bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6204: DNA-PK inhibition augment the cancer specific cytotoxicity of mitotic MTH1 inhibitor OXC-101
Authors: Danda Akhilesh Nagesh , Gad Helge , Scobie Martin , Martínez-López Laura , Carrillo Nuria Pastor , Orta Manuel Luis , Helleday Thomas , berglund Ulrika warpman , Sanjiv Kumar 
Published: April 2023

Abstract
DNA-dependent protein kinase (DNA-PK) plays an important role in the repair of DNA double-strand breaks via the non-homologous end joining (NHEJ) pathway. In addition to its role in the NHEJ pathway, DNA-PK is also known to have an emerging role in cell cycle progression and mitosis. Some studies have shown that depletion or inhibition of DNA-PK inhibitors leads to a delay in the transition from metaphase to anaphase. The mitotic MTH1 inhibitor OXC-101(TH1579, karonudib) is a dual inhibitor that both targets MTH1 and disrupts tubulin polymerization in cancer cells, causing DNA damage and mitotic catastrophe in cancer cells. Based on the involvement of DNA-PK in mitosis, we hypothesized that depletion/inhibition of DNA-PK might enhance the DNA damage and mitotic catastrophic effect of OXC-101.To test our hypothesis, we performed an in vitro drug combination experiment using the DNA-PK inhibitor nedisertib with OXC-101 in non-small cell lung carcinoma NSCLC (H460,A549), uveal melanoma (MP -38, MP -41 and MP46), osteosarcoma (U2OS) and) and neuroblastoma (IMR32, Kelly, SKNFI) cancer cell lines and non-cancerous foreskin fibroblasts(VH-10, BjhTERT). We found cancer-specific synergistic drug interactions between nedisertib and OXC-101. Combined treatment of nedisertib and OXC-101 to H460 and MP46 increased expression of s10H3 (mitotic marker) and the apoptosis marker (cPARP) compared with single treatment. However, there was no additional increase in expression of the DNA damage markerγH2AX with combined treatment. We also performed annexin V staining by FACS on MP38 andMP48 cells and observed a significant increase in the apoptotic population with combination treatment compared with single treatment. Imaging live cells, we observed a significant delay or arrest in the mitotic phase followed by death of cancer cells in mitosis in response to combination treatment, whereas cells treated individually with nedisertib or OXC-101 continued to proliferate and progress to the next phase of the cell cycle. These data suggest that the DNA-PK inhibitor may enhance the cytotoxic effect of OXC-101specifically in cancer cells. In addition, we will conduct an in-depth mechanistic study of how depletion/inhibition of DNA-PK enhances the cytotoxicity of OXC-101 and validate the drug combination in an appropriate preclinical mouse model.
Citation Format: Akhilesh Nagesh Danda, Helge Gad, Martin Scobie, Laura Martínez-López, Nuria Pastor Carrillo, Manuel Luis Orta, Thomas Helleday, Ulrika warpman berglund, Kumar Sanjiv. DNA-PK inhibition augment the cancer specific cytotoxicity of mitotic MTH1 inhibitor OXC-101 [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 6204.
Abstract 6249: Low Bcl-2 is a robust biomarker of sensitivity to nab-paclitaxel in Ewing sarcoma
Authors: Pascual-Pasto Guillem , Resa-Pares Claudia , Carcaboso Angel M. 
