bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4034: High throughput synergy screening identifies therapeutic combinations for Merkel cell carcinoma
Authors: Garman Khalid , Gelb Tara , Urban Daniel , Hall Matthew , Brownell Isaac 
Published: September 2020

Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. MCC is virus-positive (VP-MCC) in the majority of cases wherein Merkel cell polyomavirus is integrated into the host genome. The remainder of cases are virus-negative (VN-MCC) and are associated with mutations induced by ultraviolet light. Primary MCC is effectively treated by surgical resection and radiotherapy, but for metastatic MCC, outcomes for conventional chemotherapy are poor. Immune checkpoint inhibitors are more likely to produce durable responses in metastatic MCC, but they are not effective in all cases and are not a viable option for patients with immunosuppression. To address the need for better therapeutic options, we utilized high-throughput small molecule screening to assess the efficacy of ~4,000 drugs in reducing VP-MCC and VN-MCC viability. Among the compounds we screened, navitoclax was identified as an effective agent against VP-MCC cell lines, compared to VN-MCC or control cells. However, navitoclax clinical application is limited by dose-dependent thrombocytopenia. One strategy to reduce thrombocytopenia risk is to combine a lower dose of navitoclax with another MCC-effective agent. To identify effective drug combinations, we performed a synergy screen with 1912 pairings of navitoclax with each of the clinically relevant compounds in the NCATS Mechanism Interrogation PlatE (MIPE). We were able to identify synergy between navitoclax and multiple drug classes. High priority drug combinations are now being evaluated for toxicity and efficacy in pre-clinical xenograft models of MCC. Our study has identified novel therapeutic combinations for the treatment of VP-MCC. By focusing on drugs already in clinical use, validated combinations will be quickly available to patients for whom immunotherapy is not available or effective.
Citation Format: Khalid Garman, Tara Gelb, Daniel Urban, Matthew Hall, Isaac Brownell. High throughput synergy screening identifies therapeutic combinations for Merkel cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4034.
Abstract 4063: Design and development of a novel 5-FU modified siRNA against BCL2 with enhanced efficacy and the unique ability to be delivered vehicle free into cancer cells
Authors: Fesler Andrew , Hwang Ga-Ram , Yuen John , Ju Jingfang 
Published: September 2020

Abstract
Evasion of apoptosis is one of the major hallmarks of cancer and an important factor in chemoresistance. Thus, targeting apoptosis regulation is an important therapeutic approach. Anti-apoptotic BCL2, an oncogene and therapeutic target, is overexpressed in several different cancer types. There have been various approaches developed to target BCL2 including the FDA approved Venetoclax. In this study we have developed a modified siRNA against BCL2 that has enhanced efficacy and also can be delivered into cancer cells without any vehicle. We developed this siRNA by replacing uracil residues in the siRNA with 5-flurouracil (5-FU). This modification incorporates the effects of both 5-FU and siBCL2, to have an enhanced therapeutic effect. We tested several different modified siBCL2's, one with only the sense strand modified, one with only the antisense strand modified and one with both strands modified. We found the modified siBCL2 with both strands modified with 5-FU was most effective at inhibiting BCL2. Importantly, we were able to demonstrate via qRT-PCR and Western blot, that this modified siBCL2 retains its siRNA function and inhibits BCL2 expression in several different cancer types including colon cancer, lung cancer and lymphoma. In addition, in lymphoma cells, we found that our modified siBCL2 has better efficacy than BCL2 inhibitor Venetoclax. Finally, we were able to demonstrate that modified siBCL2 can be delivered into cancer cells without a delivery vehicle. This unique feature may be significant in overcoming the challenge of delivery, which remains a major obstacle for RNA therapeutics. This modified siBCL2 has therapeutic potential for several different cancers. Beyond BCL2, the modification approach we demonstrated may be applicable to other siRNAs and has potential as a platform technology for siRNA based therapeutics.
Citation Format: Andrew Fesler, Ga-Ram Hwang, John Yuen, Jingfang Ju. Design and development of a novel 5-FU modified siRNA against BCL2 with enhanced efficacy and the unique ability to be delivered vehicle free into cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4063.
Abstract 4084: A DGKA-cJUN-WEE1 signaling axis provides platinum resistance in ovarian cancer
Authors: Li Jie , Pan Chaoyun , Boese Austin C. , Umano Anna , Kang Sumin 
Published: September 2020

