bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7155: Dichloroacetate reverses cisplatin resistance in ovarian cancer through promoting ROS production
Authors: Do Yen Thi , Lee Seungmee , Shin Changmin , Chung Hyewon , Kim Jin Young , Ha Eunyoung , Shin Sojin , Seo Ji Hae 
Published: March 2024

Abstract
Chemotherapy resistance and the high rate of ovarian cancer relapse pose major challenges in the treatment of ovarian cancer. The development of chemoresistance contributes to poor overall prognosis associated with ovarian cancer and high cancer-related mortality in women worldwide. Herein, we found that Dichloroacetate (DCA), a pan-pyruvate dehydrogenase kinase (PDK) inhibitor, is a potent agent to overcome Cisplatin (CP) resistance in ovarian cancer treatment. Firstly, we elucidated that phosphorylation of pyruvate dehydrogenase (pPDH) was elevated in CP-resistant ovarian cancer cells. Then, blockage of pPDH by DCA treatment significantly inhibited cell migratory and invasive capacity in CP-resistant ovarian cancer cells through the transition of motile mesenchymal phenotypes into epithelial characteristics. DCA markedly decreased the number of sphere formations and attenuated the stem cell-like properties in CP-resistant ovarian cancer cells. In combination with CP treatment, DCA effectively inhibited cell proliferation in chemoresistant ovarian cancer cells by triggering apoptosis. Collectively, we suggested that DCA is a promising drug to reverse CP resistance for ovarian cancer treatment. We further tested the underlying mechanisms of DCA to restore CP sensitivity in ovarian cancer. We found that CP treatment promoted reactive oxygen species (ROS) production to induce cell death in CP-sensitive ovarian cancer. However, CP-resistant ovarian cancer cells exhibited higher basal levels of ROS compared with sensitive cancer cells, and CP treatment failed to generate ROS production. That means ovarian cancer cells steadily adapted to elevated ROS levels, then becoming ROS-adapted ovarian cancer cells to survive. Interestingly, DCA treatment results in the buildup of ROS production, causing cell death in CP-resistant ovarian cancer. Therefore, our study suggests that ROS production can be an attractive target in DCA treatment to restore CP sensitivity in ovarian cancer.
Citation Format: Yen Thi Do, Seungmee Lee, Changmin Shin, Hyewon Chung, Jin Young Kim, Eunyoung Ha, Sojin Shin, Ji Hae Seo. Dichloroacetate reverses cisplatin resistance in ovarian cancer through promoting ROS production [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 7155.
Abstract 7169: A real-world toxicity-atlas shows that adverse events of combination-therapies commonly result in additive interactions
Authors: Küçükosmanoglu Asli , Scoarta Silvia I. , Westerman Bart 
Published: March 2024

Abstract
Purpose: Combination-therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in an real-world setting.
Experimental Design: We provide here a proof-of-concept study using 15 million patient records from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Complex adverse-event frequencies of drugs or their combinations were visualized as heatmaps onto a 2D UMAP grid. Adverse event frequencies were shown as colors to assess the ratio between individual and combined drug effects. To capture these patterns, we trained a convolutional neural network (CNN) autoencoder using 7,300 single-drug heatmaps. Additionally, statistical synergy analyses were performed based on BLISS independence or Chi-square testing.
Results: The trained CNN model was able to decode patterns, showing that adverse events occur in global rather than isolated and unique patterns. Patterns were not likely to be attributed to disease symptoms given their relatively limited contribution to drug associated adverse events. Pattern recognition was validated using trial data from ClinicalTrials.gov and drug combination data. We examined the adverse-event interactions of 140 drug combinations known to be avoided in the clinic and found that near all of them showed additive rather than synergistic interactions, also when assessed statistically.
Conclusion: Our study provides a framework for analyzing adverse events and suggest that adverse drug interactions commonly result in additive effects with a high level of overlap of adverse event patterns. These real-world insights may advance the implementation of new combination therapies in clinical practice.
