bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A046: miR-199a-3p induces BRCA1 dysfunction in triple-negative breast cancer
Authors: Ho John C. , Shin Vivian Y. , Chen Jiawei , Siu Man T. , Cheuk Isabella , Kwong Ava 
Published: August 2018

Abstract
Background: BRCA1 mutations are highly susceptible to familial breast and ovarian cancer, as well as the more aggressive triple-negative breast cancer (TNBC). However, DNA repair defects caused by BRCA dysfunction were reported to have better response to platinum-based chemotherapy and PARP inhibitors. Increasing evidence suggest the roles of miRNAs in regulating BRCA1 functions, with emphasis on cancer progression and therapeutic sensitivity. We previously identified miR-199a-3p as a potential TNBC biomarker, and BRCA1 is the putative downstream target based on in silico prediction. In this study, we aim to investigate the functionalities of miR-199a-3p in TNBC. Methods: The correlation between BRCA1 and miR-199a-3p was investigated through expression analysis of 32 TNBC tumor specimens, and further confirmed by dual-luciferase reporter assay. The functionalities of miR-199a-3p in TNBC cells were assessed by MTT cell proliferation, migration, and clonogenic assays. The effects of miR-199a-3p on cisplatin and PARP inhibitor veliparib sensitivities were determined by MTT assays, followed by apoptosis and cell cycle analyses. Results: An inverse correlation between miR-199a-3p and BRCA1 expressions was observed in TNBC tumor specimens. miR-199a-3p was demonstrated to directly target BRCA1, and caused downregulation of BRCA1 protein expression, and suppressed luciferase activity mediated by BRCA1-3’-UTR in reporter assays. Overexpression of miR-199a-3p in TNBC cell lines (MDA-MB-231 and MDA-MB-468) was shown to inhibit cell proliferation, migration, and clonogenic ability, suggesting tumor-suppressive functions. On the other hand, cisplatin treatment induced BRCA1 expression, concurrent with reduced miR-199a-3p, in TNBC cells. Restoration of miR-199a-3p expression sensitized the cells to cisplatin and PARP inhibitor veliparib. Ectopic expression of miR-199a-3p also suppressed aldehyde dehydrogenase (ALDH)-positive stem cell-like population in cisplatin-resistant TNBC cells. Conclusions: Our results suggest that miR-199a-3p is involved in TNBC progression and chemotherapeutic sensitivity, at least partially through regulation of BRCA1.
Citation Format: John C. Ho, Vivian Y. Shin, Jiawei Chen, Man T. Siu, Isabella Cheuk, Ava Kwong. miR-199a-3p induces BRCA1 dysfunction in triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A046.
Abstract A059: Targeted RNA expression profiling for biomarker discovery in complex biologic samples
Authors: Chenchik Alex , Frangou Costa , Makhanov Mikhail 
Published: August 2018

Abstract
New rapid and robust transcriptome-based methods for cellular characterization of the tumor microenvironment and biomarker discovery are required to improve prognosis and treatment of cancer and other diseases. However, challenges with current approaches for the above applications include high sample requirements, poor sensitivity, low dynamic range, and limited throughput. To address these limitations, we have developed the DriverMap targeted RNA expression profiling assay using a genome-wide set of 19,000 validated primer pairs that leverages the sensitivity of multiplex RT-PCR with the throughput and digital readout depth of next-generation sequencing (NGS). Starting from just 10pg (single-cell) to 100ng (10,000 cells) of total RNA is sufficient to quantify over 5 orders of magnitude variation in gene expression levels with performance similar to conventional qRT-PCR. Further, the use of gene-specific primers enables direct analysis of total RNA isolate and obviates the need for globin and rRNA depletion from whole blood samples. In this study, we present the performance of the assay for immunophenotyping of immune cells in whole blood samples from sepsis patients and assess the immune responses to complex immunomodulatory stimuli in an ex vivo model system. We will also present profiling results that demonstrate how this assay can be used to analyze the level of immune cell infiltration in tumor samples, and identify active pathways in tumor and xenograft samples. Preliminary studies demonstrate the assay’s unparalleled specificity and sensitivity, resulting in better detection of low-abundance mRNA transcripts as well as an improved cost-effectiveness for high-throughput clinical applications.
Citation Format: Alex Chenchik, Costa Frangou, Mikhail Makhanov. Targeted RNA expression profiling for biomarker discovery in complex biologic samples [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A059.
Abstract A074: Killing late-stage cancer cells by coupling DNA damage induction with MAPK pathway activation
Authors: Bhattacharjee Vikram 
Published: August 2018