Abstract
Although platinum compounds are the first-line treatment for ovarian cancer, the majority of patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. Here, we report a unique platinum resistance mechanism that is mediated by a lipid messenger, phosphatidic acid (PA), in ovarian cancer. A phospho-proteomics screen revealed that PA, which is predominantly produced by diacylglycerol kinase alpha (DGKA) in ovarian cancer, activates the transcription factor c-JUN. DGKA and PA facilitate JNK recruitment to c-JUN and nuclear localization leading to its activation upon cisplatin exposure. Through a genomic screen, we identified that activated c-JUN enhances expression of WEE1 and consequently prevents cells from aberrant cell cycle progression upon cisplatin exposure. DGKA-cJUN-WEE1 signaling was elevated in tumors derived from ovarian cancer patients who did not respond to platinum-based therapy compared to tumors from patients who responded to treatment. Our study demonstrates how lipid metabolism, kinase signaling, and gene regulatory systems are intertwined to direct cisplatin resistance in ovarian cancer.
Citation Format: Jie Li, Chaoyun Pan, Austin C. Boese, Anna Umano, Sumin Kang. A DGKA-cJUN-WEE1 signaling axis provides platinum resistance in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4084.
Abstract 4085: Blocking Fra-1 sensitises triple-negative breast cancer to olaparib
Authors: Song Dandan , He Huan , Sinha Indranil , Pettersson Linnea , Yan Feifei , Haldosen Lars-Arne , Zhao Chunyan , Williams Cecilia 
Published: September 2020

Abstract
Fra-1 (FOSL1), a member of the activator protein 1 (AP-1) transcription factor complex, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor progression and treatment resistance. We have previously identified 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells in a large screen, and this included PARP1 (Poly (ADP-ribose) polymerase 1). PARP1 inhibitor olaparib is currently in use for treatment of BRCA-mutated TNBC breast cancer. Here, we corroborate that PARP1 interacts with Fra-1, and we also find that PARP1 downregulates Fra-1 and reduces AP-1 transcriptional activity. Inhibition of PARP1, on the other hand, increases Fra-1 levels and enhances AP-1 transcriptional activity. Further, we find that upon inhibition of Fra-1, TNBC cells become sensitized to olaparib treatment. By comparing the Fra-1 and PARP1 regulated transcriptomes with Fra-1 chromatin binding site, we determine that a large fraction of PARP1-regulated genes is dependent on Fra-1. Finally, we show that PARP1 protein levels significantly correlate with Fra-1 in clinical breast cancer tumors, and we identify that while high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall, it is not in basal-like tumors. In conclusion, by exploring the functionality of the Fra-1 and PARP-1 interaction, we propose that targeting Fra-1 could serve as a therapeutic approach to improve olaparib treatment outcome for TNBC patients.
Citation Format: Dandan Song, Huan He, Indranil Sinha, Linnea Pettersson, Feifei Yan, Lars-Arne Haldosen, Chunyan Zhao, Cecilia Williams. Blocking Fra-1 sensitises triple-negative breast cancer to olaparib [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4085.
Abstract 4089: Investigating translesion synthesis DNA polymerases roles on tumor protection after temozolomide induced DNA damage
Authors: Latancia Marcela Teatin , Bastos André Uchimura , Moreno Natália Cestari , Jardim Davi , Rocha Clarissa RR , Menck Carlos FM 
Published: September 2020