Published: April 2023

Abstract
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) shows potent preclinical anticancer activity in pediatric solid tumors such as Ewing sarcoma, rhabdomyosarcoma and neuroblastoma, but responses in clinical trials have been modest. In this work, we aimed to discover a rational biomarker-based approach to select the right candidate patients for this treatment. We assessed the efficacy of nab-paclitaxel in 27 patient-derived xenografts (PDX), including 14 Ewing sarcomas, five rhabdomyosarcomas and several other pediatric solid tumors. Response rate (partial or complete response) was remarkable in rhabdomyosarcomas (four of five) and Ewing sarcomas (four of 14). We addressed several predictive factors of response to nab-paclitaxel such as the expression of the secreted protein acidic and rich in cysteine (SPARC), chromosomal stability of cancer cells and expression of antiapoptotic members of the B-cell lymphoma-2 (Bcl-2) family of proteins such as Bcl-2, Bcl-xL, Bcl-W and Mcl-1. Protein (immunoblotting) and gene expression of SPARC correlated positively, while immunoblotting and immunohistochemistry expression of Bcl-2 correlated negatively with the efficacy of nab-paclitaxel in Ewing sarcoma PDX. The negative correlation of Bcl-2 immunoblotting signal and activity was especially robust (r = 0.8352; P = 0.0007; Pearson correlation). Consequently, we evaluated pharmacological strategies to inhibit Bcl-2 during nab-paclitaxel treatment. We observed that the Bcl-2 inhibitor venetoclax improved the activity of nab-paclitaxel in highly resistant Bcl-2-expressing Ewing sarcoma PDX. Overall, our results suggest that low Bcl-2 expression could be used to select patients with Ewing sarcoma sensitive to nab-paclitaxel, and Bcl-2 inhibitors could improve the activity of this drug in Bcl-2-expressing Ewing sarcoma.
Citation Format: Guillem Pascual-Pasto, Claudia Resa-Pares, Angel M. Carcaboso. Low Bcl-2 is a robust biomarker of sensitivity to nab-paclitaxel in Ewing sarcoma [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 6249.
Abstract 6275: DW91170: A novel potent EZH1/2 dual inhibitor for lymphoma treatment
Authors: Jeong Doc-Gyun , Heo Woon , Shin DongHyuk , Oh Yeonkyung , Lee Sangho , Jeong Seongsu , Park Whuijung , Woo Jiyoung , Jeon Chanseok , Kim Subin , Lim Jaekyung , Hwang Yun-Ha 
Published: April 2023

Abstract
EZH2(Enhancer of zeste homolog2) is a catalytic subunit of PRC2 (polycomb repressive complex 2) for chromatin remodeling through methyl transfer activity. Previous studies have reported correlation between EZH2 and cancer progression with overexpression and mutations in various cancers. EZH1, homolog of EZH2, also has been known to role in development and progression of cancers by complementarily replacing EZH2. In recent researches, EZH1/2 dual inhibition showed global epigenetic modification on histone methylation and acetylation. Also, cancers associated with change in epigenetic factors such as mutations in subunit of SWI/SNF responded on EZH1/2 dual inhibition. Therefore, EZH1/2 dual inhibition is expected to be an effective strategy for cancer treatment. Herein, we present a novel potent EZH1/2 dual inhibitor, DW91170, as a promising candidate for treatment of lymphoma with improved anti-cancer activity. DW91170 selectively inhibited EZH1 and EZH2 enzyme activity. DW91170 brought about histone modification by reducing tri-methylation and enhancing acetylation of H3K27, which increased expression of target genes and cell cycle arrest was confirmed by treatment of DW91170. DW91170 showed effective tumor growth inhibition in two types of EZH2 hot spot mutation models. In Pfeiffer (A677 mutation) and WSU-DLCL2 (Y641 mutation) CDX models, DW91170 showed improved tumor regression activity with no significant abnormal signs such as weight loss. In order to verify the potential of DW91170 in R/R-lymphoma patients, the anti-cancer effect was evaluated in Rituximab-resistant cell line and R/R-DLBCL patient-derived PDX model. As a result, DW91170 efficiently inhibited Rituximab-resistant cell proliferation and suppressed tumor growth in R/R-DLBCL PDX model more significantly compared to other EZH inhibitors. Moreover, DW91170 has a good absorption profile that works in a physiological condition. Taken together, we demonstrated that DW91170, a dual epigenetic regulator of EZH1 and EZH2, showed great anti-tumor activities in various lymphoma cell lines and animal models such as CDX and PDX. We are currently trying to expand indication into solid tumor to find a targetable population in clinical trials.
Citation Format: Doc-Gyun Jeong, Woon Heo, DongHyuk Shin, Yeonkyung Oh, Sangho Lee, Seongsu Jeong, Whuijung Park, Jiyoung Woo, Chanseok Jeon, Subin Kim, Jaekyung Lim, Yun-Ha Hwang. DW91170: A novel potent EZH1/2 dual inhibitor for lymphoma treatment. [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 6275.
