bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4399: HMGA1 is an epigenetic regulator and plays a critical role in melanoma recurrence
Authors: Mou Haiwei , DeRosa Kristen , Yakovishina Veronika , Chen Yeqing , Reynolds Abdiel Mandella , Xiao Min , Thomas Monzy , Herlyn Meenhard 
Published: March 2024

Abstract
Among various genetic mutation in melanoma, BRAFV600E is one of the key drivers of melanoma initiation and progression and has become the frontline target in clinical trials. Although BRAF/MEK inhibitors show very promising therapeutic outcomes, recurrence or relapse is still a major challenge and its underlying mechanisms are still poorly understood. We hypothesized that survival of recurrent tumors is BRAF independent and relies on epigenetic reprogramming. To test our hypothesis, we used either pharmacological inhibition of BRAF/MEK or CRISPR/Cas9 mediated knockout of BRAF to create cell/tumor models of BRAF-independent survival. Cut&Run sequencing was then used to identify epigenetic alterations regulated by H3K4me3 or H3K27Ac in a genome scale and capture the landscape of epigenetic alterations of BRAF-independent cell survival. Combining regular bulk RNAseq, we narrowed down our top candidates and focused on one of the functionally validated candidates, HMGA1. Interestingly, CRISPR/Cas9 mediated HMGA1 knockout cells show significantly slower growth in both in vitro colony formation assays and in vivo xenografts assay in BRAF/MEK resistant Patient-Derived-Xenograft (PDX) tumor models resembling melanoma recurrence. Furthermore, we selected CRISPR/Cas9 single knockout cells of HMGA1, which is a pure genetic depletion model, and confirmed the phenotype of impaired tumor growth of HMGA1 knockout cells. We then performed RNAseq and ChIPseq, and identified downstream targets of HMGA1 and elucidated mechanisms by which HMGA1 reprograms epigenetics of recurrence. Utilizing the single knockout cell, we re-introduced HMGA1 in the pure knockout cells, and anticipated that restoration of HMGA1 in pure HMGA1 knockout cells rescues impaired tumor growth and confer cells resistance to BRAF/MEK inhibition. Finally, we subcutaneously injected the HMGA1 single knockout cells into humanized mice and tested whether epigenetic alterations perturb the immune microenvironment and sensitize cells to immunotherapy. In conclusion, this study sheds new lights on how melanoma cells reprogram the epigenome to develop mechanisms of recurrence. Identification of HMGA1 and its upstream or downstream targets provides potential druggable targets of overcoming relapse after BRAF/MEK inhibitor therapy.
Citation Format: Haiwei Mou, Kristen DeRosa, Veronika Yakovishina, Yeqing Chen, Abdiel Mandella Reynolds, Min Xiao, Monzy Thomas, Meenhard Herlyn. HMGA1 is an epigenetic regulator and plays a critical role in melanoma recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4399.
Abstract 4401: GATA6 is a novel regulator of gene expression and 3D genome in colorectal cancer
Authors: Lyu Huijue , Chen Xintong , Cheng Yang , Zhang Te , Wang Ping , Wong Josiah Hiu-yuen , Wang Juan , Stasiak Lena , Sun Leyu , Yang Guangyu , Wang Lu , Yue Feng 
Published: March 2024

Abstract
Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies with elusive molecular causes. While the abnormal activity of transcription factors has been reported as a vital component of cancer progression, the mechanism through which they function remains unclear. Here, through the analysis of primary human CRC tissue data, we identified GATA6 as a CRC specific regulator, whose expression upregulation is potentially associated with promoter hypomethylation. In the human genome, GATA6 showed preferential binding at tumor specific active enhancers. Through both auxin-inducible degron (AID) and CRISPR knockout, we showed that GATA6 depletion severely impaired clonogenicity and proliferation. GATA6 depletion caused the loss of CRC specific open chromatin, suggesting a specific regulatory role of GATA6 in CRC pathogenesis. Interestingly, we also discovered the co-occupancy of GATA6 with CTCF and its direct involvement in promoter enhancer loops, suggesting the possibility that GATA6 mediate transcriptional regulation through 3D genome. The loss of GATA6 led to alterations in E-P chromatin interactions of a panel of oncogenes, accompanied by the oncogene downregulation. Finally, we showed that GATA6 loss is detrimental to the xenograft tumor growth and thereby rescued mice survival. Taken together, we unrevealed a novel mechanism by which GATA6 contributes to CRC.
Citation Format: Huijue Lyu, Xintong Chen, Yang Cheng, Te Zhang, Ping Wang, Josiah Hiu-yuen Wong, Juan Wang, Lena Stasiak, Leyu Sun, Guangyu Yang, Lu Wang, Feng Yue. GATA6 is a novel regulator of gene expression and 3D genome in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4401.
Abstract 4427: Do changes in lipid metabolism link obesity to pancreatic cancer
Authors: Ghosh Rita , Ajit Deepa , Woodworth Jillian , Fritze Danielle , Cigarroa Francisco G. , Halff Glenn A. , Kumar Addanki Pratap 
Published: March 2024

