bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S6 from Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma
Authors: Jain Salvia , Washington Abigail , Leaf Rebecca Karp , Bhargava Parul , Clark Rachael A. , Kupper Thomas S. , Stroopinsky Dina , Pyzer Athalia , Cole Leandra , Nahas Myrna , Apel Arie , Rosenblatt Jacalyn , Arnason Jon , Kufe Donald , Avigan David
Published: April 2023

Decitabine and GO-203 combination induces apoptosis in CTCL cells
Figure S1 from Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma
Authors: Jain Salvia , Washington Abigail , Leaf Rebecca Karp , Bhargava Parul , Clark Rachael A. , Kupper Thomas S. , Stroopinsky Dina , Pyzer Athalia , Cole Leandra , Nahas Myrna , Apel Arie , Rosenblatt Jacalyn , Arnason Jon , Kufe Donald , Avigan David
Published: April 2023

Decitabine and MUC1-C inhibitor combination increases hydrogen peroxide (H2O2) levels, which is abrogated by addition of NAC and is not synergistic in inducing cytotoxicity in MUC1-C low/negative CTCL cell lines
Supplementary Figure Legends (Fig. S1 - S7) from An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer
Authors: Ashenden Matthew , van Weverwijk Antoinette , Murugaesu Nirupa , Fearns Antony , Campbell James , Gao Qiong , Iravani Marjan , Isacke Clare M.
Published: April 2023

Figure legends for Supplementary Figures S1 - S7
Figure S5 from Site-Specific PEGylation of Anti-Mesothelin Recombinant Immunotoxins Increases Half-life and Antitumor Activity
Authors: Zheng Zeliang , Okada Ryuhei , Kobayashi Hisataka , Nagaya Tadanobu , Wei Junxia , Zhou Qi , Lee Fred , Bera Tapan K. , Gao Yun , Kuhlman William , Tai Chin-Hsien , Pastan Ira
Published: April 2023

Biodistribution of LMB-249-PEG and SS1P
Supplementary Data from Disruption of SND1–MTDH Interaction by a High Affinity Peptide Results in SND1 Degradation and Cytotoxicity to Breast Cancer Cells In Vitro and In Vivo
Authors: Li Peng , He Yunjiao , Chen Teng , Choy Kit-Ying , Chow Tsun Sing , Wong Iris L.K. , Yang Xinqing , Sun Wenqin , Su Xiaochun , Chan Tak-Hang , Chow Larry M.C.
Published: April 2023

Figures S1 to S3
Supplementary Figure 1 from Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of Complex Therapeutics to Pancreatic Cancers
Authors: Hagerty Brendan , O'Sullivan T. Norene , Zhang Xianyu , Collins N. Keith , Custer Lawrence Wendi , Bassel Laura L. , Pate Nathan , Xu Jian , Guerin Theresa M. , Kozlov Serguei , Alewine Christine
Published: April 2023

Supplemental Figure 1. TPO171 transgenic thyroid tissues are stained with CD3-specific and cleft caspase 3 (ClC3)-specific antibodies following treatment with active LMB100 itox (left set of images) vs. LMB100 inactive mutant variant (right set of images).
Supplementary Data from First-in-Class Inhibitors of Oncogenic CHD1L with Preclinical Activity against Colorectal Cancer
Authors: Abbott Joshua M. , Zhou Qiong , Esquer Hector , Pike Laura , Broneske Travis P. , Rinaldetti Sébastien , Abraham Adedoyin D. , Ramirez Dominique A. , Lunghofer Paul J. , Pitts Todd M. , Regan Daniel P. , Tan Aik Choon , Gustafson Daniel L. , Messersmith Wells A. , LaBarbera Daniel V.
Published: April 2023

Supplementary Information Section, including: materials, tables, figures, and compound characterization data.
Figure S1 from BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma
Authors: Busacca Sara , O'Regan Laura , Singh Anita , Sharkey Annabel J. , Dawson Alan G. , Dzialo Joanna , Parsons Aimee , Kumar Neelam , Schunselaar Laurel M. , Guppy Naomi , Nakas Apostolos , Sheaff Michael , Mansfield Aaron S. , Janes Sam M. , Baas Paul , Fry Andrew M. , Fennell Dean A.
Published: April 2023