Abstract 6415: CD25-targeted aptamer-drug conjugate (CD25-ApDC) depletes and blocks regulatory T cells selectivel
Authors: Lee Daekyun , Kang Ju-hyung , Song Inu 
Published: April 2023

Abstract
Background: Regulatory T cells (Tregs) have a strong immunosuppressive function, inhibit anti-tumor immunity, and promote the occurrence and development of tumors. In addition, a high infiltration of Treg cells is associated with poor survival in various types of cancer. Since CD25 is highly expressed on Treg cells, it is a potential target protein for Treg depletion.
Methods: The binding affinity(Kd) of CD25 aptamer to rhCD25 protein was calculated through bio-layer interferometry(BLI). The cell binding of Cy5-labelled CD25 aptamer was detected by flow cytometry, and the internalization was visualized by confocal microscopy. The cell internalization rate was determined using the MFI value of flow cytometry. Competitive ELISA, western blot, and qPCR were performed to investigate the effect of CD25 aptamer on CD25/IL-2 binding. In vitro cytotoxicity of prototype-ApDC was determined by CCK-8 assay. Moreover, CD25-dependent cytotoxicity of prototype-ApDC was evaluated by Karpas299(Treg-like):HuT78(Teff-like) 1:1 co-culture model using FACS analysis.
Results: CD25 aptamer binds human CD25 protein with 4.64nM affinity. CD25 aptamer showed selective binding and internalization to CD25-positive Karpas299 and had no interaction with CD25-negative Daudi. The internalization half-time of CD25 aptamer in karpas299 was determined to 9.9 min (95% CI 8.2~12.6min). Interestingly, CD25 aptamer was identified as IL-2R antagonist by evaluating competitive ELISA and the level of phosphor-STAT5 and downstream mRNA expression of TGF-beta. The IC50 value of prototype-ApDC was 24nM to Karpas299 while &gt;1uM to Daudi. These results show that prototype-ApDC has selective cytotoxicity against CD25-expressing cells. Furthermore, in a study of an in vitro co-culture model mimicking the Treg-rich intratumoral T cell environment, prototype-ApDC treatment induced CD25-specific depletion resulting in escalating the ratio of HuT89/Karpas299 with increasing exposure time.
Conclusions: Our CD25-targeted aptamer and its drug-conjugated ApDC have demonstrated the selective blocking of IL-2R-STAT5 signaling and induction of CD25-positive cell-specific depletion, respectively. Moreover, in the co-culture system of the Treg-like and Teff-like cells, CD25-ApDC also proved its cytotoxic selectivity. Therefore, one potential strategy in cancer patients is to use CD25-ApDC with excellent tumor permeability as an anticancer agent with a mechanism of Treg cell depletion through specific targeting of CD25 overexpressed in tumor-infiltrating Treg cells.
Citation Format: Daekyun Lee, Ju-hyung Kang, Inu Song. CD25-targeted aptamer-drug conjugate (CD25-ApDC) depletes and blocks regulatory T cells selectivel [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 6415.
Abstract 6494: Postdiagnosis adherence to American Cancer Society cancer prevention guidelines and mortality among survivors of obesity-related cancers
Authors: Wang Ying , Newton Christina , McCullough Marjorie L. , Teras Lauren R. , Rees-Punia Erika , Um Caroline , Patel Alpa V. 
Published: April 2023

Abstract
Purpose: To examine the combined and individual associations of postdiagnosis body mass index (BMI), physical activity, diet quality and alcohol consumption with all-cause mortality, cardiovascular disease mortality (CVDM) and cancer-specific mortality (CSM) among survivors of obesity-related cancers.
Methods: American Cancer Society (ACS) Cancer Prevention Study-II Nutrition Cohort participants diagnosed with one of 13 invasive (but non-metastatic) obesity-related cancers between 1992 and 2003 were followed for mortality until 2018. Postdiagnosis lifestyle exposures were assessed at least one year after cancer diagnosis between 1999 and 2003. A lifestyle score ranging 0-8 was created according to ﻿adherence to the American Cancer Society (ACS) 2020 cancer prevention guidelines on BMI, physical activity, diet, and alcohol, with a score of 8 representing optimal behaviors for cancer prevention. Associations of the overall and individual component scores with mortality were estimated using multivariable-adjusted Cox proportional hazards regression models.
