bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2058: BCL-2 selective inhibitor APG-2575 synergizes with BTK inhibitor in preclinical xenograft models of follicular lymphoma and diffuse large B-cell lymphoma
Authors: Fang Douglas D. , Zhai Guoqin , Gu Shoulai , Tao Ran , Tang Qiuqiong , Min Ping , Wang Qixin , Yang Dongmei , Gu Jiaxing , Li Yinfeng , Chen Dingxiong , Li Jiajun , Wang Guangfeng , Yang Dajun , Zhai Yifan 
Published: August 2019

Abstract
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are among the most prevalent B-lymphocyte neoplasms with Bruton’s tyrosine kinase (BTK) often found abnormally activated in these patients. BTK inhibitor ibrutinib has showed proven efficacy in both indications, but its clinical application is limited to gradually acquired resistance. Recent studies reported that ibrutinib-resistant cells exhibited higher BCL-2 expression and therefore increase their sensitivity to BCL-2 inhibitors. In this study, using a BCL-2 selective inhibitor APG-2575, we asked whether its combination with ibrutinib enhanced antitumor activity in FL and DLBCL in preclinical studies. Indeed, the combination treatment with APG-2575 and ibrutinib synergistically enhanced antitumor activity in DOHH2 cell-derived FL xenograft models. Similarly, enhanced activity was achieved in DLBCL xenograft models derived from OCI-LY1 cells. Interestingly, in OCI-LY1 xenografts, the combination treatment achieved a 100 % response rate, which include partially (PR) and complete tumor regression (CR), with ~80 % of CR and ~20 % of PR recorded. Durable response was continuously observed till the end of the study after dose suspension. Pharmacokinetic studies revealed that there were no significant changes in drug concentrations between single agents and the combination treatment, suggesting there was no drug-drug interaction between these two agents. On-target pharmacodynamic (PD) modulations of BTK and apoptosis pathways were observed in corresponding tumor tissues co-treated with ibrutinib and APG-2575. An increase in the levels of cleaved PARP-1 protein was observed under the combination treatment suggesting enhanced induction of apoptosis occurred, which may be the biological event contributing to the synergistic effect of the combination treatment. In summary, our study suggests that APG-2575 may be applied to the combination therapy with ibrutinib in the treatment of FL and DLBCL.
Citation Format: Douglas D. Fang, Guoqin Zhai, Shoulai Gu, Ran Tao, Qiuqiong Tang, Ping Min, Qixin Wang, Dongmei Yang, Jiaxing Gu, Yinfeng Li, Dingxiong Chen, Jiajun Li, Guangfeng Wang, Dajun Yang, Yifan Zhai. BCL-2 selective inhibitor APG-2575 synergizes with BTK inhibitor in preclinical xenograft models of follicular lymphoma and diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2058.
Abstract 2074: Bioactive marine drugs target acquired oncogenic burden in resilient pancreatic cancer
Authors: Aravindan Sheeja , Somasundaram Somasundaram T. , Natarajan Mohan , Herman Terence S. , Aravindan Natarajan 
Published: August 2019

Abstract
The upsurge of marine-derived therapeutics for cancer treatment is evident, with many drugs in clinical use and in clinical trials. Seaweeds harbor large amounts of polyphenols and their anti-cancer benefit is linear to their anti-oxidant activity. Our studies identified three superlative anti-cancer seaweed polyphenol drug candidates (SW-PD). We investigated the acquisition of oncogenic burden in radiotherapy-resilient pancreatic cancer (PC) that could drive tumor relapse, and elucidated the efficacy of SW-PD candidates as adjuvants in genetically diverse in vitro systems (Panc-1, Panc-3.27, BxPC-3, MiaPaCa-2) and a mouse model of radiation-residual disease. For residual PC studies, PC xenografts developed in nude mice were selectively exposed to clinically relevant fractionated irradiation, (2 Gy/day for 5 days per week for a total of 3 weeks), to a total dose of 30 Gy. QPCR profiling of custom archived 88 oncogenes in therapy-resilient PC cells identified a ‘shared’ activation of 40 oncogenes. SW-PD pre-treatment inflicted a significant mitigation of acquired (shared) oncogenic burden, in addition to drug- and cell-line-specific repression signatures. Tissue-microarray with IHC of radiation-residual tumors in mice signified acquired cellular localization of key oncoproteins (Fosb, cFos, Fra2, cMYC, MYB, NF2) and other critical architects (SELE, CD73, Cytokeratins, Col3, Decorin, and Sulf2). Conversely, SW-PD treatment inhibited the acquisition of these critical drivers of tumor genesis, dissemination, and evolution. Heightened death of resilient PC cells with SW-PD treatment validated the translation aspects. The results defined the acquisition of oncogenic burden in resilient PC and demonstrated that the marine polyphenols effectively target the acquired oncogenic burden and could serve as adjuvant(s) for PC treatment.