Citation Format: Asli Küçükosmanoglu, Silvia I. Scoarta, Bart Westerman. A real-world toxicity-atlas shows that adverse events of combination-therapies commonly result in additive interactions [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 7169.
Abstract 7175: Web-based cross-database exploration of molecular pharmacology data from cancer cell lines and patient genomics
Authors: Reinhold William C. , Luna Augustin , Elloumi Fathi , Varma Sudhir , Taniyama Daiki , Mizunuma Makito , del Rivero Jaydira , Thomas Anish , Reilly Karyyne , Pacak Karel , Aladjem Mirit , Pommier Yves 
Published: March 2024

Abstract
CellMiner Cross-Database (CellMinerCDB, discover.nci.nih.gov/cellminercdb) allows integration and analysis of molecular and pharmacological data within and across cancer cell line datasets from the National Cancer Institute (NCI), Broad Institute, Sanger/MGH, MD Anderson Cancer Center (MDACC), and the National Center for Advancing Translational Sciences (NCATS, discover.nci.nih.gov/rsconnect/cellminercdb_ncats/). Altogether, our database spans over 1,700 distinct cell lines, over 1,000 clinically relevant drugs, ~25,000 experimental compounds, and molecular profiling data, such as gene/protein expression, molecular signatures including epithelial mesenchymal transition (EMT), replication stress (RepStress), neuroendocrine evaluation (NE), DNA copy, methylation, mutational status, and gene dependencies (Broad DepMap). This rich and growing set of cell lines and tested drugs allows for novel avenues for response determinant discovery and clinical translation that is facilitated by 1) common annotations (e.g., tissues of origin and matched drug names) across pharmacogenomic datasets and 2) various univariate and multivariate analyses tools. A major challenge to clinical translation occurs in relating pre-clinical models to patient samples. As part of this work, we show how the CellMinerCDB infrastructure additionally supports annotated patient multi-omics data to aid researchers to relate findings from cancer cell lines with patient data; we use data from small cell lung cancer (SCLC) and neuroendocrine tumors as illustrative examples. This work provides significant pharmacogenomic integration that allows exploration within a comprehensive dataset of cancer cell lines and to inter-relationships with patient-derived datasets; this is being developed to display and mine patient samples as part of the complementary web-based tool (PatientTumorMiner).
Citation Format: William C. Reinhold, Augustin Luna, Fathi Elloumi, Sudhir Varma, Daiki Taniyama, Makito Mizunuma, Jaydira del Rivero, Anish Thomas, Karyyne Reilly, Karel Pacak, Mirit Aladjem, Yves Pommier. Web-based cross-database exploration of molecular pharmacology data from cancer cell lines and patient genomics [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 7175.
Abstract 7207: Targeting hippo signaling pathway to overcome chemoresistance in glioblastoma
Authors: Wong Cheuk Lun Ethan , Kiang Mei Yee Karrie , Leung Ka Kit Gilberto 
Published: March 2024

Abstract
The study aims to investigate whether the Hippo signaling pathway contributes to temozolomide chemoresistance in glioblastoma, and to validate whether the combinational treatment of temozolomide and YAP inhibitor is effective against glioblastoma. Temozolomide-sensitive and temozolomide-resistant U87 and U251 GBM human cell lines were previously established. Temozolomide-resistant cells were maintained in low-dose temozolomide. Here, we investigate whether Hippo signaling contributes to temozolomide chemoresistance. By modulating the Hippo signaling pathway through YAP gene knockdown, the outcome on cell proliferation was studied by cell viability assay (in vitro) and mouse orthotopic xenograft (in vivo). Finally, the therapeutic effect of YAP inhibitor is studied in vitro and in vivo respectively. Our data showed that YAP is overexpressed in temozolomide-resistant glioblastoma cells. Nuclear translocation of YAP (which becomes its active state) is increased in temozolomide-resistant cells. In fact, YAP inhibition show decreased cell viability and higher susceptibility to temozolomide. In addition, mice with tumor injection of the YAP knockdown cells reduced tumor size with temozolomide treatment. Similarly, YAP inhibitor resensitizes temozolomide-resistant cells to temozolomide. Combinational treatment of YAP inhibitor and temozolomide is effective in shrinking tumor size in mouse xenograft models. In conclusion, our data suggest dysregulated Hippo signaling pathway contributes to temozolomide chemoresistance, thus targeting the Hippo signaling pathway resensitizes GBM cells to temozolomide. This research provides pre-clinical evidence on using YAP inhibitor for combinational therapy with temozolomide for the treatment of glioblastoma.
