bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2534: Targeting defective necroptosis in colorectal cancer to overcome therapeutic resistance
Authors: Ermine Kaylee , Chen Dongshi , Lu Xinyan , Yu Jian , Zhang Lin 
Published: April 2023

Abstract
Colorectal cancer (CRC) is a leading cause of cancer related deaths in the United States. CRC patients are often treated with the chemotherapeutic drug 5-fluorouracil (5-FU), but resistance often occurs. It is well-established that 5-FU induces apoptosis in cancer cells, but apoptosis inhibition does not block the anticancer effect of 5-FU, suggesting a role of non-apoptotic cell death. Necroptosis is a regulated form of necrosis controlled by Receptor-Interacting Protein kinase 1 (RIP1), RIP3, and Mixed Lineage Kinase domain-Like (MLKL), and its role in anticancer therapy remains unclear. TCGA RNAseq data show that RIP3 is significantly downregulated in primary CRC tumors, which is correlated with worse outcomes. RIP3 downregulation also occurs in established CRC cell lines and is associated with decreased 5-FU sensitivity. Therefore, we hypothesize that necroptosis may play a critical role in anticancer therapy and that restoring defective necroptosis may enhance therapeutic sensitivity. Our studies show that RIP3-expressing (RIP3+) CRC cells undergo both apoptosis and necroptosis in response to 5-FU. As expected, knock-out of RIP3 in RIP3+ CRC cells resulted in decreased 5-FU sensitivity, as well as abrogated necroptosis induction. Additionally, stable restoration of RIP3 in RIP3-silenced (RIP3-) CRC cells appeared to enhance 5-FU response, under conditions where apoptosis was inhibited. Furthermore, we explored alternative ways to induce necroptosis in RIP3-silenced cells. Together, our results suggest that necroptosis plays an important role in 5-FU-induced cell death in CRC. These results provide novel insights into the role of necroptosis in anticancer therapy in CRC, which could be used for development of improved therapies and personalized medicine based on RIP3 status.
Citation Format: Kaylee Ermine, Dongshi Chen, Xinyan Lu, Jian Yu, Lin Zhang. Targeting defective necroptosis in colorectal cancer to overcome therapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2534.
Abstract 2546: Targeting of AKT/β-catenin signaling pathways driven hepatocellular carcinoma cell lines by combined treatment of HDAC and multi-kinase inhibitors
Authors: Elberawi Mohamed Mahmoud , Abdulqadir Mohamed , Sultan Ahmed Samir 
Published: April 2023

Abstract
Hepatocellular carcinoma (HCC) is the dominant type of liver cancer exhibiting high mortality and poor prognosis with the fastest rate of death due to its aggressiveness and lack of effective therapies. Beta-catenin is a key player transcriptional factor, which orchestrates gene expression in HCC progression. Activation of β-catenin is promoted by its phosphorylation by AKT. Although the studies of metastatic behavior of β-catenin over-expressing HCC cells are not clear, the present study is focusing on the relationship between chromatin remodelling through deacetylation and phosphorylation of β-catenin by AKT. The current study investigated the role of a combination of Lenvatinib, a multi-kinase inhibitor, and Belinostat, a histone deacetylase inhibitor (HDACI), on two HCC cell lines, Hep G2 and Hep 3B, respectively. In-depth, our data showed that combined treatment significantly induced morphological changes in the tested cell lines with activation of caspase-3 and pre-apoptotic signals of Bcl-2, Bcl-XL, and Bax, indicating apoptotic induction after 48 hours of treatment compared to the control or each drug separately. The calculated IC50 was 1µmol/L for Belinostat and 25 n mole/L for Lenvatinib. Western blotting analysis reveals that the combined treatment for 48 hours inhibited the oncogenic β-catenin, AKT, and TGFβ expression in a dose-dependent manner.In addition, the combined treatment inhibited the localization of beta-catenin in the tested cell nuclei after 48 hours as confirmed by IHC staining. Statistical analysis proved that the combination of both drugs significantly decreased the proliferation and invasion of both cell lines (P&lt;0.01, ANOVA) compared to each drug alone. In addition, the percentage of apoptotic cells was significantly increased and showed a cell cycle arrest in the G0/G1 phase of Hep-G2 cells after 48 hours of combined treatment as confirmed by flow cytometry. All in all, our data show that targeting AKT/β-catenin driven HCC progression can be targeted by Lenvatinib and Belinostat combined treatment.
Citation Format: Mohamed Mahmoud Elberawi, Mohamed Abdulqadir, Ahmed Samir Sultan. Targeting of AKT/β-catenin signaling pathways driven hepatocellular carcinoma cell lines by combined treatment of HDAC and multi-kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2546.
Abstract 2587: AHR-WLS complex correlates with poor prognosis in B-cell precursor acute lymphoblastic leukemia
Authors: Wang Li-Ting , Hsu Shih-Hsien 
Published: April 2023