Citation Format: Sheeja Aravindan, Somasundaram T. Somasundaram, Mohan Natarajan, Terence S. Herman, Natarajan Aravindan. Bioactive marine drugs target acquired oncogenic burden in resilient pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2074.
Abstract 2076: Targeting vulnerable aberrant cancer-associated pathways by rationalized triple combination regimens to effectively control urothelial carcinoma cells in vitro and in vivo
Authors: Wang Hwa-Chain R. , Pattarawat Pawat , Wang Jinquan , Donnell Robert 
Published: August 2019

Abstract
Urinary bladder cancer (UBC) is the fifth-most common cancer in the United States, and urothelial carcinomas (UCs) account for more than 90% of UBCs. Although current therapies are effective in the short-term treatment of UCs, the high tendency (&gt;50%) for them to recur and progress to life threatening, advanced muscle-invasive UCs requires life-long surveillance with extended medical care. Thus, it still requires extensive therapeutic development to achieve an effective control of UC recurrence and improve the response rate and overall survival for UC patients. To develop effective and safe regimens to control the development and recurrence of advanced UCs, we investigated the efficacy of rationalized combination regimens in controlling UC cells in vitro and UC cell-derived xenografts (CDXs) in vivo. Our in vitro studies identified a triple combination of gemcitabine, romidepsin, and cisplatin, which are all FDA-approved anticancer agents, effective in synergistically inducing death and reducing drug resistance of various UC cell lines. Our studies also revealed that UC-associated aberrant pathways, including mitochondrial reactive oxygen species (ROS) and the ERK-Nox pathway, which were already induced in UC cells, were enhanced by the triple combination regimen to play essential roles for inducing apoptosis and reducing resistance. We also detected that the unfolded protein response played a role in modulating cell death induced by the regimen. Our in vivo studies used a tolerable protocol for administering combination regimens into animals. Our studies verified the efficacy of the triple combination gemcitabine plus romidepsin and cisplatin regimen, versus double combination regimens, in controlling UC CDXs in immune-deficient mice. In conclusion, our studies indicated that a rationalized triple combination of gemcitabine plus romidepsin and cisplatin regimen was more effective than double combination regimens in modulating UC-associated vulnerable aberrant pathways and controlling UC tumor development and recurrence in animals with low tolerable/ reversible adverse effects. Thus, the triple combination gemcitabine plus romidepsin and cisplatin regimen should be promptly considered as an advanced treatment over the conventional double combination gemcitabine plus cisplatin regimen in clinical trials in order to control advanced UCs.
Citation Format: Hwa-Chain R. Wang, Pawat Pattarawat, Jinquan Wang, Robert Donnell. Targeting vulnerable aberrant cancer-associated pathways by rationalized triple combination regimens to effectively control urothelial carcinoma cells in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2076.