Citation Format: Cheuk Lun Ethan Wong, Mei Yee Karrie Kiang, Ka Kit Gilberto Leung. Targeting hippo signaling pathway to overcome chemoresistance 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 7207.
Abstract 7253: Oncolytic virus therapy with two-factor authentication shows robust safety and efficacy in liver cancer
Authors: Moles Chad M. , Weijmarshausen Peter , Basu Rupsa , Ho Brenda , Farhat Manal , Flaat Taylor , Smith Bruce F. , Whitt Michael , Woodfield Sarah E. , Vasudevan Sanjeev A. 
Published: March 2024

Abstract
Background: Humane Genomics is pioneering multi-factored authenticated oncolytic virotherapy (OVT) using glycoprotein receptor matching and aptazyme technology to positively control replication in cytoplasm. Using VSV as a platform the OVTs show excellent safety and remain highly lytic. Sindbis virus glycoprotein was mutated to eliminate natural infectivity and retargeted to GPC3 with a codon optimized nanobody. An aptazyme was used to regulate viral replication. As far as we are aware, this was the first report of a functional ON switch using a cancer biomarker.
Methods: 293T cells were used for virus rescue and titration by TCID50. Identity was confirmed by Nanopore sequencing. We evaluated safety on off-target SK-Hep-1 and NCI-H28 cell lines, and efficacy on target HepG2 and patient derived HB17 cells. Cell health and GFP was measured at multiple timepoints up to 72 hours.
Results: Safety testing of HGI498 on SK-Hep-1 (GPC3 negative) and NCI-H28 (GPC3 negative, biomarker negative) showed no virus induced cell cytopathic effects in a range of 0.01 ≤ MOI ≤1. HGI498’s efficacy testing on HepG2 and HB17 showed tumor cytotoxicity at MOI 0.01 (p&lt;0.001). Endpoint dilution assay showed a 159-fold and 316-fold difference between off-target NCI-H28 and on-target HepG2 and HB17, respectively. We incorporated an optimized aptazyme with the GPC3 targeted glycoprotein (HGI572), which was similarly rescued, titered, and evaluated for selectivity. HGI572 demonstrated approximately 1000-fold higher titer on target HepG2 and HB17 cells than off-target cells. Initial in vivo MTD study shows that both HGI498 and HGI572 are well tolerated, and are currently being investigated in vivo for efficacy on Hep3B in NSG mice. HGI498 has shown no seroprevalence (in vitro) and is stable at cryostorage for a minimum of 11 months.
Conclusion: We have successfully engineered a two-factor authentication enabled OVT to address an unmet need for a therapy for liver cancer. As far as we are aware, this is the first report of an ON switch using a cancer protein to control viral replication, and the ON/OFF control is the highest to date.
Citation Format: Chad M. Moles, Peter Weijmarshausen, Rupsa Basu, Brenda Ho, Manal Farhat, Taylor Flaat, Bruce F. Smith, Michael Whitt, Sarah E. Woodfield, Sanjeev A. Vasudevan. Oncolytic virus therapy with two-factor authentication shows robust safety and efficacy in liver 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 7253.
