brain cancer cells, due to their high basal metabolic rate, are more susceptible to ROS. Inducing an increased intracellular ROS levels in brain cancer cells may trigger cell death and destroy malignant cells, while sparing normal cells. Our preliminary results confirmed that mefloquine and its derivatives induce apoptosis through autophagy and ROS signaling in brain cancer cells at a much lower concentration, and these compounds reduces tumor growth and extends animal survival in mouse models. Our results pave the way for translation of those compounds to the clinic.
Citation Format: Jian Teng, Litia Carvalho, Elie Tabet, Bakhos Tannous. Repurposing low dose of quinoline methanol derivatives as a novel treatment for pediatric glioblastoma [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 A109. doi:10.1158/1535-7163.TARG-19-A109
Abstract A114: Quantitative mass spectrometry imaging: A game changer in the pharmaceutical industry
Authors: Ait-Belkacem Rima , Hochart Guillaume , Marini Joseph , Tomezyk Aurore , Mantefeul p , Jung B. , Bonnel David , Kenzie Don Mc , Stauber Jonathan 
Published: March 2020

Abstract
Developing a drug requires to demonstrate its efficacy in preclinical and clinical studies but also to characterize its pharmacokinetics properties. If Quantitative Whole-Body Autoradiography (QWBA) is still a gold standard to support the design of radiolabelled clinical studies, its lack of molecular specificity limits the understanding of the distribution of the drug and its metabolites, with no establishing of separate quantitative results for each target tissue of interest. On the contrary, the use of high resolution mass spectrometers such as FT-ICR MS allows a quantitative characterization of the metabolic profile of the drug at the tissue level in order to further understand its behaviour in the organism. A comparative analysis between QWBA and QMSI was applied as a complementary approach to follow chloroquine and one of its metabolites (desethyl-chloroquine) at different time-points after a single administration of a radiolabeled dose to Long-Evans male rats (30 mg/kg). 1H-Chloroquine and 1H-desethyl chloroquine were well detected by MALDI-FTICR in the eye including; the uveal tract, the vitreous humor, the lens and the Harderian gland. In the mid whole-body region, both compounds were also detected in various organs from the unique prepared T4h sections. Interestingly the two compounds were co-localized into the tissue sections and their distributions matched the zones obtained by QWBA. In QWBA additional regions containing the radiolabeled moiety could be clearly identified because of the high sensitivity of the technique. The advantage brought by MALDI QMSI was the ability to discriminate between parent drug 1H-choloroquine and its metabolite 1H-desethyl chloroquine so that each compound had its own distribution image and thus its own quantification data directly in one tissue section. The used labeled forms of both compounds during the matrix deposit allowed normalizing the data for each position targeted with the MALDI onto the section of interest and the calibration range of both 1H-choloroquine and 1H-desethyl chloroquine and quantifying each compound into the organs of interest with the ILC approach. Finally the QMSI was able to demonstrate the disappearance of the drug and its metabolite with time to better understand differential pharmacokinetics analysis demonstrating the additional input of the technology compared to QWBA.