Results: Among 7,945 cancer survivors, 4,862 died between 1992 and 2018. Higher ACS guideline score was associated with 6-8% lower risk of mortality per 1 point score increase (all-cause: HR: 0.94, 95% CI: 0.92-0.95; CVDM: HR:0.92, 95% CI:0.89-0.95; CSM: HR: 0.93, 95% CI 0.90-0.97) among cancer survivors. Individual scores of BMI, physical activity, and diet were inversely associated with overall mortality; however, alcohol score was positively associated with all-cause mortality, only among female survivors. Compared with participants who had low scores both before and after cancer diagnosis, those with high scores after diagnosis had lower risk of all-cause mortality, CVDM, and possibly CSM.
Conclusion: Following ACS guidelines on diet and physical activity for cancer prevention after a cancer diagnosis is associated with better survival outcomes among survivors of obesity-related cancers.
Citation Format: Ying Wang, Christina Newton, Marjorie L. McCullough, Lauren R. Teras, Erika Rees-Punia, Caroline Um, Alpa V. Patel. Postdiagnosis adherence to American Cancer Society cancer prevention guidelines and mortality among survivors of obesity-related cancers. [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 6494.
Abstract 6498: Association of lifestyle related risk factors with multiple myeloma mortality rates in the United States
Authors: Gaddam Shiva Jashwanth , Grewal Udhayvir Singh , Avvaru Himaja Kumari , Ramadas Poornima 
Published: April 2023

Abstract
Background: The prognosis for multiple myeloma (MM) has significantly improved over the years. Lifestyle risk factor modifications have improved the quality of life in MM patients, however, their effect on the survival outcomes in these patients remains unknown.
Methods: We extracted data on age-adjusted mortality rate (AAMR) rates of MM (per 100,000 population) for all 50 U.S. states and the District of Columbia from the Center for Disease Control (CDC) WONDER database (2015-2019). Data on risk factors such as obesity, physical activity, alcohol, tobacco abuse, and nutrition were obtained from the Behavioral Risk Factor Surveillance System (BRFSS, 2021). Florida was excluded due to missing information. Correlations were analyzed using Pearson’s coefficient. Statistical analysis was performed using VassarStats.
Results: Median AAMR of MM in the US was 3.2 (IQR 2.7, 3.7) per 100,000 population. States with higher age-adjusted prevalence (AAP) percentages of obesity had higher AAMR (r=0.39, p=0.004) of MM. This association was significant in non-Hispanic white (r=0.32, p=0.021), and non-Hispanic black (r=0.31, p=0.034) subgroups as well. States with a higher AAP of adherence to recommended weekly aerobic activity had lower AAMR (r=-0.37, p=0.007). We did not identify any correlation of AAMR with AAP of binge drinking (r=-0.036, p=0.803), consumption of fruits (r=0.04, p=0.75), vegetables (r=-0.133, p=0.357), and smoking history (r=0.052, p=0.72).
Conclusions: In the current analysis, a higher prevalence of obesity and lower rates of aerobic physical activity were strongly associated with increased AAMR of MM. Our results, therefore, underscore the need for emphasis on a holistic approach in the management of MM by including lifestyle-based risk factor modification, to further improve the survival outcomes in patients with MM.
Citation Format: Shiva Jashwanth Gaddam, Udhayvir Singh Grewal, Himaja Kumari Avvaru, Poornima Ramadas. Association of lifestyle related risk factors with multiple myeloma mortality rates in the United States [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 6498.