Abstract
The near equal incidence and mortality rates of pancreatic cancer, combined with projections that pancreatic cancer will become the second-most common cancer-related deaths by 2050, underscore the need to identify patients with early disease and interrupt this trajectory. Obesity, weight gain and waistline have been implicated in increasing the risk of pancreatic cancer. Although metabolomic analyses of pancreatic cancer patients have established correlations between phospholipids, lysophospholipids with treatment outcomes, the association between metabolites, obesity, and pancreatic cancer remains largely understudied. The objective of this pilot study was to determine differences in serum metabolites in obese and overweight pancreatic cancer patients compared with healthy non-obese subjects. Our long-term goal is to develop serum marker(s) that may be used to prevent advanced pancreatic cancer and thus improve outcomes for these patients. Serum was obtained from healthy subjects (n=11; BMI range from 18-25), overweight (n=9; 25-30) and obese (n=7; &gt;30) pancreatic cancer patients from an IRB approved study. Males (n=12) and females (n=15) were represented in the study. Global metabolic profiles were determined using Ultrahigh performance liquid chromatography-tandem mass spectroscopy. Raw data was extracted, peaks were identified and processed at Metabolon using the Laboratory Information Management System. Comparison between overweight pancreatic cancer patients and healthy controls identified 403 biochemicals (111 upregulated and 292 downregulated; p &lt;0.05) and 93 biochemicals (40 upregulated and 53 downregulated; 0.05&lt;p&lt;0.10). Comparison of the differences in biochemicals between obese pancreatic cancer patients and healthy controls showed changes in 293 biochemicals (71 upregulated and 222 downregulated; p &lt;0.05) and 123 biochemical changes at 0.05&lt;p&lt;0.10 (42 increased and 81 decreased). 38 (p &lt;0.05) and 47 (0.05&lt;p&lt;0.10) differential levels of biochemicals were identified when obese and overweight pancreatic cancer patients were compared. Random forest analysis showed that the 30 top ranking biochemicals were involved in lipid metabolism, amino acid metabolism, nucleotide metabolism, peptide, xenobiotics, and carbohydrate metabolism. These data suggest an association between changes in lipid metabolism may be another link between obesity and pancreatic cancer. This project was funded in part by VA-Merit Award (I01 BX003876).
Citation Format: Rita Ghosh, Deepa Ajit, Jillian Woodworth, Danielle Fritze, Francisco G. Cigarroa, Glenn A. Halff, Addanki Pratap Kumar. Do changes in lipid metabolism link obesity to pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4427.
Abstract 4439: Decoding the metabolic symphony TP53 mutation-driven rewiring of cellular metabolism in non-small cell lung carcinoma
Authors: Khan Jiyauddin , Rehman Asad Ur , Mathur Ankit , Bhatrajuc Naveen Kumar , Tulid Anannya , Rajput Divya , Iqbal Mohammad Askandar , Saluja Daman 
Published: March 2024