BRCA2 is not required for vinorelbine-induced cell death MSTO and REN cells were transfected with siNT and siBRCA2. 24 hours following transfection, cells were treated with vinorelbine 100 nM for a further 48 hours and caspase 3 activity measured. Data were normalised to untreated siNT control. Western blots show downregulation of BRCA2 after silencing. MSTO-211H: siNT NT vs siNT VNB p<0.0001; siBRCA2 VNB vs siBRCA2 VNB p<0.0001. REN: siNT NT vs siNT VNB p<0.0001; siBRCA2 VNB vs siBRCA2 VNB p<0.0001.
Figure S4 from Rapid Resistance of FGFR-driven Gastric Cancers to Regorafenib and Targeted FGFR Inhibitors can be Overcome by Parallel Inhibition of MEK
Authors: Lau David K. , Luk Ian Y. , Jenkins Laura J. , Martin Andrew , Williams David S. , Schoffer Kael L. , Chionh Fiona , Buchert Michael , Sjoquist Katrin , Boussioutas Alex , Hayes Sarah A. , Ernst Matthias , Weickhardt Andrew J. , Pavlakis Nick , Tebbutt Niall C. , Mariadason John M.
Published: April 2023

Supplementary Figure 4
Video 1 from Paclitaxel Induces Micronucleation and Activates Pro-Inflammatory cGAS–STING Signaling in Triple-Negative Breast Cancer
Authors: Hu Yang , Manasrah Baraa K. , McGregor Stephanie M. , Lera Robert F. , Norman Roshan X. , Tucker John B. , Scribano Christina M. , Yan Rachel E. , Humayun Mouhita , Wisinski Kari B. , Tevaarwerk Amye J. , O'Regan Ruth M. , Wilke Lee G. , Weaver Beth A. , Beebe David J. , Jin Ning , Burkard Mark E.
Published: April 2023

Mononucleated H2B-RFP Tub-GFP MDA-MB-231 Bipolar Division
Supplementary Figure from Proteolytic pan-RAS Cleavage Leads to Tumor Regression in Patient-derived Pancreatic Cancer Xenografts
Authors: Vidimar Vania , Park Minyoung , Stubbs Caleb K. , Ingram Nana K. , Qiang Wenan , Zhang Shanshan , Gursel Demirkan , Melnyk Roman A. , Satchell Karla J.F.
Published: April 2023

Supplementary Figure from Proteolytic pan-RAS Cleavage Leads to Tumor Regression in Patient-derived Pancreatic Cancer Xenografts
Supplementary Figure from Niraparib Shows Superior Tissue Distribution and Efficacy in a Prostate Cancer Bone Metastasis Model Compared with Other PARP Inhibitors
Authors: Snyder Linda A. , Damle Rajendra , Patel Shefali , Bohrer Jared , Fiorella Anna , Driscoll Jenny , Hawkins Rebecca , Stratton Christopher F. , Manning Carol D. , Tatikola Kanaka , Tryputsen Volha , Packman Kathryn , Mamidi Rao N.V.S.
Published: April 2023

Supplementary Figure from Niraparib Shows Superior Tissue Distribution and Efficacy in a Prostate Cancer Bone Metastasis Model Compared with Other PARP Inhibitors
Supplementary Table from Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells With Increased Tumor Infiltration and Persistence for Treating Solid Tumors
Authors: Tomar Sakshi , Zhang Jingli , Khanal Manakamana , Hong Jessica , Venugopalan Abhilash , Jiang Qun , Sengupta Manjistha , Miettinen Markku , Li Nan , Pastan Ira , Ho Mitchell , Hassan Raffit
Published: April 2023