Abstract
B cell precursor acute lymphoblastic leukemia (BCP ALL), the most common childhood cancer, is a malignant disorder that originates from the lymphoid precursor cells committed to B-cell lineage in the bone marrow. Although genetic abnormalities disturb the normal maturation process of these lymphoid precursor cells resulting in the formation of leukemia cells and suppression of normal hematopoiesis, environmental factors seem to modulate disease progression. The underline mechanism is not clear yet. In this study, we hypothesize environmental pollutants-AHR and small molecule chaperone-WLS are involved in promoting the oncogenic effect and disease relapse of BCP-ALL leukemia cells and inhibiting normal hematopoietic function. Here, we show that Indeno [1,2,3-cd] pyrene (IP) promotes oncogenic activities in vitro and in vivo. Mechanistically, IP treatment activates AHR-IDOs axis to enhance tryptophan metabolism and bioactive metabolite- kynurenine (kyn) level, further promoting kyn-AHR signal enhanced loop. In orthotopic xenograft mouse model, IP treatment decreases disease relapse time and increases cell population of BCP ALL. These results show PAH (IP) exposure promotes the disease progression of BCP ALL.
Citation Format: Li-Ting Wang, Shih-Hsien Hsu. AHR-WLS complex correlates with poor prognosis in B-cell precursor acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2587.
Abstract 2606: Requirement of MDM2 E3 ligase activity for regulating p53 during normal development, cell cycle regulation and genome integrity
Authors: Chinnam Meenalakshmi , Lama Rati , Xu Chao , Zhang Xiaojing , Cedeno Carlos , Wang Yanqing , Stablewski Aimee B. , Goodrich David W. , Wang Xinjiang 
Published: April 2023

Abstract
p53 tumor suppressor, the most mutated gene in human cancer, is negatively regulated by MDM2 and MDM4 proteins. Two distinct mechanisms of MDM2/MDM4 regulation of p53 include, one, suppression of p53 transactivation activity by direct interaction of MDM2/MDM4 with p53 protein, thus blocking its transactivation interface and two, targeting p53 to proteasomal degradation by MDM2 E3 ligase activity. However, the importance of these mechanisms in normal p53 regulation in vivo has remained controversial. To genetically separate these two mechanisms of p53 regulation we generated a novel Mdm2 mutant mouse (Mdm2L466A) that lacks E3 ligase activity but retains the ability of Mdm2 to heterodimerize with Mdm4 and inhibit p53 transactivation. Homozygous Mdm2L466A mice are embryonic lethal due to dysregulated p53 activity, thus demonstrating Mdm2 E3 ligase mediated regulation of p53 is essential during embryonic development. Additionally, we uncovered novel p53-independent functions of MDM2 E3 ligase in cell cycle regulation and genome integrity in cells. Cells lacking MDM2 E3 ligase activity have defective G2-M transition during cell cycle and developed elevated levels of aneuploidy regardless of p53 status. This study unequivocally demonstrates the requirement of Mdm2 E3 ligase activity for normal regulation of p53 and uncovers previously unknown p53-independent role of Mdm2 in cell cycle regulation and maintaining genome integrity. A current therapeutic approach involves blocking MDM2-p53 interaction to promote p53 tumor suppression function in cancer cells. Our findings suggest that this approach alone is insufficient because MDM2 has other potential oncogenic mechanisms independent of its role as negative regulator of p53. Hence, targeting MDM2 E3 ligase activity is likely to be more effective cancer therapy as it addresses both p53-dependent and p53-independent oncogenic mechanisms of MDM2.
Citation Format: Meenalakshmi Chinnam, Rati Lama, Chao Xu, Xiaojing Zhang, Carlos Cedeno, Yanqing Wang, Aimee B. Stablewski, David W. Goodrich, Xinjiang Wang. Requirement of MDM2 E3 ligase activity for regulating p53 during normal development, cell cycle regulation and genome integrity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2606.
Abstract 2649: Discovery of a potent, selective, and tumor-suppressing antibody antagonist of DKK1
Authors: Wang Linya , Peterson Sean M. , Lujan Ana , Chan Kara Y. , Hu Cameron F. , Villalta Mouna , Yuan Tom Z. , Han Zhen , Yang Marisa , Prabhu Vishwas , Htoy Tammy , VanDyke Paul , Holliday Carson , Franco Hector , Wadhwa Hansika , Giang Hoa , Stafford Ryan , Axelrod Fumiko , Sato Aaron 
Published: April 2023