Abstract 2078: Mitochondrial DNA copy number correlates with trifluridine sensitivity of human tumor cell lines
Authors: Kobunai Takashi , Matsuoka Kazuaki , Nukatsuka Mamoru , Tsukihara Hiroshi , Takechi Teiji 
Published: August 2019

Abstract
Background: Trifluridine (FTD) is a key component of the novel oral antitumor drug trifluridine/tipiracil, which was approved for the treatment of patients with metastatic colorectal cancer refractory to standard chemotherapies. FTD, an antineoplastic thymidine analogue, is incorporated into the genomic DNA of tumor cells. However no detailed analysis of the relation between mitochondrial DNA (mtDNA) in human tumors and FTD’s cytotoxic effects has been reported yet. In this study, we analyzed mtDNA copy number of 23 human cancer cell lines and its relation with FTD sensitivity.
Method: Twenty-three human cancer cell lines, representing the nine main tumor types, were tested for sensitivity to FTD by WST-8 assay. The cell lines included lung (NCI-H226, NCI-H23), colon (COLO 205, HCT 116, HCT-15, SW620), pancreas (PANC-1), breast (Hs 578T, MCF7, MDA-MB-231, T-47D), melanoma (Malme-3M, SK-MEL-28, SK-MEL-5), prostate (DU 145, PC-3), renal (786-O, A-498), leukemia (CCRF-CEM, HL-60, MOLT-4), and ovary (OVCAR-3, SK-OV-3). Genomic DNA was purified using a silica membrane spin column-based centrifugation procedure. The copy number of mtDNA was quantitated by array-based digital PCR and real-time PCR. Furthermore, the mtDNA heterogeneity of each cell line was assessed by deep-sequencing as follows: a DNA panel targeting 222 amplicons covering the entire mitochondrial genome was used for NGS library preparation; NGS libraries were subjected to cluster generation in a flow cell and paired-end sequencing for 300 cycles; and finally, the resulting fastq files were uploaded to mtDNA-server for mapping and heteroplasmy evaluation.
Results: The IC50s of FTD ranged from 0.6 uM to 52 uM (Median: 5.6 uM). While cell lines were arbitrarily classified as FTD-high- and FTD-low sensitive cell lines according to their respective IC50 values at median, mtDNA copy numbers of FTD-high sensitive cell lines were significantly lower than those of FTD-low sensitive cell lines (p = 0.01). Median heteroplasmy level and counts were 0.057 and 137, respectively. Interestingly, significant negative correlation was found between mtDNA copy number and heteroplasmy level. (Spearman’s Rho = -0.46, p= 0.02). While 6 out of 23 cell lines were microsatellite instable, MSI status also significantly correlated with mtDNA copy number, FTD-sensitivity, and heteroplasmy level (p&lt; 0.05).
Conclusions: Integrated analysis of mtDNA copy number and mutational profiling may be useful to predict FTD sensitivity of cancer cells.
Citation Format: Takashi Kobunai, Kazuaki Matsuoka, Mamoru Nukatsuka, Hiroshi Tsukihara, Teiji Takechi. Mitochondrial DNA copy number correlates with trifluridine sensitivity of human tumor cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2078.
Abstract 2087: Mechanistic studies reveal novel molecular insights on anticancer properties of F10 compound in human colon cancer cells
Authors: Mani Chinnadurai , Gmeiner William , Palle Komaraiah 
Published: August 2019

Abstract
Fluoropyrimidine (FP) drugs, mainly 5-Fluorouracil (5-FU), constitute the backbone of combination chemotherapy regimens (e.g. FOLFOX and FOLFIRI) for treating colorectal cancer (CRC) and provide a survival benefit for patients with stage II, III, and IV colorectal cancer. However, 5 year survival rate for CRC patients with metastatic disease is less than 10%. This dreadful situation suggests urgent need for novel and more potent FPs to improve the outcomes of these patients. We have developed novel fluoropyrimidine drug polymers (e.g. F10) that show promising antitumor activity in multiple pre-clinical models even while displaying reduced systemic toxicities. F10 is taken up by malignant cells via active transport compared to 5-Fluorouracil, which is taken up by diffusion in malignant and non-malignant cells. Additionally, F10 compound is primarily incorporated into DNA, and produced thymidylate synthase and topoisomerase toxic metabolites at greater levels, whereas 5-Fluorouracil is primarily incorporated into RNA, and only has about 5-10% production of active form of thymidylate synthase toxic metabolites. MMR is involved in repairing the DNA mismatches and FP drugs induced DNA damage. Interestingly, our studies show that F10 acts by different mechanisms compared to 5-FU. Particularly, F10 treated CRC cells exhibit replication stress as evidenced by paused and slow progression of replication forks and R-loops formation at the active transcriptional regions, suggesting replication and transcription dependent generation of DNA lesions in these cells. F10 treatment induced several fold increased DNA double strand breaks (DSB) as measured by COMET assays and about 1000 folds more cytotoxicity to CRC cells compared to 5-FU. Similarly, F10 treatment activated distinctive DNA damage responses in MMR proficient CRC cells compared MMR deficient cells. Additionally, our studies suggest F10 as a promising therapeutic agent for CRC therapy either alone or in combination with CHK1 and PARP inhibitors.