Abstract
Translesion DNA polymerases are capable of replicating damaged DNA, without removing the lesions, performing translesion synthesis (TLS), a mechanism of DNA damage tolerance. Tumor cells use this mechanism in order to survive lesions caused by chemotherapy and, therefore, this may be a strategy that tumor cells use to resist treatments. Moreover, it is an error-prone process and can lead to mutagenesis increasing resistance potential of tumor cells. Little is known about the role of TLS in Temozolomide (TMZ) tumor treatment. Our aim is to investigate how TMZ affects TLS mutated cells. Hence, we firstly treated primary fibroblasts cells lacking TLS mechanisms (XP-V) and analyzed cell proliferation by flow cytometry, cell viability by a colorimetric assay (XTT), for survival by apoptotic markers (such sub-G1) and clonogenic assays. In fact, XP-V cells are more sensitive to TMZ, indicating that TLS mechanisms are important to overcome DNA damage. TCGA data was also used to analyze TLS expression in glioblastoma patients. Curiously, in recurrently patients treated with TMZ, POLK expression was significantly increased. CRISPR/CAS9 knockout (KO) cells of glioblastoma cell lines, such as U251, were constructed for other TLS DNA polymerases enzymes genes, such as Pol Iota and Pol kappa. Gene KO was validated using Sanger sequencing and mutations resulted in stop codon. These pol iota and pol kappa KO cells had impaired viability after TMZ treatment. Moreover, genotoxic stress, as indicated by phosphorylated gH2AX, were increased in TMZ-treated cells. In summary, we can infer that TLS polymerases protect tumor cells from TMZ-induced DNA damage and thus, play important roles on overcoming resistance to this drug. As perspectives for this work, we intend to observe how replication is affected in these KO cells treated with TMZ by DNA Fiber Assays and measure DNA strand breaks in those cells by comet assay. Financial support: FAPESP, CNPq and CAPES.
Citation Format: Marcela Teatin Latancia, André Uchimura Bastos, Natália Cestari Moreno, Davi Jardim, Clarissa RR Rocha, Carlos FM Menck. Investigating translesion synthesis DNA polymerases roles on tumor protection after temozolomide induced DNA damage [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4089.
Abstract 4144: A tissue-microfluidic derived aptamer displays prognostic and therapeutic characteristics in serous ovarian carcinoma through heat shock protein 70(HSP70)
Authors: Lin Chang-Ni , Liang Yu-Ling , Wu Pei-Ying , Lee Gwo-Bin Vincent , Hsu Keng-Fu 
Published: September 2020

Abstract
Background: Previously, we have identified aptamers through ovarian cancer (OC) tissue microfluidic platform which show high specificity to ovarian cancer tissue and cells. However, the clinical diagnostic and therapeutic roles of these aptamers are still largely unknown.
Materials and Methods: Liquid chromatography-mass spectrometry (LC-MS) was used to find binding candidates of aptamer, Tx-01, from serous type ovarian cancer cells. Immunohistochemistry (IHC), clinical survival analysis, western blotting and confocal microscopic images were performed to detect the expression of Tx-01 and HSP70/ Notch1 intracellular domain (NICD) in OC tissues. The functions of Tx-01 were studied in vitro and in vivo experiments. Inhibitors treatment, nuclear protein extraction and western blotting were carried out to demonstrate the possible mechanisms of Tx-01 function.
Results: High expression Tx-01 in OC tissues was correlated to poor patients' survival in serous ovarian carcinoma. In vitro experiments showed that Tx-01 has a feature of recognizing membrane-bound HSP70. In the meantime, Tx-01 inhibit HSP70 signal activation via interrupting intracellular HSP70/NICD interaction to reduce cell migration and invasion. Furthermore, Tx-01 inhibited the tumor growth in the mice experiment.
Conclusion: Our data showed that Tx-01 acted as a prognostic predictor in serous OC through recognizing the membrane-bound HSP70. Also, Tx-01 reduced the tumor cell migration, invasion through blocking HSP70 signal activation. Thus, our work demonstrated that Tx-01 might be a prognostic biomarker and potential inhibitor in serous OC therapy.
Citation Format: Chang-Ni Lin, Yu-Ling Liang, Pei-Ying Wu, Gwo-Bin Vincent Lee, Keng-Fu Hsu. A tissue-microfluidic derived aptamer displays prognostic and therapeutic characteristics in serous ovarian carcinoma through heat shock protein 70(HSP70) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4144.
Abstract 417: Developing mouse models to dissect the function of a driver gene epimutation in lung tumorigenesis
Authors: Yang Li , Mandala Anusha , Chen Yi , Shen Lanlan 
Published: September 2020