Abstract 7269: Karyopherin α-2, a nuclear export protein, promotes cancer progression in lung adenocarcinoma
Authors: Cheon Inyoung , Kim Seoree , Cho Sengran , Lee Heejin , Yoon Jung-Sook , Lee Ji Hyun , Chun Sang Hoon , Won Hye Sung , Hong Soon Auck , Ko Yoon Ho , Ahn Young-Ho 
Published: March 2024

Abstract
Introduction: Karyopherin α-2 (KPNA2), a nucleocytoplasmic transport protein, regulates the nuclear import of macromolecules and contributes to carcinogenesis. Actually, KPNA2 is upregulated in various types of cancer tissues and serum from cancer patients. In particular, it is associated with cancer invasiveness and poor prognosis in patient. Here, we tried to present the molecular mechanism and clinical significance of KPNA2 in lung cancer progression and metastasis.
Method: First, we retrospectively analyzed the data extracted from EMR for patients with non-small cell lung cancer receiving curative surgical resection in Uijeongbu and Bucheon St. Mary’s Hospitals (n=165). Immunohistochemistry staining was performed on the tumor microarray samples using antibodies against KPNA2. The functional assay and gene silencing was conducted.
Result: The clinical and pathological information of the experimental group is as follows. Based on the TMA staining, mean KPNA2 score was 36.5 [0-240] and median value was 10. Based on the TMA staining, patients with high KPNA2 expression were related to lymphatic invasion (p = 0.00782), advanced stage (p = 0.0202), and current smoker (p = 0.0074). KPNA2 expression was higher in squamous cell carcinoma than in adenocarcinoma histotype. Patients with high KPNA2 expression showed shorter survival than those with low KPNA2 (median OS (months), 72.8 vs 42.2, P &lt; 0.0001; median RFS (months), 72.8 vs 32.1, P &lt; 0.0011) and relevant to high recurrence (recurrence rate (%), 24.7 vs 44.7, p = 0.007). Further, high KPNA2 expression was associated with poor survival outcomes. Knockdown of KPNA2 in lung cancer cells suppressed the invasion and migration of lung cancer cells and inhibited metastasis in a mouse model of lung cancer. Inversely, KPNA2 overexpression promoted cancer cell growth, invasion, and migration. Moreover, ectopic expression of KPNA2 made lung cancer cells less sensitive to anticancer drugs, Talazoparib and Olaparib, indicating that KPNA2 enhances drug resistance in lung cancer cells.
Conclusion: Collectively, this study suggest that KPNA2 promotes invasiveness and metastasis and is associated with poor patient outcomes; therefore, KPNA2 will be a good therapeutic target or a biomarker in lung adenocarcinoma.
Citation Format: Inyoung Cheon, Seoree Kim, Sengran Cho, Heejin Lee, Jung-Sook Yoon, Ji Hyun Lee, Sang Hoon Chun, Hye Sung Won, Soon Auck Hong, Yoon Ho Ko, Young-Ho Ahn. Karyopherin α-2, a nuclear export protein, promotes cancer progression in lung adenocarcinoma [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 7269.