Citation Format: Rima Ait-Belkacem, Guillaume Hochart, Joseph Marini, Aurore Tomezyk, p Mantefeul, B. Jung, David Bonnel, Don Mc Kenzie, Jonathan Stauber. Quantitative mass spectrometry imaging: A game changer in the pharmaceutical industry [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 A114. doi:10.1158/1535-7163.TARG-19-A114
Abstract A129: Vertical inhibition overcomes adaptive resistance to KRASG12C inhibition
Authors: Ryan Meagan B , Cruz Ferran Fece de la , Phat Sarah , Myers David T , Shahzade Heather A , Hong Catriona B , Corcoran Ryan B 
Published: March 2020

Abstract
The three RAS genes are the most commonly mutated oncogenes in cancer and have long been considered an “undruggable” target. Alterations in KRAS occur at the highest frequency, with G12D, G12V, and G12C mutations being the most common. The recent development of novel covalent inhibitors selective for the KRASG12C mutation offers the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS-MAPK pathway in have been hampered by adaptive feedback, which drives pathway reactivation and resistance. We find evidence of rapid adaptive RAS-MAPK pathway feedback reactivation following KRASG12C inhibition in the majority of KRASG12C models, including lung, colon, and pancreatic lines. Reactivation of the RAS-MAPK pathway correlates with activation of multiple upstream RTKs and subsequent increase of wild-type RAS activity. We find that co-inhibition of SHP2, a common node downstream of RTKs, or co-inhibition of individual RTKs such as EGFR or FGFR enhances the efficacy of KRASG12C inhibition both in vitro and in vivo by overcoming adaptive reactivation of the RAS-MAPK pathway. Notably, only the combination of KRASG12C and SHP2 inhibitor treatment displays tumor regressions in vivo in multiple models when compared to either inhibitor alone. We also see evidence that combining KRASG12C inhibitors with MEK or ERK inhibitors as an additional potential vertical inhibition strategy in KRASG12C models. We propose a vertical inhibition strategy anchored with KRASG12C inhibitors with either RTK or SHP2 inhibitors as a potential strategy for the treatment of KRASG12C mutant tumors.
Citation Format: Meagan B Ryan, Ferran Fece de la Cruz, Sarah Phat, David T Myers, Heather A Shahzade, Catriona B Hong, Ryan B Corcoran. Vertical inhibition overcomes adaptive resistance to KRASG12C inhibition [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 A129. doi:10.1158/1535-7163.TARG-19-A129
Abstract A130: Cannabidiol overcomes oxaliplatin resistance by enhancing autophagy through reduction NOS3 and SOD2
Authors: Kim Bu Gyeom , Jeong Soyeon , Kim Dae Yeong , Kim Bo Ram , Kim Jung Lim , Park Seong Hye , Na Yoo Jin , Jo Min Jee , Yun Hye Kyeong , Jeong Yoon A , Lee Sun Il , Jeong Yoon A , Kim Hong Jun , Kim Han Do , Kim Dae Hyun , Lee Dae-Hee , Oh Sang Cheul 
Published: March 2020

Abstract
Although oxaliplatin is an effective chemotherapeutic drug for colorectal cancer (CRC) treatment, patients often develop resistance to it. Therefore, a new strategy for CRC treatment is needed. The purpose of this study was to determine the effect of cannabidiol (CBD), one of the components of the cannabis plant, in overcoming oxaliplatin resistance in CRC cells. We established oxaliplatin-resistant cell lines, DLD-1 R and colo205 R, in CRC DLD-1 and colo205 cells. Autophagic cell death was induced when oxaliplatin-resistant cells were treated with both oxaliplatin and CBD. Additionally, phosphorylation of nitric oxide synthase 3 (NOS3) was increased in oxaliplatin-resistant cells compared to that in parent cells. Combined treatment with oxaliplatin and CBD reduced phospho-NOS3 levels and NO production and resulted in the production of reactive oxygen species (ROS) by reducing the levels of superoxide dismutase 2, an antioxidant present in the mitochondria, causing mitochondrial dysfunction. Taken together, these results suggest that elevated phosphorylation of NOS3 is essential for oxaliplatin resistance. The combination of oxaliplatin and CBD decreased NOS3 phosphorylation, which resulted in autophagy, by inducing the overproduction of ROS through mitochondrial dysfunction, thus overcoming oxaliplatin resistance.