Abstract
Background: Cancer is a complex disease caused by the accumulation of both genetic and epigenetic alterations in oncogenes and tumor suppressor genes. Although an extensive catalog of epigenetic changes has been generated in patients with lung cancer, we have only a fragmentary understanding of their functional roles, particularly for the initiation and maintenance of tumors. The use of genetically engineered mouse models definitively demonstrate that mutations at specific genes cause cancer. An analogous “epigenetically engineered mouse models” should not only lead to important insights about how cancer develop but could provide in vivo platforms in which to screen and validate novel epigenetic therapies.
Methods and Results: We published the first epigenetically engineered mouse cancer model based on a driver gene epimutation of p16 (also known as cyclin-dependent kinase inhibitor 2A). In human lung cancers, p16 epimutation is common, occurring in ~50% of cases. Importantly, p16 epimutation is frequently detected in lung pre-neoplastic lesions and p16 is of the best documented gene that controls K-RAS oncogene-induced senescence. Therefore, to elucidate the functional role of p16 epimutation for lung cancer establishment and progression, we developed a mouse model that combines oncogenic K-ras with p16 epimutation. We found that mice with combined K-ras mutation and p16 epimutation (K-ras+/G12D; p16meth/meth) displayed substantially increased tumor numbers and sizes, with tumor progression to adenocarcinoma. In addition, to investigate the therapeutic effects of reversing p16 epimutation, we developed a mouse model that enables conditional and inducible CRISPR based epigenetic gene editing. Our system utilizes deactivated Cas9 (dCas9) fused to a repetitive protein scaffold known as SunTag, which recruits multiple copies of antibody-fused demethylase TET1. We showed that this system is robust and reproducible to achieve targeted DNA demethylation at CpGs within 100 bp from the sgRNA target site of p16 promoter and to reactivate p16.
Conclusion: We have established clinically relevant and immunocompetent mouse models based on defined genetic and epigenetic alterations to drive benign lung tumor growths towards the ultimate malignant phenotype. Our model should prove useful as an in vivo preclinical platform for testing epigenetic therapeutic strategies.
Citation Format: Li Yang, Anusha Mandala, Yi Chen, Lanlan Shen. Developing mouse models to dissect the function of a driver gene epimutation in lung tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 417.
Abstract 4170: Decursin inhibits gastric cancer cell growth and autophagic flux by suppressing cathepsin C
Authors: Kim Solbi , Joo Mina , KIM Nayoung , Lee Myung-Won , Jeon Heung Jin , Ryu Hyewon , Song Ik-Chan , Lee Hyo Jin 
Published: September 2020

