bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1501: Epigenetic dedifferentiation as a therapeutic strategy in adrenal cancer
Authors: Mohan Dipika R. , Borges Kleiton S. , Finco Isabella , LaPensee Christopher R. , Rege Juilee , Little Donald W. , Else Tobias , Almeida Madson Q. , Dang Derek , Haggerty-Skeans James , Latronico Ana Claudia , Mendonca Berenice B. , Auchus Richard J. , Rainey William E. , Marie Suely K. , Giordano Thomas J. , Venneti Sriram , Fragoso Maria Candida B. , Breault David T. , Lerario Antonio M. , Hammer Gary D. 
Published: April 2023

Abstract
Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex without curative medical therapies. CIMP-high is an aggressive ACC molecular subtype defined by global CpG island hypermethylation with paradoxical activation of adrenal differentiation (driven by master transcription factor SF1) and stemness (driven by β-catenin). We show DNA hypermethylation redistributes histone methyltransferase EZH2 and its mark, H3K27me3. EZH2 inhibition remains lethal to CIMP-high ACC cells, erasing transcriptional programs without altering DNA methylation. We reconcile this phenomenon by discovery of two nuclear complexes, SF1/β-catenin and EZH2/β-catenin, present in physiology and persistent through advanced ACC. We find SF1/β-catenin is a chromatin-bound complex that controls the ACC super-enhancer landscape, while EZH2/β-catenin is restricted to off-chromatin pools. EZH2 inhibition purges SF1/β-catenin from chromatin, sparing EZH2/β-catenin, inducing dedifferentiation and restraining ACC growth in vitro and in vivo. Our studies illustrate how cell-of-origin programs dictate cancer evolution, exposing differentiation as an therapeutic vulnerability.
Citation Format: Dipika R. Mohan, Kleiton S. Borges, Isabella Finco, Christopher R. LaPensee, Juilee Rege, Donald W. Little, Tobias Else, Madson Q. Almeida, Derek Dang, James Haggerty-Skeans, Ana Claudia Latronico, Berenice B. Mendonca, Richard J. Auchus, William E. Rainey, Suely K. Marie, Thomas J. Giordano, Sriram Venneti, Maria Candida B. Fragoso, David T. Breault, Antonio M. Lerario, Gary D. Hammer. Epigenetic dedifferentiation as a therapeutic strategy in adrenal cancer [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 1501.
Abstract 1572: Antiproliferative activity of enzalutamide and alisertib in prostate cancer cells overexpressing HMGA2
Authors: Liadi Yusuf Mansur , Odero-Marah Valerie 
Published: April 2023

Abstract
Prostate cancer is one of the common types of cancer and remains the second leading cause of cancer-related deaths in men in the United States. High Mobility Group Protein AT-hook 2 (HMGA2), a DNA binding protein acts as a transcriptional regulating factor in gene transcription and facilitates epithelial-mesenchymal transition (EMT), which is usually the onset of prostate cancer progression and metastasis. HMGA2 isoforms include wild-type or full length that induces EMT, while the truncated isoform is associated with elevated proliferation and migration. Enzalutamide is a second-generation antiandrogen drug known to inhibit androgen receptor (AR) translocation into the nucleus by competitively binding AR and preventing androgen binding. Alisertib (MLN8237) is a small molecule inhibitor of Aurora kinase A has been utilized in clinical trials for neuroendocrine cancers and can also inhibit EMT. We aim to investigate which of the two drugs is effective in reducing proliferation in prostate cells overexpressing HMGA2 isoforms (wild-type and truncated). In this study, we treated LNCaP cells overexpressing HMGA2 with enzalutamide (1-30 µM) and alisertib (2.5-40 µM). Treatment with enzalutamide and alisertib indicated a dose-dependent decrease in cell proliferation with optimal dose at 20 µM for both drugs. LNCaP cells (LNCaP Neo) expressing low level of HMGA2 were observed to respond better to enzalutamide treatment, while those overexpressing HMGA2 (WT and TR) respond better to alisertib treatment. Interestingly, treatment with 20 µM enzalutamide and alisertib followed by Western blot indicated enzalutamide to have no effects on protein expression of HMGA2 isoforms, but greatly decreased the expression of AR in LNCaP cell overexpressing truncated HMGA2. On the other hand, alisertib increased the expression of wild-type HMGA2 whilst having no effects on protein expression of AR. Both drugs at 20 µM did not have any significant effect on the expression of EMT markers (snail and vimentin).In conclusion, alisertib is more potent than enzalutamide in decreasing cell proliferation in prostate cancer cells expressing HMGA2. Further studies need to be conducted to understand the role of HMGA2 in promoting resistance to enzalutamide and whether alisertib may be a better drug for patients that express HMGA2.