Abstract
Acquired resistance of metastatic melanoma (MM) tumors to BRAF V600E inhibitors (BRAFis) is commonplace in the clinic. Habitual relapse of patients contributes to &lt;20% 5-year survival rates in MM. We previously identified serine synthesis as a critical mechanism of late-stage cancer cell resistance to BRAFis. Pretreatment with DNA-damaging agent and nucleoside analog gemcitabine resensitized drug-resistant cancer cells to BRAFis dabrafenib (Tafinlar) and vemurafenib (Zelboraf). The combination treatments were effective against BRAF wild type cancer cells, potentially expanding the clinical reach of BRAFis. In this study, we identify two additional DNA-damaging agents that resensitized drug-resistant MM and pancreatic cancer cells to BRAFis dabrafenib and encorafenib. We identify the antifolate and DNA-damaging agent methotrexate (MTX), and the topoisomerase 1 inhibitor and DNA-damaging agent camptothecin (Camp) as sensitizers of late-stage, drug-resistant cancer cells to BRAFis dabrafenib and encorafenib (LGX818). Importantly, we show a novel positive correlation between DNA repair delay and and allosteric MAPK activation via BRAFi treatment in BRAF wild type cells. Cells arrest in G1/S following DNA-damaging agent + BRAFi combination treatments and ultimately, cell death is triggered via apoptosis, presumably due to DNA damage repair delays. Additionally, we have identified activating KRAS codon 12 mutations as critical to the efficacy of combination treatments. In summary, we have elucidated a novel method of cell death induction via DNA-damaging agent + BRAFi combination treatments that has the potential to significantly impact late-stage MM and pancreatic cancer therapy in the clinic.
Citation Format: Vikram Bhattacharjee. Killing late-stage cancer cells by coupling DNA damage induction with MAPK pathway activation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A074.
Abstract A075: Metabolic targeting of hypoxia and HIF-1α in colorectal cancer potentiates the therapeutic efficacy of oxaliplatin
Authors: Chen Ching-Chow 
Published: August 2018

Abstract
The stabilization of hypoxia inducible factor-1α (HIF-1α) protein plays an important role in the gene transcription in hypoxia. Overexpression of HIF-1α has been reported in various human cancers. It is degraded under normoxic conditions by proline hydroxylation through prolyl hydroxylase domain-containing protein (PHD), leading to von Hippel-Lindau (VHL) E3-ubiquitin ligase-mediated ubiquitination and rapid degradation by proteasome. Succinate is produced when PHD hydroxylates HIF-1α, implying that elevated succinate in normoxia represents an increase in PHD activity. We found that DNA methyltransferase (DNMT) inhibitor zebularine could downregulate HIF-1α expression in various colorectal cancer (CRC) cells. Zebularine enhanced the degradation of HIF-1α protein through inducing its hydroxylation. Metabolomic analysis showed that zebularine reversed the reduced succinate level in hypoxia, indicating an increase in PHD activity. Zebularine also reduced angiogenesis in CRC. Furthermore, zebularine potentiated the anticancer effect of oxaliplatin in CRC cells and in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mouse model. This finding provides a new pharmacologic strategy to increase HIF-1α hydroxylation and overcome oxaliplatin resistance to enhance the anti-CRC therapy.
Citation Format: Ching-Chow Chen. Metabolic targeting of hypoxia and HIF-1α in colorectal cancer potentiates the therapeutic efficacy of oxaliplatin [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A075.
Abstract A076: Potent and water-soluble C-3’ modified docetaxel analogs by enthalpic driven optimization
Authors: Fang Weishuo , Wang Hongbo , Gago Federico 
Published: August 2018