Abstract 65: HIRA is a master regulator of the proliferation-to-dormancy switch in breast cancer
Authors: Drapela Stanislav , Raizada Devesh , Mukherjee Ananya , Tejero Joanne , Ilter Didem , Bravo-Cordero Jose Javier , Gomes Ana P 
Published: April 2023

Abstract
Most cancer-related deaths are caused by recurrent metastatic disease with latency periods that range from years to even decades. This halt in disease progression is driven by cancer dormancy, a stage in which residual disease is present but remains asymptomatic before reawakening and often causes lethal forms of the disease. Cell fate decisions, such as the ones that underlie dormancy and reawakening of cancer cells, often require extensive epigenetic remodeling, which in turn allows for the expression of specific genetic programs that trigger cell fate decisions. Therefore, epigenetic remodeling is likely essential for the switch between dormant and proliferative states throughout the metastatic process. Here we focus on epigenetic regulator, histone H3.3 chaperone HIRA and its role in the proliferation-to-dormancy switch in breast cancer cells. In this study, we demonstrate that HIRA suppression leads to cell cycle arrest and induces canonical dormancy pathways via phosphorylation of p38 and induction of p27 expression. In addition, HIRA suppression triggers induction of stress-inducible transcription factors NRF2, MITF and ATF3 to enable the activation of genetic programs that maintain homeostasis and promote survival in dormant cells. Our data also portray that HIRA is suppressed in the well-established isogenic models of dormancy when compared to their metastatic counterparts. Altogether we present for the first-time histone chaperone HIRA as a major regulatory point of cell fate for disseminated cancer cells by controlling their transition between dormant and proliferative states, and therefore suggest HIRA as a novel and tremendously needed therapeutic target for metastatic breast cancer.
Citation Format: Stanislav Drapela, Devesh Raizada, Ananya Mukherjee, Joanne Tejero, Didem Ilter, Jose Javier Bravo-Cordero, Ana P Gomes. HIRA is a master regulator of the proliferation-to-dormancy switch in breast 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 65.
Abstract 6516: Comparison study between a ketogenic diet and a high-fat diet on pancreatic cancer incidence in mice
Authors: Bacha Tarek , Penso Natalia Cortez , Rodriguez Maria , Hong Brian , Mackenzie Gerardo 
Published: April 2023

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) remains among the most lethal cancers. PDAC can take up to 15-20 years to develop from the occurrence of the first initiating mutational event, which opens the opportunity for intervention and prevention strategies. In particular, nutritional interventions could provide an avenue to prevent or slow down pancreatic carcinogenesis, since certain diets such as high-fat diets (HFD) have shown to promote it. On the other hand, ketogenic diets (KD), characterized by a high fat and very low carbohydrate content, have gained attention for their anti-tumor and anti-inflammatory potential. However, the role of a KD in the onset and progression of PDAC is still unknown. In this project, we investigated the impact of both a HFD and a KD on late-stage pancreatic carcinogenesis. For this purpose, we used an animal model of pancreatic cancer carrying a pancreas-specific oncogenic KRASG12D mutation [LSL-KRASG12D; P48+/Cre; (KC mice)]. On average, KC mice develop PDAC at 12-15 months of age, so they are a valuable tool to study late-stage carcinogenesis. We hypothesized that a HFD would accelerate PDAC progression while a KD would slow it down. To test our hypothesis, 6 months-old male and female KC mice (n=18/group) were randomized and fed, either a control diet (CD), a HFD, or a KD for 6 months and then euthanized at 12-months of age to evaluate pancreatic cancer incidence and progression. At 12-months of age, HFD-fed mice had significantly higher body weight compared to the other two groups. Moreover, KD-fed mice had significantly higher levels of blood ketone bodies, with lower levels of glucose and serum insulin levels, when compared to KC mice fed a HFD. However, after 6 months on the diets, no significant differences in pancreas weight nor in PDAC incidence were observed across all diet groups. Of note, male KC mice experienced double the PDAC incidence rates (55%) than female KC mice (27%), irrespectively of the group. In addition, no significant differences among the groups were observed in RAS/RAF/ERK and PI3K/AKT/mTOR pathways, known to be associated with cancer proliferation. In summary, despite the improvement in insulin and increases in ketone bodies, consumption of a strict KD failed to improve late-stage pancreatic carcinogenesis in mice.
Citation Format: Tarek Bacha, Natalia Cortez Penso, Maria Rodriguez, Brian Hong, Gerardo Mackenzie. Comparison study between a ketogenic diet and a high-fat diet on pancreatic cancer incidence in mice. [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 6516.