Abstract
Wnt signaling plays an important role in embryonic development and tumorigenesis. These biological effects are exerted by activation of the β-catenin/TCF transcription complex and consequent regulation of a set of downstream genes. Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1) has been shown to be a potent inhibitor of Wnt signaling via competing Wnt binding to LRP5/6. DKK1 is tumorigenic in multiple cancer types and also immunosuppressive via MDSCs and NK cells. Emerging evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. With Twist’s precision DNA writing technologies, we have created phage display libraries with diversity greater than 1 × 1010, and utilized machine learning model for optimal discovery. In this study, we discovered anti-DKK1 antibodies blocking the binding of DKK1 to the receptor. The in vitro functional assays showed that the interaction of Wnt to its receptor was restored in the presence of anti-DKK1 antibodies, resulting in TCF/LEF signaling upregulation. Moreover, anti-DKK1 antibodies induced immune cell activation, and led to tumor cell cytotoxicity. In addition, anti-DKK1 antibodies binding to different domains of DKK1 led to different functional effect. In vivo study indicated anti-DKK1 antibodies is potent in tumor regression. Our anti-DKK1 leads shows promising efficacy in cancer immunotherapy.
Citation Format: Linya Wang, Sean M. Peterson, Ana Lujan, Kara Y. Chan, Cameron F. Hu, Mouna Villalta, Tom Z. Yuan, Zhen Han, Marisa Yang, Vishwas Prabhu, Tammy Htoy, Paul VanDyke, Carson Holliday, Hector Franco, Hansika Wadhwa, Hoa Giang, Ryan Stafford, Fumiko Axelrod, Aaron Sato. Discovery of a potent, selective, and tumor-suppressing antibody antagonist of DKK1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2649.
Abstract 2668: Long non-cording RNA TUG1 promotes cisplatin resistance in ovarian cancer via DNA polymerase eta
Authors: Sonobe Ryosuke 
Published: April 2023