Acknowledgements: These studies were supported by NIH/NIMHD 2U54MD007590 and 5U54MD013376-8281.
Citation Format: Yusuf Mansur Liadi, Valerie Odero-Marah. Antiproliferative activity of enzalutamide and alisertib in prostate cancer cells overexpressing HMGA2 [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 1572.
Abstract 1574: Homoharringtonine is effective in treating acute lymphoblastic leukaemia via modulation of apoptotic pathway
Authors: Jiao Anan , Yuen Kei Ching , DIN Rahman Ud , Wong On Yi Phoebe , Chun-Fung Sin 
Published: April 2023

Abstract
Acute lymphoblastic leukaemia (ALL) is an aggressive and highly lethal malignancy caused by clonal mutations in lymphoid progenitor cells. The prognosis for adult ALL remains poor, with only 30-40% of adult patients achieving long-term remission. Therefore, novel therapies are needed. Homoharringtonine (HHT) is a natural-derived plant alkaloid from tree of Cephalotaxus. FDA approved the use of HHT in the treatment of chronic myeloid leukaemia (CML) in 2012. Limited pre-clinical or clinical studies were conducted for therapeutic efficacy and molecular mechanisms of HHT on ALL to the best of our knowledge. To fill this knowledge gap, here we investigated the antileukemic activity of HHT in T lymphoblastic leukaemia (T-ALL) and B lymphoblastic leukaemia (B-ALL). In this study, T-ALL cell lines namely JURKAT, MOLT-4, LOUCY, CCRF-CEM and B-ALL cell clines namely PALL-2, SUP-B15 were used. Cell viability was reduced upon treatment of HHT at time and dose-dependent manner. Percentage of apoptotic cells that determined by flow cytometric analysis of PI and Annexin V double staining was increased upon treatment of HHT. Moreover, HHT was able to induce apoptosis in both T-ALL and B-ALL cell lines. Western blot analysis showed that MCL-1 protein level was reduced upon treating with HHT for 24 hours. The above findings provide conclusive evidence for the therapeutic effect of HHT on various ALL cell lines by modulating the apoptotic pathway.
Citation Format: Anan Jiao, Kei Ching Yuen, Rahman Ud DIN, On Yi Phoebe Wong, Sin Chun-Fung. Homoharringtonine is effective in treating acute lymphoblastic leukaemia via modulation of apoptotic pathway [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 1574.
Abstract 1596: The promising recipe sorafenib rosiglitazone and adipogenesis inducers cocktail for in vitro hepatocellular carcinoma differentiation induction besiege carcinogenesis
Authors: Anis Aya , Mostafa Ahmed M. , Hamdy Nadia M. , Sultan Ahmed S. 
Published: April 2023

Abstract
Aim: The present study is focusing on using sorafenib, rosiglitazone, and adipogenesis-inducers cocktail (Insulin, Dexamethasone and IBMX) as a combination treatment to induce hepatocellular carcinoma (HCC) cell lines differentiation into adipocyte functioning cells, a strategy for effecting examined cancer cell lines to lose carcinogenicity properties and hopefully, turning into near-normal cells, with near-normal activity. The liver is one of the most vital organs in the body, any malfunctioning in the liver affects the whole body's health and performance. By 2040, 1.4 million people could be diagnosed with liver cancer and 1.3 million people could die from the disease, thus, trying an attempt to stop or reverse this cancer, would be a great break-through.