Abstract
A dual strategy aimed at enhancing the binding affinity for microtubules and improving the water solubility of docetaxel led to the design and synthesis of a series of novel C-2 and C-3' modified analogs. Among the latter, a compound demonstrated a higher affinity constant for microtubules that resulted in the ability to overcome resistance in cultured P-gp overexpressing tumor cells and a superior activity to docetaxel in drug-resistant A2780/AD ovarian cancer cells xenografted in mice. In addition, the considerably lower hydrophobicity of this compound relative to both docetaxel and paclitaxel led to a 3-fold better aqueous solubility. A molecular modelling was performed to explain its potent activity at structural level.
Citation Format: Weishuo Fang, Hongbo Wang, Federico Gago. Potent and water-soluble C-3’ modified docetaxel analogs by enthalpic driven optimization [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A076.
Abstract A097: Phase II trial of the c-Met inhibitor tepotinib in patients with advanced non-small cell lung cancer harboring MET exon 14-skipping mutations
Authors: Felip Enriqueta , Veillon Remi , Viteri Santiago , Scheele Jürgen , Bruns Rolf , Paik Paul K. 
Published: August 2018

Abstract
Background: Approximately 3-4% of non-small cell lung cancers (NSCLCs) harbor activating mutations of the MET proto-oncogene that cause exon 14 skipping (METex14) and accumulation of c-Met lacking a juxtamembrane domain. Such tumors are sensitive to nonselective kinase inhibitors with activity against c-Met, so selective c-Met inhibitors may have greater efficacy and/or tolerability. This single-arm phase II trial (NCT02864992) is investigating the efficacy and safety of the potent and selective c-Met inhibitor tepotinib in patients (pts) with NSCLC harboring METex14. Methods: Eligible patients (pts) are adults with stage IIIB/IV NSCLC and METex14 mutations identified in tumor and/or circulating tumor DNA (ctDNA) in plasma (liquid biopsy) by a central laboratory. Pts with EGFR-activating mutations, ALK rearrangements, or &gt;2 lines of prior therapy are excluded. Pts receive tepotinib 500 mg QD on a 21-day cycle until disease progression, intolerable toxicity, or withdrawal from treatment for other reasons. Primary endpoint: objective response rate (ORR). Secondary endpoints: progression-free and overall survival, safety, pharmacokinetics, and quality of life. Recruitment of up to 120 (minimum 60 tumor, 60 ctDNA METex14-positive) pts in Europe, USA, and Japan is planned. Results: Five pts (age 55-77 years; 4 stage IV, 1 stage IIIB; all male; 4 Caucasian, 1 Asian) have been enrolled. Pts have currently completed 0-8 cycles of tepotinib therapy. Most adverse events observed to date have been grade 1/2 in severity, mostly unrelated to tepotinib treatment. One grade ≥3 tepotinib-related AE has occurred: grade 3 increased serum amylase. One pt has died due to his disease. Of the four pts with post-baseline tumor evaluations, two have confirmed partial response, one unconfirmed partial response, and one (with only one post-baseline assessment) stable disease. Conclusions: Initial data suggest that tepotinib 500 mg QD has promising activity in METex14 NSCLC. The safety profile of tepotinib appears favorable. Recruitment to the trial is ongoing.
Citation Format: Enriqueta Felip, Remi Veillon, Santiago Viteri, Jürgen Scheele, Rolf Bruns, Paul K. Paik. Phase II trial of the c-Met inhibitor tepotinib in patients with advanced non-small cell lung cancer harboring MET exon 14-skipping mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A097.
Abstract A110: Hypoxia-selective DNA-PK inhibitor
Authors: Kyle Alastair H. , Baker Jennifer H.E. , Fryer Karen H. , Banaáth Judit , Wang Taixiang , Porres Soraya S. , Mann Sam E. , Hynd George , Menear Keith , Minchinton Andrew I. 
Published: August 2018