Supplementary Table from Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells With Increased Tumor Infiltration and Persistence for Treating Solid Tumors
Supplementary Tables from Identification and Characterization of IMD-0354 as a Glutamine Carrier Protein Inhibitor in Melanoma
Authors: Feng Yongmei , Pathria Gaurav , Heynen-Genel Susanne , Jackson Michael , James Brian , Yin Jun , Scott David A. , Ronai Ze'ev A.
Published: April 2023

Supp Tables 1-2: Table S1 List of hits selected from the primary screen. Table S2. Chemical structures of hits selected for validation.
Supplementary Figures and Tables from Preclinical Studies of OBI-999: A Novel Globo H–Targeting Antibody–Drug Conjugate
Authors: Yang Ming-Chen , Shia Chi-Sheng , Li Wan-Fen , Wang Chun-Chung , Chen I-Ju , Huang Teng-Yi , Chen Yu-Jung , Chang Hui-Wen , Lu Chi-Huan , Wu Yueh-Chin , Wang Nan-Hsuan , Lai Jiann-Shiun , Yu Cheng-Der , Lai Ming-Tain
Published: April 2023

Supplementary Figures and Tables
Supplementary Figure from Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation
Authors: Owens Jake L. , Beketova Elena , Liu Sheng , Shen Qi , Pawar Jogendra Singh , Asberry Andrew M. , Yang Jie , Deng Xuehong , Elzey Bennett D. , Ratliff Timothy L. , Cheng Liang , Choo Richard , Citrin Deborah E. , Polascik Thomas J. , Wang Bangchen , Huang Jiaoti , Li Chenglong , Wan Jun , Hu Chang-Deng
Published: April 2023

Supplementary Figure from Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation
Supplementary Data from Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation
Authors: Owens Jake L. , Beketova Elena , Liu Sheng , Shen Qi , Pawar Jogendra Singh , Asberry Andrew M. , Yang Jie , Deng Xuehong , Elzey Bennett D. , Ratliff Timothy L. , Cheng Liang , Choo Richard , Citrin Deborah E. , Polascik Thomas J. , Wang Bangchen , Huang Jiaoti , Li Chenglong , Wan Jun , Hu Chang-Deng
Published: April 2023

Supplementary Data from Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation
Supplementary Data from A Novel Therapeutic Anti-ErbB3, ISU104 Exhibits Potent Antitumorigenic Activity by Inhibiting Ligand Binding and ErbB3 Heterodimerization
Authors: Hong Mirim , Yoo Youngki , Kim Miyoung , Kim Ju Yeon , Cha Jeong Seok , Choi Myung Kyung , Kim Uijin , Kim Kyungyong , Sohn Youngsoo , Bae Donggoo , Cho Hyun-Soo , Hong Seung-Beom
Published: April 2023

Figure S1-S6, Table S1-S7
Supplementary Movie 7 from Resistance Profile and Structural Modeling of Next-Generation ROS1 Tyrosine Kinase Inhibitors
Authors: Keddy Clare , Shinde Pushkar , Jones Kristen , Kaech Stefanie , Somwar Romel , Shinde Ujwal , Davare Monika A.
Published: April 2023

Supplementary Movie 7
Z-stack Animation of live confocal imaging.
Supplementary Movie 1 from Resistance Profile and Structural Modeling of Next-Generation ROS1 Tyrosine Kinase Inhibitors
Authors: Keddy Clare , Shinde Pushkar , Jones Kristen , Kaech Stefanie , Somwar Romel , Shinde Ujwal , Davare Monika A.
Published: April 2023

Supplementary Movie 1
Z-stack Animation of live confocal imaging.
Supplementary Data from Exploration of Tumor Biopsy Gene Signatures to Understand the Role of the Tumor Microenvironment in Outcomes to Lisocabtagene Maraleucel
Authors: Olson N. Eric , Ragan Seamus P. , Reiss David J. , Thorpe Jerill , Kim Yeonhee , Abramson Jeremy S. , McCoy Candice , Newhall Kathryn J. , Fox Brian A.
Published: April 2023