Citation Format: Chinnadurai Mani, William Gmeiner, Komaraiah Palle. Mechanistic studies reveal novel molecular insights on anticancer properties of F10 compound in human colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2087.
Abstract 2092: Metabolic approach to EGFR-targeted therapy in non-small cell lung cancer
Authors: Kam Yoonseok , Swain Pamela , Romero Natalia , Dranka Brian P. 
Published: August 2019

Abstract
Mutation of the epidermal growth factor receptor (EGFR) is a major genetic driver of non-small cell lung cancer (NSCLC). While first-line tyrosine-kinase inhibitors (TKIs) have improved patient survival, many patients eventually develop resistance to these drugs. Combination therapies are now being researched to overcome this resistance. Pathways that may synergize with EGFR signaling are of interest since a liability created with one compound may then be exploited by a second. It is well known that glycolysis is controlled by EGFR signaling in cancer cells. However, the interplay of cell metabolism and EGFR inhibitors is not fully understood. Using PC9 cells which have known constitutive EGFR activation, we examined the relative poise of ATP production from mitochondria and glycolysis. In response to any of four different TKIs: afatinib, CO-1686, dacomitinib and erlotinib, a rapid decrease in glycolytic activity was induced. However, the total ATP production rates were not changed significantly as a result of increased mitochondrial ATP production. We next examined the mitochondrial fuel sources which support this increase by selectively blocking individual fuel pathways. In the presence of either a mitochondrial pyruvate carrier or glutaminase inhibitor, total ATP production rate decreased, and cell viability followed. Taken together, these data suggest that a combinational application of EGFR-targeted therapy and mitochondrial-targeted therapy may provide metabolic stress to cancer cells. Further study is required to understand the interplay of the tumor microenvironment and metabolic niches that may be found therein.
Citation Format: Yoonseok Kam, Pamela Swain, Natalia Romero, Brian P. Dranka. Metabolic approach to EGFR-targeted therapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2092.