Abstract
TP53 is a critical regulator of major metabolic pathways. Metabolic reprogramming is one of the "hallmarks of cancer" and drives tumorigenesis. Frequent p53mutations not only eradicate tumour suppressor capacities but also confer various activities that impact the alteration of metabolic pathways now regarded as central for tumour development and progression. We selected three hotspot mutants (R175H, R273H and R249S) and wtp53 to evaluate the effects in the human non-small cell lung carcinoma cell line (NCI-H1299). Differential expressions of p53 mutants were observed in normal and glucose/glutamine starvation. However, WTp53 expression was not found to be affected. Under both the glucose and glutamine starvation, inhibition of the cell growth and migratory potential of mutant cells was observed which was more prominent in glutamine starvation. Basal respiration and ATP production in p53-/- R273H and R249S significantly increased under glucose starvation. However, Non-mitochondrial oxygen consumption and maximal respiration were found to be decreased in all the cell lines. Importantly, the cells harbouring mutation R175H increase the glycolysis and TCA cycle. The metabolic intermediates of the urea cycle were found to be increased by nearly fourfold in R273H cells. Indicating increased utilization of the urea cycle instead of the TCA cycle, which has been known to be fueled by glutamine for anaplerosis. This study demonstrates that mutp53 influences several metabolic processes and has an influence on cancer cell aggression under starvation of main carbon sources (Glucose and Glutamine). In starved conditions, cells with p53 mutations enhance mitochondrial activity and use alternative pathways in non-small cell lung cancer cells. This might provide a foundation for the development of more effective targeted therapeutics/pharmacological approaches toward variants of mutant p53.
Citation Format: Jiyauddin Khan, Asad Ur Rehman, Ankit Mathur, Naveen Kumar Bhatrajuc, Anannya Tulid, Divya Rajput, Mohammad Askandar Iqbal, Daman Saluja. Decoding the metabolic symphony TP53 mutation-driven rewiring of cellular metabolism in non-small cell lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4439.
Abstract 4454: Manipulation of the amino acid metabolism promotes therapeutic efficacy through targeting lysosome in glioblastoma
Authors: Jing Yongwei , Kobayashi Masahiko , Hirao Atsushi 
Published: March 2024

Abstract
Nutrients are converted by the body to smaller molecules, which are utilized for both anabolic and catabolic reactions. Cooperative regulation of these metabolic processes is critical for maintaining tissue homeostasis. Based on these findings, our group has been focusing on how the regulation of nutrient-driven metabolism controls the malignancy of cancer cells. Metabolic regulation has been considered crucial for cellular adaptation to environmental changes and promoting survival and proliferation. Recent studies showed the successful applications of targeting specific nutrients for cancer therapy. In this study, we developed a new lysosome-targeting therapeutic strategy, centered around the manipulation of the amino acid metabolism for GBM. Using patient-derived GBM cells, we found that lysosomal proteolytic activity is a unique metabolic biomarker representing malignant phenotypes of GBM and that it is closely correlated with the efficacy of current conventional therapy for GBM patients. Furthermore, the MiT/TFE family members, TFEB and TFE3, which are the master regulators of lysosomal biogenesis, controlled malignant progression and therapeutic efficacy in vitro and vivo. Combinatory analyses with clinical patient samples and xenograft models demonstrated that the MiT/TFE family plays a crucial role as a regulator of malignant properties in GBM. Analysis of The Cancer Genome Atlas (TCGA) glioma dataset, which includes data from patients with Grade 2, 3, and 4 (GBM) gliomas, showed that higher expression of the MiT/TFE family was significantly associated with shorter survival. Interestingly, we discovered that an essential amino acid controls lysosomal biogenesis and membrane integrity by regulation of nitric oxide signaling pathway. Finally, we screened the potential anti-cancer drugs, including temozolomide, exhibiting the synergy effect in amino acid-restriction conditions by conducting a drug screening using a clinically available anti-cancer drug library. Our study demonstrated that lysosomal function, supported by amino acid metabolism, plays a critical role in the regulation of GBM malignant status and proposed precision nutrition as a promising therapeutic approach.
Citation Format: Yongwei Jing, Masahiko Kobayashi, Atsushi Hirao. Manipulation of the amino acid metabolism promotes therapeutic efficacy through targeting lysosome in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4454.
Abstract 4475: Discovery of an oral tricyclic STING agonist with superior pharmacokinetic properties and potent in vivo efficacy
Authors: Zhao Hong-Yi , Liu Zhongwei , Mao Shuai , He Miao , Wang Meilin , Wen Bo , Gao Wei , Sun Duxin 
Published: March 2024