Supplementary Methods; Supplementary Figures S1-S9; Supplementary Tables S1-S7
Supplementary Data from Eradication of Heterogeneous Tumors by T Cells Targeted with Combination Bispecific Chemically Self-assembled Nanorings
Authors: Petersburg Jacob , Vallera Daniel A. , Wagner Carston R.
Published: April 2023

Supplementary data and supplementary figures 1-9
Figure FS6 from Tinengotinib (TT-00420), a Novel Spectrum-Selective Small-Molecule Kinase Inhibitor, Is Highly Active Against Triple-Negative Breast Cancer
Authors: Peng Peng , Qiang Xiaoyan , Li Guoyu , Li Lin , Ni Shumao , Yu Qi , Sourd Laura , Marangoni Elisabetta , Hu Chao , Wang Dong , Wu Di , Wu Frank
Published: April 2023

Tinengotinib effectively blocks JAK/STAT3/IDO signaling pathway.
Figure FS2 from Tinengotinib (TT-00420), a Novel Spectrum-Selective Small-Molecule Kinase Inhibitor, Is Highly Active Against Triple-Negative Breast Cancer
Authors: Peng Peng , Qiang Xiaoyan , Li Guoyu , Li Lin , Ni Shumao , Yu Qi , Sourd Laura , Marangoni Elisabetta , Hu Chao , Wang Dong , Wu Di , Wu Frank
Published: April 2023

As shown in Figure 2, Image J was applied for semi-quantification for each protein level as indicated.
Supplementary Table from Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression
Authors: McGovern Karen , Castro Alfredo C. , Cavanaugh Jill , Coma Silvia , Walsh Meghan , Tchaicha Jeremy , Syed Sakeena , Natarajan Prabitha , Manfredi Mark , Zhang Xiaoyan M. , Ecsedy Jeffrey
Published: April 2023

Supplementary Table from Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression
Supplementary Data from Computational Modeling of TP63–TP53 Interaction and Rational Design of Inhibitors: Implications for Therapeutics
Authors: Ozdemir E. Sila , Gomes Michelle M. , Fischer Jared M.
Published: April 2023

Supplementary Data from Computational Modeling of TP63–TP53 Interaction and Rational Design of Inhibitors: Implications for Therapeutics
Supplementary Figure from PLGA–Nano-Encapsulated Disulfiram Inhibits Hypoxia-Induced NF-κB, Cancer Stem Cells, and Targets Glioblastoma In Vitro and In Vivo
Authors: Kannappan Vinodh , Liu Ying , Wang Zhipeng , Azar Karim , Kurusamy Sathishkumar , Kilari Rajagopal S. , Armesilla Angel L. , Morris Mark R. , Najlah Mohammad , Liu Peng , Bian Xiu-Wu , Wang Weiguang
Published: April 2023

Supplementary Figure from PLGA–Nano-Encapsulated Disulfiram Inhibits Hypoxia-Induced NF-κB, Cancer Stem Cells, and Targets Glioblastoma In Vitro and In Vivo
Supplementary Table S1 from ER-851, a Novel Selective Inhibitor of AXL, Overcomes Resistance to Antimitotic Drugs
Authors: Tsukamoto Shuntaro , Sugi Naoko Hata , Nishibata Kyoko , Nakazawa Youya , Ito Daisuke , Fukushima Sayo , Nakagawa Takayuki , Ichikawa Kenji , Kato Yu , Kakiuchi Dai , Goto Aya , Itoh-Yagi Machiko , Aota Tomoki , Inoue Satoshi , Yamane Yoshinobu , Murai Norio , Azuma Hiroshi , Nagao Satoshi , Sasai Ken , Akagi Tsuyoshi , Imai Toshio , Matsui Junji , Matsushima Tomohiro
Published: April 2023