Abstract
Ovarian cancer (OVCA) is the most malignant gynecologic cancer. Despite the use of surgery and platinum-based chemotherapy, the 5-year survival rate is approximately 30% at the time of diagnosis. Cisplatin inhibits DNA synthesis by cross-linking DNA and then induces cell apoptosis. However, cisplatin resistance often causes treatment failure and tumor relapse in OVCA patients. To overcome the cisplatin resistance in OVCAs, we studied the mechanism of chemoresistance by a long non-coding RNA (lncRNA), TUG1 (taurine upregulated gene 1), which is associated with carcinogenesis and drug sensitivity in OVCAs. The expression level of TUG1 in cisplatin-resistant OVCA clinical samples is significantly higher than that of cisplatin-sensitive samples by public database. A depletion of TUG1 increased the sensitivity of OVCA cells to cisplatin together with upregulation of a set of miRNAs in vitro. We examined the targets of miRNAs and found that TUG1 depletion downregulates DNA polymerase eta (Polη) by upregulating the miRNAs. Polη is a major translesion DNA synthesis (TLS) DNA polymerase, which bypasses DNA lesions produced by DNA damaging agents and helps DNA replication. The expression level of Polη showed a positive correlation with that of TUG1 in OVCA clinical samples. Overexpression of Polη recovered cisplatin resistance in TUG1-depleted cells. Finally, cisplatin treatment combined with TUG1 depletion effectively inhibited tumor growth in xenograft mouse models, indicating the efficacy of TUG1 depletion in vivo. Our data provide a strong rationale for targeting TUG1 as a novel therapeutic approach to overcome cisplatin resistance in OVCA.
Citation Format: Ryosuke Sonobe. Long non-cording RNA TUG1 promotes cisplatin resistance in ovarian cancer via DNA polymerase eta [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2668.
Abstract 2689: Targeting the proteasome pathway in dactinomycin resistant Wilms tumors
Authors: Tiburcio Patricia Denise Ballesteros , Chen Kenneth S. 
Published: April 2023

Abstract
Nephroblastomas or Wilms tumors are the most common pediatric renal cancer. Across all cases, the 5-year overall survival is over 90%. This is largely in part due to brute-force, chemotherapy regimens such as dactinomycin (actD) that have been routinely used to treat Wilms tumors. However, those that do respond to treatment still face a 15% chance of relapse. Patients with anaplastic tumor histology require more toxic therapies, and yet they still face a worse prognosis of only 66% 4-year survival and relapse rate of 43%. Furthermore, recurrence cuts survival rate down to 50%. With the widespread use of actD in Wilms tumors and other childhood malignancies, understanding the mechanism to recalcitrance against this chemotherapy can potentially reveal important vulnerabilities that can be exploited in the clinic. While transcriptomic and genomic analyses have been done in Wilms tumors, no targetable pathways have been identified in actD chemotherapy-resistant and anaplastic tumor cases. To that end, we performed ribosome sequencing of actD-treated anaplastic Wilms tumor cell line WiT49 and uncovered that the proteasome pathway is preferentially translated. Moreover, loss of proteasome subunits in a CRISPR library dropout screen sensitized the cells to actD. Consistent with these findings we found upregulation of proteasome subunit levels and proteasome enzymatic activity in Wilms tumor lines following actD treatment. To interrogate the effect of cotreating bortezomib with dactinomycin in vivo, we subcutaneously implanted anaplastic Wilms tumor patient-derived xenograft (PDX) lines in NOD/SCID Gamma (NSG) mice. Combinatorial treatment was found to be retard tumor growth compared to vehicle and single drug conditions. With further investigation, our findings can provide a foundation for exploring proteasome inhibitors with dactinomycin in clinical trials. Our study has important implications to improving the outcomes for not just for recurrent and anaplastic Wilms tumors, but to other pediatric cancers that use actD as well.
Citation Format: Patricia Denise Ballesteros Tiburcio, Kenneth S. Chen. Targeting the proteasome pathway in dactinomycin resistant Wilms tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2689.
Abstract 2701: pH-responsive targeted-nanoparticle releases encapsulated ERK-inhibitor effectively in the hypoxic microenvironment and sensitizes gemcitabine in pancreatic cancer cells
Authors: Dutta Debasmita , De Archana , Hazra Raj Shankar , Ghosh Pratyusha , Quadir Mohiuddin , Banerjee Snigdha , Banerjee Sushanta K. 
Published: April 2023