Abstract 2108: Chromatin state as a mechanism of anthracycline response in breast cancer
Authors: Seoane Jose A. , Kirkland Jacob G. , Caswell-Jin Jennifer L. , Crabtree Gerald R. , Curtis Christina 
Published: August 2019

Abstract
The aim of this study is to determine the effect of chromatin regulators on anthracycline response in breast cancer. Anthracyclines are a highly effective component of curative breast cancer chemotherapy, but can be associated with substantial side effects. Because anthracyclines work in part via inhibition of topoisomerase II (TOP2) on accessible DNA, we hypothesized that expression levels of chromatin regulatory proteins that mediate DNA accessibility might predict anthracycline response. We used RNA-sequencing data from the TCGA breast cancer cohort to infer a breast cancer chromatin regulatory network using the ARACNE algorithm. A panel of 45 breast cancer cell lines with accompanying gene expression and growth inhibitory (GI50) data was used to build a genome-wide signature of anthracycline response. Based on the GI50, cell lines were classified as sensitive or resistant. The VIPER algorithm was then used to identify chromatin regulatory genes (CRGs) from the ARACNE network whose targets were significantly enriched in the anthracycline resistance signature. We further compiled a metacohort of 1006 clinically annotated early-stage breast cancer patients with gene expression data, allowing us to identify CRGs whose expression levels were associated with outcome after adjuvant treatment with anthracyclines. 24 CRGs associated (P&lt;0.1) with anthracycline response in vitro and 54 CRGs associated (P&lt;0.05) with anthracycline response in the patient cohort, 9 of which overlapped with the in vitro CRGs. In the patient cohort, CRG expression associated strongly with anthracycline response in all major subgroups of breast cancer (ER+/HER2-, HER2+, and triple-negative). In general, CRGs that promoted open chromatin (BAF and COMPASS) were, at high levels of expression, associated with anthracycline sensitivity, while CRGs associated with closed chromatin (PRC2) were, at high levels of expression, associated with anthracycline resistance. We functionally validated KDM4B as a predictor of anthracycline, but not taxane, sensitivity in a breast cancer cell line model through shRNA knockdown. We present a set of CRGs that control the chromatin accessibility in breast cancer both in vitro and in vivo; we infer that those tumors with more open chromatin as determined by the expression of these CRGs are intrinsically more sensitive to anthracyclines, while those with more closed chormatin are more resistant. Future work into the predictive power of these CRGs may allow us to target anthracyclines to only those patients who will benefit.
Citation Format: Jose A. Seoane, Jacob G. Kirkland, Jennifer L. Caswell-Jin, Gerald R. Crabtree, Christina Curtis. Chromatin state as a mechanism of anthracycline response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2108.
Abstract 2111: Increased heme influx dictates tumorigenic functions of non-small cell lung cancer cells
Authors: Sohoni Sagar Shashikant , Ghosh Poorva , Zhang Li 
Published: August 2019

Abstract
Heme, iron protoporphyrin IX, is a central metabolic and signaling molecule that regulates diverse molecular and cellular processes relating to oxygen utilization and metabolism. Heme serves as a cofactor or a prosthetic group for complexes II, III, and IV in electron transport chain. Hence, it has a direct role in oxidative phosphorylation and energy generation in cells. Most human cells can synthesize and uptake heme from circulation. A number of epidemiological studies have shown that high heme intake is associated with an increased risk of cancer, including lung cancer. Our lab has previously shown that an array of non-small cell lung cancer cells (NSCLCs) exhibit high heme synthesis and uptake. This increased heme flux correlates with an enhanced oxygen consumption and ATP production. NSCLCs also exhibited significantly elevated levels of hemoproteins and mitochondrial biogenesis proteins compared to normal lung cell lines. Expression levels of these proteins correlate with increased oxygen consumption and the total heme content of NSCLCs suggesting a possible role of heme in energy metabolism and mitochondrial biogenesis.
In order to assess the involvement of heme in tumorigenicity of the NSCLC cell lines, we overexpressed heme synthesis enzyme, ALAS1 or heme transporters, HCP1 or HRG1 using lentivirus system. NSCLC cell lines A549 and H1299 were infected with a lentivirus carrying ALAS1 or HCP1 or HRG1 plasmid. Stable clones were obtained with antibiotic selection and checked for overexpression with western-blots. Cells overexpressing ALAS1, HCP1 and HRG1 showed significantly higher rates of heme influx as well as intensified oxygen consumption and ATP formation compared to eGFP controls. Tumorigenic properties such as invasion, migration and colony formation were also found to be significantly increased in these cell lines compared to their eGFP counterparts. Subcutaneous xenografts generated with overexpression cell lines also showed significantly high tumor growth rates and mass compared to eGFP controls. Our data from both in vitro and in vivo experiments show that heme directly improves the tumorigenic properties of NSCLC cells by substantially improving the respiration rates and energy metabolism.
Citation Format: Sagar Shashikant Sohoni, Poorva Ghosh, Li Zhang. Increased heme influx dictates tumorigenic functions of non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2111.