Supplementary Table S1
Data from A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE)
Authors: Pan Elizabeth , Xie Wanling , Ajmera Archana , Araneta Arlene , Jamieson Christina , Folefac Edmund , Hussain Arif , Kyriakopoulos Christos E. , Olson Adam , Parikh Mamta , Parikh Rahul , Saraiya Biren , Ivy S. Percy , Van Allen Eliezer M. , Lindeman Neal I. , Kochupurakkal Bose S. , Shapiro Geoffrey I. , McKay Rana R.
Published: April 2023

Abstract
Given that radium-223 is a radiopharmaceutical that induces DNA damage, and olaparib is a PARP inhibitor that interferes with DNA repair mechanisms, we hypothesized their synergy in metastatic castration-resistant prostate cancer (mCRPC). We sought to demonstrate the safety and efficacy of olaparib + radium-223.

We conducted a multicenter phase I 3+3 dose escalation study of olaparib with fixed dose radium-223 in patients with mCRPC with bone metastases. The primary objective was to establish the RP2D of olaparib, with secondary objectives of safety, PSA response, alkaline phosphatase response, radiographic progression-free survival (rPFS), overall survival, and efficacy by homologous recombination repair (HRR) gene status.

Twelve patients were enrolled; all patients received a prior androgen receptor signaling inhibitor (ARSI; 100%) and 3 patients (25%) prior docetaxel. Dose-limiting toxicities (DLT) included cytopenias, fatigue, and nausea. No DLTs were seen in the observation period however delayed toxicities guided the RP2D. The RP2D of olaparib was 200 mg orally twice daily with radium-223. The most common treatment-related adverse events were fatigue (92%) and anemia (58%). The rPFS at 6 months was 58% (95% confidence interval, 27%–80%). Nine patients were evaluable for HRR gene status; 1 had a BRCA2 alteration (rPFS 11.8 months) and 1 had a CDK12 alteration (rPFS 3.1 months).

Olaparib can be safely combined with radium-223 at the RP2D 200 mg orally twice daily with fixed dose radium-223. Early clinical benefit was observed and will be investigated in a phase II study.
Abstract 1220: Carcinogenic nickel(II) is a replication stressor causing genotoxicity via DNA incorporation of rNMPs
Authors: Krawic Casey , Valiente Sophia , Zhitkovich Anatoly
Published: April 2023

Nickel(II) is a long-established inhalation carcinogen that causes lung and nasal tumors in humans and rodents. Despite its being a complete carcinogen, Ni(II) is DNA-unreactive and tested negative in the standard mutagenicity assays and consequently, is described as nongenotoxic. However, we have recently found that Ni(II) caused activation of the genotoxic stress-sensitive transcription factor p53, suggesting that this metal may possess some atypical, poorly detectable form(s) of genotoxicity. To determine what genotoxic or other cellular injury by Ni(II) upregulated p53, we examined multiple DNA damage responses and the role of several stress-sensitive kinases. We found that Ni(II)-induced phosphorylation and stabilization of p53 was mediated by ATR kinase but in its absence, by ATM kinase. Phosphorylation of p53 and CHK1 (another ATR target) occurred specifically in S phase, as determined by immunofluorescence and using synchronized cell populations. Inhibition of ATR strongly increased severity of replication stress and triggered activation of ATM kinase. Replication stress by Ni(II) was found to result from depletion of ribonucleotide reductase subunits through their higher turnover. We developed a novel fluorescent assay for detection of DNA-embedded rNMPs and found that Ni(II) induced a large increase in the DNA burden of ribonucleotides. The biological significance of DNA-incorporated rNMPs in Ni(II)-induced genotoxic responses was confirmed by the hypersensitivity of cells with inactivated ribonucleotide excision repair (RNAse H2 knockdown). Thus, our findings identified carcinogenic Ni(II) as a replication stressor inducing DNA incorporation of genotoxic rNMPs which are poorly detectable in the standard mutagenicity tests. Other protein-reactive carcinogen may also engage similar genotoxicity mechanisms.