Abstract
Stimulator of interferon genes (STING) plays a pivotal role in regulating immune microenvironment for cancer immunotherapy. However, the use of most STING agonists has been hindered by the necessity for intra-tumoral or intravenous administration, underscoring the challenge in developing an orally bioavailable STING agonist with favorable pharmacokinetic (PK) properties. In this study, we discovered oral STING agonists featuring a novel tricyclic benzo[4,5]thieno[2,3-c]pyrrole-1,3-dione scaffold, thus achieving both superior PK properties and potent in vivo efficacy. Our lead compound, ZSA-51, exhibited nanomolar cellular STING activation activity (EC50 = 100 nM) in THP1 cells, surpassing the reported oral STING agonist MSA-2 by 32-fold (EC50 = 3200 nM). Furthermore, ZSA-51 demonstrated superior PK properties with an oral bioavailability of 49%, and robust in vivo antitumor activity both in colon and pancreatic cancers model upon oral administration. Notably, ZSA-51 displayed preferential distribution to the lymph nodes and spleen, enhancing its systemic immune-stimulating effects. The specificity of ZSA-51 was further confirmed by a comparison with a negative control compound (ZSA-52NC2) that was unable to stimulate in vitro and in vivo STING activity. Molecular docking and MD simulation confirmed that the active form of ZSA-51 stably bound to STING dimer with validated hydrogen bond network. Taken together, our findings suggest ZSA-51 as a promising oral STING agonist characterized by superior PK properties and potent in vivo efficacy, holding potential for future development for cancer immunotherapy.
Citation Format: Hong-Yi Zhao, Zhongwei Liu, Shuai Mao, Miao He, Meilin Wang, Bo Wen, Wei Gao, Duxin Sun. Discovery of an oral tricyclic STING agonist with superior pharmacokinetic properties and potent in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4475.
Abstract 4489: Developing dual FLT3/MNK inhibitors to overcome sorafenib resistance in FLT3-ITD AML cells
Authors: Zhao Linxiang , Zuo Shuwei , Xing Kun , Yue Xiaoshuang , Zhang Huimin , Zhang Jingyi , Waxman Samuel , Jing Yongkui 
Published: March 2024

Abstract
Acute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors developed only result in transient disease remission with disease relapse and resistance. Agents overcoming FLT3-ITD inhibitor resistance need to be developed. Sorafenib is one of FLT3-ITD inhibitors used in clinic. Using FLT3-ITD AML MOLM-13 cell line, we established a sorafenib resistant subclone MOLM-13/Sor, explored the resistance mechanism and revealed the overactivated mTOR signaling. MNK as one of the alternative mTOR signaling pathways is activated. MNK inhibitor eFT508 could overcome sorafenib resistance. Previously we developed a dual pyrido[3,2-d]pyrimidine MNK/PIM inhibitor 21o. Through optimization of 21o we obtained two new compounds H104 (IC50 values: MNK1 19 nM; MNK2 8 nM; FLT3-ITD 46 nM; PIM1 1388 nM) and H118 (IC50 values: MNK1 35 nM; MNK2 21 nM; FLT3-ITD 25 nM; PIM1 518 nM) with selective inhibition of MNK and FLT3 and losing PIM inhibition ability. H104 and H118 show better antiproliferative efficacy in FLT3-ITD MOLM-13 cells (GI50: 1.07±0.04 μM and 0.99±0.08 μM) than non-FLT3-ITD HL-60 cells (GI50: 7.04±0.15 μM and 4.78±0.31 μM). More intriguingly H104 and H118 exhibit superior antiproliferative effects in sorafenib resistant MOLM-13/Sor cells (GI50: 0.44±0.05 μM and 0.24±0.06 μM). H104 and H118 decreased the levels of p-eIF4E, c-myc and Mcl-1, the downstream substrates of FLT3-ITD and MNK. Our data indicate that the activated MNK is one mechanism of FLT3-ITD resistance and the dual MNK/FLT3 inhibitors have advantage for FLT3-ITD AML treatment.
Citation Format: Linxiang Zhao, Shuwei Zuo, Kun Xing, Xiaoshuang Yue, Huimin Zhang, Jingyi Zhang, Samuel Waxman, Yongkui Jing. Developing dual FLT3/MNK inhibitors to overcome sorafenib resistance in FLT3-ITD AML cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4489.
Abstract 4512: Discovery of highly potent, selective, and orally bioavailable IKZF2 degrader and its anti-tumor activity in syngeneic mouse models
Authors: Park Seulki , Moon Jeong Hee , Lee Gaseul , Kim Hyun Jin , Kim Jeong-Hoon , Hwang Jong Yeon 
Published: March 2024