Abstract
Targeting tumor hypoxia continues to be a goal of translational radiation oncology owing to overwhelming preclinical and clinical validation of the importance of tumor oxygenation to radiation sensitivity. We describe a rational, structure-based drug development and characterization program for novel prodrugs that can target DNA-PK selectively within hypoxic tumor cells. The dual selectivity of these prodrugs has the potential to substantially improve the therapeutic index of radiation therapy used to treat numerous cancers. Using several biochemical, cell and novel tissue-based screening systems we explored the mechanistic and biologic activity of two new classes of DNA-PK inhibitors. Iterative improvements in molecular activity were driven by high-throughput assays utilizing both immunostaining and clonogenic survival endpoints. Kinase selectivity and in vitro ADME assays facilitated the identification of drug-like compounds with the potential for good oral bioavailability. 3D-tissue culture models helped explore tissue penetration and bystander effects and experiments analyzing the oxygen dependence of prodrug cleavage to the active DNA-PK inhibitors guided the selection of hypoxic trigger moieties. Novel parental compounds and hypoxia-activated prodrugs in two distinct chemical classes that are potent inhibitors of DNA-PK have been developed. Lead compounds exhibit high in vitro potency and good oral drug-like properties and show significant enhancement of radiation-induced cytotoxicity. In vivo experiments indicate excellent oral bioavailability with plasma T½‘s exceeding 30 minutes and significant antitumor activity against human xenografts.
Citation Format: Alastair H. Kyle, Jennifer H.E. Baker, Karen H. Fryer, Judit Bana áth, Taixiang Wang, Soraya S. Porres, Sam E. Mann, George Hynd, Keith Menear, Andrew I. Minchinton. Hypoxia-selective DNA-PK inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A110.
Abstract A120: The effect of targeted nanoemulsion on pancreatic cancer cells
Authors: Fei QinQin , O'Barr Sophia , Lambros Maria P. 
Published: August 2018

Abstract
Purpose: Pancreatic cancer is characterized by its extreme aggressiveness and limited treatment options. This work evaluates the targeting of a nanoemulsion containing doxorubicin (DOX) to different pancreatic cancer cell lines and its mechanism of uptake. Methods: Three human pancreatic cancer cell lines, PANC-1, BxPC-3, and MIA PACA-2, were seeded separately into 12-well plates (1.0 x 105 cells/well). Then the cells were treated with DOX alone or DOX in targeted or nontargeted nanoemulsions. Cells treated with culture medium only were used as negative controls. The cellular uptake of the different DOX formulations by the different pancreatic cancer cell lines was evaluated using a fluorescence microscope (EVOS) and a flow cytometer (Accuri). The cytotoxicity of different formulations was evaluated using the SRB assay. The uptake mechanism of the DOX in targeted and nontargeted nanoemulsions was evaluated by comparing the uptake when cells were incubated at 40C and 370C. The uptake mechanism was further evaluated by pretreatment of the cells with inhibitors: cytochalasin D (inhibits caveolin-mediated endocytosis), chlorpromazine (inhibits clathrin mediated endocytosis), amiloride (inhibits micropinocytosis), and nystatin (depletes cholesterol and affects rafts). Results: The uptake of DOX in targeted nanoemulsion by PANC-1, BxPC-3, and MIA PACA-2 cell lines was 1.4-fold, 1.2-fold, and 1.2-fold higher, respectively, compared to that of DOX in the nontargeted nanoemulsion. The IC50 value for DOX in targeted nanoemulsion was 0.3 uM, for DOX in nontargeted nanoemulsion was 0.6 uM, and for DOX only was 1.3 uM. The uptake of DOX in targeted nanoemulsion and nontargeted nanoemulsion was higher at 370C compared to that at 40C. None of the inhibitors used had a significant effect on the uptake of DOX in the targeted or nontargeted nanoemulsions. Conclusion: The results show that DOX in the targeted nanoemulsion has significantly higher cellular uptake and cytotoxicity compared to that of the nontargeted nanoemulsion. The uptake of DOX in targeted and nontargeted nanoemulsion is energy dependent. However, none of the inhibitors used has a significant effect on the uptake of DOX in the targeted nanoemulsion, which requires further studies.
Citation Format: QinQin Fei, Sophia O'Barr, Maria P. Lambros. The effect of targeted nanoemulsion on pancreatic cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A120.
Abstract A129: A second-site mutation in BRAF confers resistance to RAF inhibition in a BRAF V600E-mutant brain tumor
Authors: Wang Jiawan , Yao Zhan , Jonsson Philip , Allen Amy , Qin Alice Can Ran , Pisapia David , Rosen Neal , Taylor Barry S. , Pratilas Christine A. 
Published: August 2018