Abstract
Therapeutic strategies for Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, remain challenging with poor prognosis, high mutational rate, and lowest patient survival among other cancers. The treatment options for managing PDAC are limited to surgery, radiation, and chemotherapy. However, surgery is the only treatment option that can cure the disease in about twenty percent of cases. Thus, Gemcitabine (GEM) remains the first-line drug in the clinic for PDAC treatment despite suboptimal clinical effects. These are primarily due to weak drug delivery and the development of chemoresistance resulting from mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic cages. Several new therapeutic approaches, including nanoparticle-based drug delivery procedures, are currently being investigated. In this study, we designed a pH-responsive PEG-b-poly (carbonate) block copolymer encapsulated ERK inhibitor (SCH772984) nanoparticles surface functionalized with tumor-penetrating peptide, iRGD to specifically target PDAC tumor tissue. By utilizing the ERKi-encapsulated pH-responsive targeted nanoparticles, we performed a combinational drug treatment of GEM and ERKi. We found that the pH-responsive targeted nanocarrier efficiently released ERKi in the hypoxic environment. The free GEM, combined with nanoencapsulated ERKi, demonstrated significant synergistic outcomes in vitro colony forming ability, migration, and motility in pancreatic cancer cell line MiaPaCa2. Moreover, combination therapy significantly enhanced the GEM effect in reducing PDAC growth in KPC mice and increasing the survival of the mice. Thus, our studies indicate that pH-responsive targeted nanocarrier-based delivery of ERKi in the hypoxic area of PDAC enhances the efficacy of GEM in PDAC.
Citation Format: Debasmita Dutta, Archana De, Raj Shankar Hazra, Pratyusha Ghosh, Mohiuddin Quadir, Snigdha Banerjee, Sushanta K. Banerjee. pH-responsive targeted-nanoparticle releases encapsulated ERK-inhibitor effectively in the hypoxic microenvironment and sensitizes gemcitabine in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2701.
Abstract 2715: Utilizing a pH sensitive peptide (pHLIP) for tumor targeted delivery of an immunogenic peptide motif
Authors: Yurkevicz Annali M. , Liu Yanfeng , Glazer Peter M. 
Published: April 2023

Abstract
Chimeric antigen receptor (CAR) T cell and immune-cell therapies are revolutionizing how patients are treated in the clinic by targeting tumor-specific antigens. Specifically, advances in antigen targeting of CD20 and CD19 with CAR T cell therapy has increased overall survival of this patient population and has influenced to expand T cell repertoire to novel antigen targets. However, limitations to these cell-based therapies are the lack of development against solid tumor antigens, partly due to the paucity of antigen candidates that are sufficiently specific to epithelial cancers. Therefore, technologies that can mark tumor cells for immune recognition could prove beneficial in the treatment of these solid cancers. This project aims to artificially deliver an antigen to tumor cells by harnessing a universal property of tumors: acidic microenvironment. The pH low insertion peptide (pHLIP) is a technology that targets solid tumors based on the low pH produced by the Warburg effect. pHLIP-conjugates have undergone extensive development for drug delivery, with one notable candidate CBX12 entering phase I clinical trials in 2021. Our system uses a pHLIP-conjugated SIINFEKL peptide (derived from ovalbumin) to serve as our model antigen system, with SIINFEKL-targeting T cells (OT1) that can be used as a tool to investigate antigen delivery, recognition, and functionality. We have observed through immunofluorescence that B16 F10 mouse melanoma cells treated in vitro with the 1uM pHLIP-SIINFEKL construct under acidic conditions can recruit OT1 cells and induce a T cell synapse. Preliminary in vivo experiments in C57BL/6-Tg OT1 mice bearing B16 F10 flank tumors showed that treatment with pHLIP-SIINFEKL by intravenous administration led to a suppression of tumor growth compared to controls, with approximately 50% smaller fold change in tumor volume. Cumulatively, these initial results suggest that pHLIP-SIINFEKL can be delivered to tumors to recruit OT1 cells to engage in antigen recognition and lead to efficacy in tumor growth delay in vivo. This technology has the capability to provide a novel approach to decorate solid tumors with engineered antigens for enhanced immune recognition and anti-tumor efficacy.
Citation Format: Annali M. Yurkevicz, Yanfeng Liu, Peter M. Glazer. Utilizing a pH sensitive peptide (pHLIP) for tumor targeted delivery of an immunogenic peptide motif [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2715.