Citation Format: Bu Gyeom Kim, Soyeon Jeong, Dae Yeong Kim, Bo Ram Kim, Jung Lim Kim, Seong Hye Park, Yoo Jin Na, Min Jee Jo, Hye Kyeong Yun, Yoon A Jeong, Sun Il Lee, Yoon A Jeong, Hong Jun Kim, Han Do Kim, Dae Hyun Kim, Dae-Hee Lee, Sang Cheul Oh. Cannabidiol overcomes oxaliplatin resistance by enhancing autophagy through reduction NOS3 and SOD2 [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 A130. doi:10.1158/1535-7163.TARG-19-A130
Abstract B093: 50 gene breast cancer (BC) RNA subtype classifier and colorectal cancer (CRC) CMS subtype classifier applied to 90 prostate cancer (PC) patients reveals distinct subtype differences
Authors: Adashek Jacob J , Pal Sumanta K , Veerapaneni Saihitha , Obeid Elias , Szeto Christopher W , Reddy Sandeep K , Nussenzveig Roberto , Agarwal Neeraj 
Published: March 2020

Abstract
Background: BC and CRC are heterogeneous diseases with several distinct disease subtypes. A 50-gene qPCR assay (PAM50) identifies 5 intrinsic biological subtypes: luminal A, luminal B, HER2-enriched, basal-like, and normal-like in breast cancer. Consensus molecular subtype in CRC (CMS) identifies 4 subtypes: CMS1-4. PC can be classified by specific genomic rearrangements, such as the TMPRSS2-ERG fusion occur or whether specific mutations such as SPOP and FOXA1 or germline BRCA is present, yet 25% of PC remains difficult to classify based on molecular drivers. We used comprehensive genomic and transcriptomic data to determine the association of somatic and germline mutations in molecular PC subtypes using the CMS and 50-gene breast cancer classifiers. Methods: Retrospective analysis on Whole exome (WES) DNA tumor and paired germline and matched deep whole transcriptomic sequencing (RNA-Seq) (∼200x106reads per tumor) data from NantHealth was performed. BC Intrinsic Subtypes and CMS sorting based on RNAseq assay was used to classify PC into 5 BC subtypes and CMS 1-4. Results: 90 PC patients were classifiable using RNAseq and WES DNA. BC subtype distribution was 64.4% Luminal A, 31.1% Luminal B, 2.2% HER2-enriched, 2.2% normal-like, and 0 classified as Basal-like. The CMS subtype distribution was 83.3% CMS4, 15.6% CM1, 1.1% CMS3, and 0 CMS2. Overlap comparison revealed that almost all LumA are CMS4 (56/58, 96.6%) and CMS1 are LumB (11/14, 78.6%). Analysis of germline DDR mutations in LumB compared to LumA showed LumB has significantly more DDR mutants than LumA (OR 2.68, p = 0.035 one-sided Fishers exact test). Conclusions: PC molecularly profiled using 50-gene and CMS classification we found LumA subtype as the predominant subgroup characterized by low TMB and high CMS4. LumB was characterized as higher TMB and greater CMS1 suggesting potential immunotherapy eligibility in this subtype. The presence of potentially pathogenic germline variants in DDR genes is associated with subsequent somatic increase in TMB, however, somatic expression subtyping (by BC or CRC types) is a stronger indicator of TMB than germline pPV in DDR genes.
Citation Format: Jacob J Adashek, Sumanta K Pal, Saihitha Veerapaneni, Elias Obeid, Christopher W Szeto, Sandeep K Reddy, Roberto Nussenzveig, Neeraj Agarwal. 50 gene breast cancer (BC) RNA subtype classifier and colorectal cancer (CRC) CMS subtype classifier applied to 90 prostate cancer (PC) patients reveals distinct subtype differences [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 B093. doi:10.1158/1535-7163.TARG-19-B093
Abstract B098: A novel monoclonal antibody for a cancer stem cell marker CD133 exerts antitumor and antimetastasis activities for colon cancers
Authors: Kato Yukinari , Ohishi Tomokazu , Kawada Manabu , Kaneko Mika K 
Published: March 2020

Abstract
Background: Cancer stem cells contribute to tumorigenesis, chemoresistance, and metastasis. CD133 is a pentaspan membrane glycoprotein, and is used for the isolation of stem-like cells from cancer tissues. However, specific and sensitive monoclonal antibodies (mAbs), which are useful in every application, such flow cytometry, Western blot, and immunohistochemical analyses have not been established. Furthermore, antibody drugs targeting CD133 have not been established. Purpose: We aimed to develop novel anti-CD133 mAbs, which not only are useful for all applications but also exerts anti-tumor and anti-metastasis activities. Methods: We employed Cell-Based Immunization and Screening (CBIS) method for the development of anti-CD133 mAbs. The full-length CD133-overexpressed LN229 glioblastoma cells were immunized into mice, and flow cytometry was used for the first screening. Western blot and immunohistochemical screenings were further performed. Human colon cancer cell lines were used for examining the anti-tumor and the anti-metastasis activities of anti-CD133 mAbs. Results: We established a novel anti-CD133 mAb, CMab-43 (IgG2a, kappa), which demonstrated a sensitive and specific reaction against colon cancer cells in flow cytometry, Western blot, and immunohistochemical analyses. CMab-43 showed cancer-specific staining patterns in colon cancer tissues. Furthermore, CMab-43 significantly reduced tumor development of colon cancer cell xenografts, and inhibited experimental metastasis of colon cancer cells. Conclusion: CMab-43, which was developed by CBIS method, is useful for many applications and exerts anti-tumor or anti-metastasis activities. CMab-43 could be advantageous for antibody therapy against CD133-expressing colon cancers.