Abstract
BRAF V600E drives tumors by hyperactivating ERK signaling, is activated in a RAS-independent manner, and signals as a monomer. Selective inhibitors of RAF potently inhibit BRAF V600E and downstream ERK signaling, and have been associated with impressive clinical responses in patients whose tumors harbor V600E mutations in BRAF. Almost all patients, however, ultimately develop resistance. To date, acquired resistance mechanisms validated in patient samples have included splice forms of BRAF, mutations in NRAS, and BRAF amplification, all of which promote formation of RAF dimers, and mutations in MEK. Second-site point mutations in BRAF that promote dimer formation and are associated with acquired resistance have not previously been identified in RAF inhibitor-resistant tumors.
Here, we report a complete response followed by clinical progression of a BRAF V600E-mutant pediatric brain tumor treated with the RAF inhibitor dabrafenib. We identified a second-site mutation in BRAF at the time of progression that was not present in the pretreatment tumor. Further study indicated the acquired mutation is in cis with V600E. We demonstrate that the acquired resistance mutation induces RAF dimer formation, and is sufficient to confer resistance to dabrafenib. Moreover, we showed that ERK signaling activated by the double mutation is sensitive to MEK inhibition or to the RAF plus and MEK inhibitor combination. We also find that two novel RAF dimer inhibitors may overcome resistance mediated by the novel mutation in BRAF.
This is the first study, to our knowledge, that demonstrates the emergence of a confirmed second-site mutation in BRAF V600E and validates that this mutation is responsible for acquired resistance in an initially responding patient treated with dabrafenib. The mechanism of acquired resistance can be abrogated by the novel RAF dimer inhibitors. Our data confirm that a novel class of RAF dimer inhibitors are active against an acquired resistance mutation, suggesting an improved personalized treatment option for patients who harbor similar second-site mutations in BRAF.
Citation Format: Jiawan Wang, Zhan Yao, Philip Jonsson, Amy Allen, Alice Can Ran Qin, David Pisapia, Neal Rosen, Barry S. Taylor, Christine A. Pratilas. A second-site mutation in BRAF confers resistance to RAF inhibition in a BRAF V600E-mutant brain tumor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A129.
Abstract A130: ANXA1 is involved in resistance to 5-FU in colon cancer cells
Authors: Saito Motonobu , Onozawa Hisashi , Sakuyama Misato , Ashizawa Mai , Kikuchi Tomohiro , Okayama Hirokazu , Endo Hisahito , Fujita Shotaro , Sakamoto Wataru , Saze Zenichiro , Momma Tomoyuki , Ohki Shinji , Kono Koji 
Published: August 2018

Abstract
Annexin A1 (ANXA1), which belongs to the annexin superfamily, is a 37 kDa calcium-dependent phospholipid-linked protein that is associated with regulation of cellular differentiation, proliferation, and apoptosis, anti-inflammatory effects, and drug resistance. Through these functions, ANXA1 is considered to be associated with cancer development and metastasis in various malignant tumors. We previously reported that a case of positive ANXA1 expression by immunohistochemical (IHC) staining in colorectal cancer was associated with venous invasion (P=0.023) as well as lymph node metastasis (P=0.042). We therefore performed further investigation of the role of ANXA1 in colorectal cancer metastasis and treatment. In vitro cell experiments revealed that ANXA1 expression was significantly induced in the colon cancer cells resistant to 5-FU compared to the control cells. We then revealed that overexpression of ANXA1 induced a significant increase of cell viability to 5-FU, whereas ANXA1 knockdown induced a significant decrease of cell viability to 5-FU. Further experiments revealed that ANXA1 expression was induced by hypoxia in colon cancer cells, inducing cellar invasion. These results suggest that ANXA1 expression may be induced by hypoxia during colorectal cancer progression and metastasis. Our results provide a possible strategy to overcome 5-FU resistance by modulating ANXA1 expression.
Citation Format: Motonobu Saito, Hisashi Onozawa, Misato Sakuyama, Mai Ashizawa, Tomohiro Kikuchi, Hirokazu Okayama, Hisahito Endo, Shotaro Fujita, Wataru Sakamoto, Zenichiro Saze, Tomoyuki Momma, Shinji Ohki, Koji Kono. ANXA1 is involved in resistance to 5-FU in colon cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A130.