Materials, Methods and Results: Using the current differentiation-induction cocktail to turn HepG2 and Hep3B HCC cancer cells into adipocytes, was confirmed by Oil Red O staining and morphological changes, and significantly expressed "adiponectin" level. Moreover, the cellular molecular markers p53, PPAR-γ, E-cadherin/β-catenin complex, and caspase-3 activities were significantly enhanced in the cocktail induced-differentiated cells, confirming the effectiveness of the proposed cocktail for ameliorating STAT3 together with inducing apoptosis (clonogenicity) , in comparison to control cells or HCC cells treated with the cocktail individual drugs. The differentiation-induction cocktail through rosiglitazone activated PPAR-γ which in turn increased HCC cells sensitivity to insulin to induce lipid uptake. Sorafenib, in the cocktail, role to block tumor cell proliferation via inhibiting STAT3 signaling pathway activation. In conclusion, the current proposed differentiation-induction cocktail after further in vivo confirmation (future prospective) might open a different avenue for liver cancer treatment.
Citation Format: Aya Anis, Ahmed M. Mostafa, Nadia M. Hamdy, Ahmed S. Sultan. The promising recipe sorafenib rosiglitazone and adipogenesis inducers cocktail for in vitro hepatocellular carcinoma differentiation induction besiege carcinogenesis [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 1596.
Abstract 1650: Discovery of a novel Kevetrin analog as a potential therapeutic for ovarian cancer
Authors: Raza Asif , Krzeminski Jacek , Amin Shantu , Sharma Arun 
Published: April 2023

Abstract
Kevetrin is an investigational new drug in phase I clinical trial on solid tumors (NCT01664000). It has shown its efficacy in various tumors, including lung, breast, colon, and ovarian cancer cell and xenograft models, both in a p53-dependent and -independent manner. In ovarian cancer cell lines with the TP53 mutation, p21 expression was found to be upregulated without the involvement of p53. Additionally, it was proposed that Kevetrin caused the histone deacetylase 6 (HDAC6) enzyme to be downregulated, negatively affecting the HDAC6-Hsp90 chaperone axis and causing the degradation of p53 in the mutant mice. In the present study, we designed and synthesized a novel analog (compound 900) of Kevetrin and its cytotoxicity was assessed using four different ovarian cancer cell lines viz. OVCAR-3, OVCAR-10, ES2, drug-resistant HeyA8 cells, and normal fibroblast cells (FHC). Compared to the control and Kevetrin, compound 900 inhibited the ovarian cancer cell viability in a dose- and time-dependent manner. The IC50 value of compound 900 was 0.8 μM, 0.7 μM, 0.8 μM, and 0.9 μM for OVCAR-3, HeyA8, OVCAR-10, and ES2 cells, respectively, while for Kevetrin the IC50 value was &gt;100 μM for 48 h treatment. Compound 900 was thus found to be &gt;100 times more potent than standard Kevetrin. To further acquaint the effect of 48 h treatment on cell proliferation, we performed trypan blue cell viability assay, trypan blue dye exclusion assay, Annexin V/7-AAD, Caspase 3/7 apoptosis assays, and Western blotting of apoptotic proteins involved in apoptosis. Compound 900 significantly induced apoptosis in OVCAR-3 and HeyA8 cells in a dose-dependent manner. Upregulation of several apoptotic proteins, as evident by Western blot, suggested that 900 causes the induction of apoptotic pathways efficiently. Further, the cell cycle analysis showed a significant arrest of OVCAR-3 and HeyA8 cells in the S-phase, which was further confirmed by the analysis of cyclin A2, cyclin-E1, p21, and p27 protein expression. Additionally, compound 900 caused a significant increase in the expression of the cell cycle inhibitory genes p21 and p27 in a p53-independent manner, compared to Kevetrin. Kevetrin has shown promise in preliminary clinical studies in solid tumor patients. The new analog 900 is &gt;100 fold more potent than Kevetrin and holds great promise to be developed further for ovarian and other mechanistically relevant cancers.
Citation Format: Asif Raza, Jacek Krzeminski, Shantu Amin, Arun Sharma. Discovery of a novel Kevetrin analog as a potential therapeutic for ovarian cancer [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 1650.