Abstract
Molecular glue degraders (MGDs) are emerging as innovative therapeutic modalities, owing to their efficacy in targeting previously undruggable targets. MGDs induce close proximity between the target protein and E3 ligase, resulting in the degradation of the target protein. In the wake of the remarkable success of PD-1/PD-L1 inhibitors, various approaches to modulate the activity of regulatory T cells (Tregs) activity have been explored. Tregs represent the primary immune suppressor and significantly impede antitumor immune responses. IKZF2, a marker of stable suppressive Treg, is essential for maintaining the stable Treg cell phenotype. Depletion of IKZF2 can induce a transition from Treg to effector T cell (Teff) phenotypes, thereby enhancing anti-tumor responses. Leveraging an Immunomodulatory drug (IMiD), Novartis has developed the IKZF2 degrader DKY709, which is currently undergoing Phase I clinical trials, both as a monotherapy and in combination with a PD-1 immune checkpoint inhibitor. In this presentation, we present the preclinical results of the best-in-class IKZF2 degrader, PRT-101. PRT-101 elicits rapid and robust degradation of IKZF2, demonstrating subnanomolar DC50 and achieving 100% Dmax in a proteasome- and CRBN-dependent manner. However, PRT-101 does not induce the degradation of well-known neosubstrates, including IKZF1, IKZF3, SALL4, and CK1a. Global proteomic analysis reveals that PRT-101 exclusively facilitates IKZF2 degradation. The degradation of IKZF2 by PRT-101results in an increase in IL-2 secretion, a marker of T effector function. Furthermore, oral administration of PRT-101 exhibits excellent pharmacokinetics, concurrent with IKZF2 degradation, yielding superior anti-tumor effects compared to DKY709 in the MC38 mouse syngeneic model. In conclusion, our findings underscore the potential of the novel IKZF2 degrader as a promising immuno-oncology target for the treatment of solid tumors.
Citation Format: Seulki Park, Jeong Hee Moon, Gaseul Lee, Hyun Jin Kim, Jeong-Hoon Kim, Jong Yeon Hwang. Discovery of highly potent, selective, and orally bioavailable IKZF2 degrader and its anti-tumor activity in syngeneic mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4512.
Abstract 4515: Orally bioavailable PROTAC based MDM2 degrader
Authors: Aguilar Angelo , Yang Jiuling , Li Yangbing , McEachern Donna , Wang Shaomeng 
Published: March 2024

Abstract
Activation of the tumor suppressor p53, through inhibition of the MDM2 protein, has been pursued as a cancer therapeutic strategy and has produced many distinct inhibitors that are in clinical trials. A limitation arising from inhibiting the MDM2-p53 interaction is the upregulation of MDM2, itself a target gene of p53, and this attenuates the activation of p53 and efficacy of the inhibitors. To circumvent this limitation, we previously reported the first PROTAC based MDM2 degraders. These induced and sustained robust degradation of MDM2, achieved stronger p53 activation, and more potent anticancer activity than MDM2 inhibitors thus representing a new therapeutic strategy for targeting MDM2. Currently, all the PROTAC based MDM2 degraders are all dosed intravenously. Here we describe our design, synthesis, and optimizations that led to the discovery of the first orally bioavailable PROTAC based MDM2 degrader and our investigation of its therapeutic potential and mechanism of action. Consistent with its design to effectively degrade MDM2, our PROTAC effectively induces rapid degradation of MDM2 resulting in accumulation of wild-type p53 protein and activates p53 transcriptional activity in leukemia cells without accumulation of MDM2 protein. Consequently, it potently inhibits cell growth and induces apoptosis at low nano-molar concentrations in ALL and AML cell lines &gt;10-100 times more potent than MDM2 inhibitors; and, after 50 mg/kg oral dose, 5 days/week for 3 weeks, it increased the median survival by 26 days of mice with disseminated RS4;11 cancer.
Citation Format: Angelo Aguilar, Jiuling Yang, Yangbing Li, Donna McEachern, Shaomeng Wang. Orally bioavailable PROTAC based MDM2 degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4515.