Citation Format: Yukinari Kato, Tomokazu Ohishi, Manabu Kawada, Mika K Kaneko. A novel monoclonal antibody for a cancer stem cell marker CD133 exerts antitumor and antimetastasis activities for colon cancers [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 B098. doi:10.1158/1535-7163.TARG-19-B098
Abstract B128: K-11706 exerts potent anti-cancer activity via suppression of GATA2/AR/cMyc signaling axis in castration resistant prostate cancer
Authors: Kaochar Salma , Rajapakshe Kimal , Robertson Matthew J. , Song Yongcheng , Cristian Coarfa , Mitsiades Nicholas 
Published: March 2020

Abstract
Despite recent therapeutic advances, prostate adenocarcinoma (PC) progression to lethal castration-resistant PC (CRPC) remains a major clinical problem, creating an unmet need for innovative treatment approaches. Targeted therapies for PC have mostly focused on the androgen receptor (AR) axis, while several other PC drivers, such as GATA2, c-Myc, FOXM1, CENPF, and EZH2, remain undruggable in the clinic so far. We and others have previously reported several critical functions of GATA2 in AR signaling in PC: GATA2 induces AR expression; serves as a pioneer factor for AR binding to chromatin; and also post-translationally promotes transcriptional activity of both full-length and splice-variant AR. GATA2 is often elevated in CRPC. Here, we investigated the role of GATA2 in PC cells beyond the AR signaling axis, and characterized the pharmacological potency of the GATA2 small molecule inhibitor (SMI) K-11706 against PC cells. Chromatin immunoprecipitation and RNA sequencing analysis revealed that GATA2 is a key modulator of cMyc expression, which induces the expression of FOXM1 and EZH2. We extensively profiled five CRPC cell lines following treatment with K-11706, which inhibited the proliferation and invasive behavior of PC cells, and dramatically reduced the genome-wide transcriptional activity of GATA2, AR, and cMyc, leading to downregulation of several PC drivers and AR/cMyc effector genes, notably FOXM1, EZH2, and CENPF. Transcriptional profiling and functional pathway analysis of the K-11706 transcriptomic footprint against curated databases delineated a biological network composed of genes involved in cell cycle/proliferation, stemness, metastasis and DNA repair. In vivo, K-11706 suppressed the growth of multiple cell-derived and patient-derived xenograft PC models. We propose that GATA2 is a master regulator of multiple PC drivers and a promising actionable therapeutic target in CRPC. Pharmacologic inhibition of GATA2, via a potent second-generation small molecule inhibitor is feasible and effective in PC models both in vitro and in vivo.
Citation Format: Salma Kaochar, Kimal Rajapakshe, Matthew J. Robertson, Yongcheng Song, Coarfa Cristian, Nicholas Mitsiades. K-11706 exerts potent anti-cancer activity via suppression of GATA2/AR/cMyc signaling axis in castration resistant prostate cancer [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 B128. doi:10.1158/1535-7163.TARG-19-B128