Abstract 1728: Exosomal delivery of Fas-associated factor 1 (FAF1), a multifunctional tumor suppressor and genuine exosome cargo, effectively antagonizes tumor growth
Authors: Han Jeong-Hoon , Park DaeHo , Jung Bumjun , Yoo Hyeong-Gwon , Cho Kyung-Ok , Kim Eunhee 
Published: April 2023

Abstract
Introduction: Exosomes are extracellular vesicles of 30-150 nm and can stably deliver their cargos to the target with low immunogenicity and efficient transmission. FAF1 is a genuine exosome cargo and, therefore, loaded into exosomes without additional engineering. FAF1 is a tumor suppressive protein with multifunctional roles including death-promotion (both apoptosis and necrosis), cell cycle arrest, anti-inflammation, and anti-angiogenesis. FAF1 also inhibits metastasis via inhibition of TGF-β pathway. Moreover, FAF1 elicits low expression profiles in several types of cancer. Therefore, this study examined whether exosomal delivery of FAF1 is a plausible strategy for anti-tumor therapeutics.
Methods: Stable suspension cells originated from HEK293 cells inducibly overexpressing FAF1 were screened using Tet on-off system to avoid cell death due to continuous FAF1 expression. FAF1 was overexpressed by Doxycycline induction and the amounts of FAF1 loaded on exosomes were normalized by exosome markers. The efficacy of exosomal FAF1 was evaluated in mouse xenograft models implanted with various human carcinoma cells.
Results: Cell lines showing FAF1 expression with more than 3 fold of control cells were picked. Among FAF1-overexpressing cells, F5-3 cell line showing highest expression of exosomal FAF1 (showing 23 fold of FAF1 loading efficiency compared to parental cells) was used for exosomal source for in vivo experiments. Furthermore, F5-3 produced about 70 times of exosomal FAF1 when compared to that of HEK293 cell in the same volume of culture medium. The exosomal FAF1 produced in F5-3 cells inhibited tumor growth in various cancer types including lung, breast, liver, and pancreas in mouse xenograft models. In addition, exosomal FAF1 consistently demonstrated superior tumor-suppressive potential to soluble FAF1 in all tumors investigated in this study. Also, there were no serious side effects based on weight changes.
Conclusion: This study demonstrated the tumor-suppressive potential of exosomal FAF1, demonstrating the feasibility of exosomal delivery of FAF1 as an efficient therapeutic measure. Furthermore, the selective and massive production properties of F5-3 cell realizes efficient and scalable production of exosomal FAF1.
Citation Format: Jeong-Hoon Han, DaeHo Park, Bumjun Jung, Hyeong-Gwon Yoo, Kyung-Ok Cho, Eunhee Kim. Exosomal delivery of Fas-associated factor 1 (FAF1), a multifunctional tumor suppressor and genuine exosome cargo, effectively antagonizes tumor growth [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 1728.
Abstract 1749: The synergic effect of cisplatin and a chemokine receptor antagonist sensitizes drug resistant gastric cancer cells and inhibits tumoroid formation
Authors: Mora-Lagos Bárbara , Reyes María Elena , Lobos-Gonzalez Lorena , Campo Matías del , Ili Carmen Gloria , Buchegger Kurt , Mora Yuselin , Zanella Louise , Riquelme Ismael , Brebi Priscilla 
Published: April 2023

Abstract
Introduction: Gastric cancer (GC) is an important cause of death worldwide. Cisplatin (CDDP) is the most used drug in the chemotherapy of advanced GC. However, CDDP resistance reduces GC survival. The CCR5/CCL5 axis has been associated with GC development, but its role in CDDP resistance in GC has not been elucidated. The aim of this study was to determine the effects of CCR5/CCL5 axis blockade by a chemokine receptor antagonist (CRA), alone and in combination with CDDP, on in vitro and 3D tumorid models from AGS R-CDDP cells.
Methodology: AGS R-CDDP cells (CDDP-resistant human gastric adenocarcinoma cells) were previously established using a stepwise drug dosing protocol and characterized. CCL5 was selected through transcriptomic analysis and its expression level was validated by qRT-PCR. Cytotoxicity assays were determined by using MTT. Apoptosis and cell cycle assays were evaluated by flow cytometry. Tumoroid formation was performed from AGS R-CDDP cells in low adhesion plates (NunclonTMSpheraTM). After 10 days in culture, tumoroid &gt;150 µm in diameter were scored and pharmacological stimuli were added on days 14, 17 and 20. CRA was used alone and in combination with CDDP in all assays.