Abstract
Purpose: Autophagy is a series of processes in which biomolecules are digested and recycled, and it also provides energy for the development and progression of cancer. Thus, autophagy inhibitors can be used to suppress the progression of cancer. In this study, we investigated whether decursin, which is derived from natural products, inhibits the growth and autophagy of cancer cells.
Methods: The gastric cancer cell lines SNU216 and NCI-N87 were treated with or without decursin. Cell growth was evaluated by Cell-Counting Kit-8, colony formation, and BrdU assays, as well as by propidium iodide staining, and autophagic flux was evaluated by western blotting, LC3 puncta, GFP-RFP-LC3, and transmission electron microscopy. Finally, tumor spheroids and patient-derived gastric cancer organoids were used to confirm the effect of decursin in three-dimensional culture.
Results: Decursin reduced the growth and anchorage-dependent viability of gastric cancer cells. LC3 cleavage and LC3-GFP puncta were increased by decursin in a time- and concentration-dependent manner. However, the increase in autophagosome formation did not lead to an increase in autophagic flux. Decursin downregulated cathepsin C (CTSC), a lysosomal protease, irrespective of cellular pH. In addition, knockdown of CTSC reduced the mRNA and protein levels of E2F3, resulting in cell-cycle arrest. Decursin also reduced cell growth in both tumor spheroids and patient-derived gastric cancer organoids.
Conclusion: The results demonstrated that decursin inhibited tumor growth and progression by suppressing CTSC-mediated autophagic flux and cell-cycle progression. Therefore, decursin is a novel inhibitor of autophagic flux, with potential for the treatment of gastric cancer.
Citation Format: Solbi Kim, Mina Joo, Nayoung KIM, Myung-Won Lee, Heung Jin Jeon, Hyewon Ryu, Ik-Chan Song, Hyo Jin Lee. Decursin inhibits gastric cancer cell growth and autophagic flux by suppressing cathepsin C [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4170.
Abstract 4177: Preclinical development of ABM-1310, a novel BRAF Inhibitor to treat cancer with brain metastasis
Authors: Hu Yong , Chen Chen , Huang Charles , Xu Min , Chen Youqin , Chen Xiyuan , Zhao Li 
Published: September 2020

Abstract
BRAF is a key molecule activated by RAS in the MAPK pathway that mainly controls cell proliferation. BRAF mutation is detected in about 8% of all cancer population, and more than 50% is BRAFv600e, which causes constitutive MAPK activation. BRAFv600 mutation is found in various cancers such as melanoma, colorectal cancer, glioma, lung cancer, thyroid cancer, pancreatic cancer, ovary cancer etc.
ABM-1310 is a novel small molecule BRAF inhibitor that specific inhibits BRAFv600 mutant form with high water solubility, cell permeability, and blood brain barrier (BBB) penetration. Although current target or immune-therapies are reported with some variable effects, melanoma with brain metastasis is still a significant challenge in clinic. With high BBB penetration and high exposure in brain, ABM-1310 has good potential to treat tumors bearing BRAFv600 mutation with brain metastasis.
In-vitro data shown similar on-target enzyme activity of ABM-1310 to marketed BRAF inhibitors on BRAFv600e, as well as high anti-proliferation activity in multiple cancer cell lines with BRAF V600E mutation like A375, Colo-829, and HT-29 etc. In vivo pharmacology studies demonstrated that ABM-1310 had good potency of tumor growth inhibition with oral dose as low as 1mg/kg/day. ABM-1310 treatment also improved animal overall survival in several cell-line derived xenograft (CDX) models, including subcutaneous, intracranial and intracardiac melanoma models. Non-clinical pharmacokinetics studies also shown ABM-1310 had a favorable ADME profile both in vitro and in vivo in animals. ABM-1310 demonstrated excellent brain penetration in animals.
Single-dose, seven-day repeat dose non-GLP studies and four-week GLP toxicity studies in SD rats and beagle dogs all revealed that ABM-1310 had a good safety profile with NOAEL of 100mg/kg/day in SD rats and 30mg/kg/day in beagle dogs.
Based on these supportive preclinical study results, IND of ABM-1310 was submitted in 2019 Q4 to investigate its safety in humans as signal reagent, which will be followed by further clinic development of ABM-1310, or combination with other molecules to treat cancers with BRAFv600 mutation, especially with brain metastasis.
Citation Format: Yong Hu, Chen Chen, Charles Huang, Min Xu, Youqin Chen, Xiyuan Chen, Li Zhao. Preclinical development of ABM-1310, a novel BRAF Inhibitor to treat cancer with brain metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4177.