Abstract 7270: Combination targeting of SKP2 and KDM5B induces senescence in castration-resistant prostate cancer cells via AKT signaling
Authors: Brown LaKendria K. , Kanagasabai Thanigaivelan , Li Guoliang , Celada Sherly I. , Chen Zhenbang 
Published: March 2024

Abstract
Prostate cancer (PCa) is the second-leading cause of cancer mortalities and morbidities in the United States and is the most commonly diagnosed malignancy in men. Despite the fact that androgen deprivation therapy is the first-line option to initial responses, most PCa patients invariably develop castration-resistant prostate cancer (CRPC). CRPC is a lethal type of malignancy, therefore, novel and effective treatment strategies are needed. The goal of this study was to evaluate the combination treatment of small molecule inhibitors, SZL-P1-41, a SKP2 target and PBIT, a KDM5B target on PCa growth and progression; as well as to delineate the underlying mechanisms of suppressing CRPC. Literature reports that S-Phase Kinase Associated Protein 2 (SKP2) is upregulated in PCa and Lysine-specific demethylase 5B (KDM5B) serves as a histone demethylase with a crucial role in cancers. Studies showed that KDM5B is increased in human PCa and KDM5B knockout decreases carcinogenic properties of PCa cells. We previously reported that SKP2 loss partially decreases the growth of prostate tumors and that KDM5B levels are reversely regulated by SKP2 in PCa cells. However, the mechanisms of KDM5B and SKP2 interplay on PCa malignancy is unknown. We hypothesize that combination of PBIT and SZL-P1-41 treatment will enhance anti-cancer effects on PCa progression by inducing cellular senescence. Here, we showed that inhibition of KDM5B and SKP2 decreased the proliferation of PCa cells, and KDM5B KO cells were more vulnerable to SKP2 inhibition. More importantly, a combined inhibition of KDM5B and SKP2 significantly blocked malignant progression and migration of PCa cells. Mechanistically, combined inhibition of KDM5B and SKP2 in PCa cells abrogated AKT activation, resulting in an induction of cellular senescence, which was measured via Western blot analysis and senescence-associated β-galactosidase (SA-β-Gal) staining. Taken together, our results show that combined inhibition of KDM5B and SKP2 is more efficacious in inhibiting proliferation and migration in CRPC cells, and this regimen would be an ideal therapeutic approach for treating CRPC.
Citation Format: LaKendria K. Brown, Thanigaivelan Kanagasabai, Guoliang Li, Sherly I. Celada, Zhenbang Chen. Combination targeting of SKP2 and KDM5B induces senescence in castration-resistant prostate cancer cells via AKT signaling [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 7270.
Abstract 731: pHLIP targeted intracellular delivery of calicheamicin
Authors: DuPont Michael , Klumpp Craig , Iraca Marissa , Allababidi Dana , Visca Hannah , Engelman Donald , Andreev Oleg , Moshnikova Anna , Reshetnyak Yana 
Published: March 2024

Abstract
Calicheamicin is a potent, cell-cycle independent enediyne antibiotic that binds and cleaves DNA. Toxicity has led to its approved use in a targeted form as antibody-drug conjugates (ADC) for the treatment of liquid tumors. Mylotarg, one of the first such ADCs, was voluntarily withdrawn from the market due to safety concerns. However, Mylotarg was recently reapproved for acute myeloid leukemia based on new data that demonstrated efficacy with an acceptable safety profile. Besponsa, a related ADC, was approved for acute lymphocytic leukemia in 2017. In both agents, Mylotag and Besponsa, calicheamicin is conjugated to antibodies via an acid-labile hydrazone linker. We used a reduced calicheamicin to conjugate it to a single cysteine residue at the membrane-inserting end of a pH Low Insertion Peptide (pHLIP) via a disulfide bond to generate a linkerless cytoplasmic release. The cytoplasmic reduction of the disulfide releases the calicheamicin, which leads to its activation, DNA binding, and strand scission. pHLIP is a tumor-targeting agent now in clinical trials with imaging and therapeutic payloads. We studied the interaction of pHLIP-calicheamicin with liposomal and cellular membranes and demonstrated that the agent exhibits cytotoxic activity both in highly proliferative cancer cells and in non-proliferative immune cells, such as polarized M2 macrophages. In mice, treatment led to the growth inhibition of immuno-suppressive CT26 tumors with no signs of toxicity. Biodistribution studies confirmed tumor targeting with no accumulation of the agent in organs and tissues. The fluorescent version of the agent was observed within the tumor mass and tumor-stroma interface, where CD206+ M2 tumor-associated macrophages (M2-TAMs) reside. Treatment of tumors led to the depletion of M2-TAMs within the tumor core. Thus, pHLIP-calicheamicin could be developed into an effective therapeutic for the treatment of solid tumors with abundant immuno-suppressive M2-TAMs.
Citation Format: Michael DuPont, Craig Klumpp, Marissa Iraca, Dana Allababidi, Hannah Visca, Donald Engelman, Oleg Andreev, Anna Moshnikova, Yana Reshetnyak. pHLIP targeted intracellular delivery of calicheamicin [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 731.