Results: CRA/CDDP combination triggered a re-sensitized phenotype in AGS R-CDDP cells, decreasing cell viability but not increasing apoptosis compared to independent treatments. AGS R-CDDP cells treated with CRA/CDDP were mainly arrested in S phase. CCL5 showed a decrease in mRNA levels after the CRA/CDDP combination compared to separate treatments. AGS R-CDDP cells showed a higher potential in the ability to form tumoroids compared to AGS WT cells. Finally, CRA/CDDP combination inhibited tumoroid formation compared to independent treatments.
Discussion and Conclusion: CCL5 showed a decrease in mRNA levels after the CRA/CDDP combination, possibly correlating with allosteric inhibition of the CCR5 receptor. CRA/CDDP combination has a synergic effect that sensitizes AGS R-CDDP cells and inhibits tumoroid formation. This combination could be used as a potential coadjuvant in GC therapy allowing to reduce the doses of CDDP and therefore to reduce side effects.
Citation Format: Bárbara Mora-Lagos, María Elena Reyes, Lorena Lobos-Gonzalez, Matías del Campo, Carmen Gloria Ili, Kurt Buchegger, Yuselin Mora, Louise Zanella, Ismael Riquelme, Priscilla Brebi. The synergic effect of cisplatin and a chemokine receptor antagonist sensitizes drug resistant gastric cancer cells and inhibits tumoroid formation [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 1749.
Abstract 1772: Development of a novel L1CAM-targeted CAR-T, CX804, and its therapeutic efficacy in ovarian and gastric cancer
Authors: Che Xiumei , Yun Un-Jung , Lee Seokwon , Kim Youngyoub , Lee Junshub , Chae Jina , Suh Jehee , Nam Eun-Ji , Kim Gun Min , Kim Hyoyoung , Jung Minkyu 
Published: April 2023

Abstract
L1 cell adhesion molecule (L1CAM) is involved in cancer development and aberrantly expressed in various tumor. It is also associated with aggressive progression, metastasis, and poor prognosis. Public database, a Kaplan-Meier plotter (http://www.kmplot.com) shows that L1CAM high-expression significantly reduced survival of ovarian and gastric cancer patients. We developed a novel chimeric antigen receptor (CAR)-T cell targeted to L1CAM. A novel scFV candidate (Clone H8) to L1CAM was obtained by bio-panning of phage displaying human synthetic scFv fragments to human and mouse L1CAM proteins. H8 scFV was linked to IgD-IgG1 hinge, CD28 transmembrane domain, CD28 and ICOS co-stimulation domain, and CD3ζ domain, resulting in CX804 CAR-T. The efficacy of L1CAM CAR-T cells, CX804 showed correlation with the level of L1CAM in human ovarian and gastric cancer cells. CX804 exerted cytotoxicity toward 293T cells expressing human or mouse L1CAM protein. CX804 also reacted with L1CAM-positive ovarian SKOV3 cancer cell and gastric MKN-28 and AGS cancer cells and secreted T-cell activation cytokines, IFN-γ and TNF-α, in response to these cells. However, CX804 rarely lysed L1CAM-negative normal 293 cells and SNU-719 gastric cancer cells. Furthermore, L1CAM CAR-T cells dramatically lysed high L1CAM expressing patient derived cell (PDC) of gastric cancer compared with low L1CAM expressing PDC cell. Xenograft model of ovarian cancer was developed by intraperitoneal (IP) injecting SKOV3-Fluc cells into NOD/SCID or NSG mice. CAR-T cells were administrated via intravenous (IV) or IP route on 5 days after tumor inoculation. Administration of CX804 significantly decreased tumor burden and increased survival in mouse model of ovarian cancer. Route of administration significantly affected bio-distribution and antitumor effect of CX804 where antitumor activity of CX804 was only observed when CX804 were given IP, but not the IV route. Taken together, our results suggest that CX804 exerts potent and specific effect against L1CAM positive cancer cells in vitro and in vivo. Furthermore, we propose that newly established CAR-T cells targeting L1CAM facilitate therapy against L1CAM-positive ovarian and gastric cancer patients
Citation Format: Xiumei Che, Un-Jung Yun, Seokwon Lee, Youngyoub Kim, Junshub Lee, Jina Chae, Jehee Suh, Eun-Ji Nam, Gun Min Kim, Hyoyoung Kim, Minkyu Jung. Development of a novel L1CAM-targeted CAR-T, CX804, and its therapeutic efficacy in ovarian and gastric cancer [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 1772.