Citation Format: Casey Krawic, Sophia Valiente, Anatoly Zhitkovich. Carcinogenic nickel(II) is a replication stressor causing genotoxicity via DNA incorporation of rNMPs [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 1220.
Abstract 1224: Quaking overexpression downregulates epithelial-mesenchymal transition in lung cancer cells
Authors: Kao Ying-Shiun , Hung Jung-Jyh
Published: April 2023

Background: Lung cancer is the leading cause of cancer death worldwide. Tumor recurrence is the most common cause of treatment failure after surgical resection. Quaking (QKI) is a functional protein that mediate alternative splicing, which belongs to the STAR family of the KH domain, containing RNA binding proteins. QKI regulate various genes via alternative splicing and circRNA formation during epithelial-mesenchymal transition (EMT). QKI takes an important part in tumorigenesis. QKI has been reported to be associated with progression of human cancer. However, several studies have indicated that QKI was associated with repression of EMT. Furthermore, the prognostic value of QKI in lung cancer patients and its regulatory mechanisms in EMT in lung cancer cells remains unknown.

Materials and Methods: A total of 79 patients with resected lung adenocarcinoma were included in the study. QKI expression was determined by immunohistochemistry in tumor specimens. The prognostic value of QKI overexpression and its relationship with clinicopathological variables were investigated. QKI knockdown was performed in H1299 and A549 cells. Western blotting analysis was performed to demonstrated QKI, E-cadherin and vimentin expression.

Results: QKI overexpression was significantly associated with female gender (P = 0.045). There was no significant association between QKI overexpression and predominant pattern group (lepidic/acinar/papillary vs. micropapillary/solid) (P = 0.180). Univariate analysis indicated that predominant pattern group (lepidic/acinar/papillary vs. micropapillary/solid) (P = 0.006) was a significant prognostic factor for worse recurrence-free survival (RFS). QKI overexpression (P = 0.042) was a significant prognostic factor for better RFS. Increased vimentin expression and decreased E-cadherin expression were identified in H1299 and A549 cells after QKI knockdown.

Conclusions: QKI overexpression has the potential to be a significant prognostic factor for better RFS in patients with resected lung adenocarcinoma. Increased vimentin expression and decreased E-cadherin expression were identified in H1299-QKIi cells. QKI may possess the ability to inhibit invasion and migration through repressing EMT.

Citation Format: Ying-Shiun Kao, Jung-Jyh Hung. Quaking overexpression downregulates epithelial-mesenchymal transition in lung 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 1224.
Abstract 1427: NQO1/c-Fos/CKS1 signaling pathway regulates cell cycle progression at the G2/M phase
Authors: Oh Eun-Taex , Kim Ha Gyeong , Cho Yunmi , Park Heon Joo
Published: April 2023

Overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is associated with tumor cell proliferation and growth in several human cancer types. However, the molecular mechanisms underlying the activity of NQO1 in cell cycle progression are currently unclear. Here, we report a novel function of NQO1 in modulation of cyclin-dependent kinase subunit (CKS1), a cell cycle regulator, at the G2/M phase, through effects on the stability of c-Fos. We analyzed the roles of NQO1/c-Fos/CKS signaling pathway in cell cycle progression in cancer cells using synchronization of cell cycle and flow cytometry. The mechanisms of NQO1/c-Fos/CKS1-mediated regulation of cell cycle progression in cancer cells were studied by siRNA, overexpression system, reporter assay, co-immunoprecipitation, pull-down assay, microarray analysis, and CDK1 kinase assay. In addition, publicly available data sets and immunohistochemistry were used to investigate the correlation between NQO1 expression levels and clinicopathological features in cancer patients. Our results suggest that NQO1 directly interacts with the unstructured DNA-binding domain of c-Fos implicated in proliferation, differentiation, development and survival of cancer and inhibits its proteasome-mediated degradation, thereby inducing CKS1 expression and regulating cell cycle progression at the G2/M phase. Notably, NQO1 deficiency in human cancer cell lines led to suppression of c-Fos-mediated CKS1 expression and cell cycle progression. Consistent with this finding, high NQO1 expression was correlated with increased CKS1 and poor prognosis in cancer patients. Our collective results support a novel regulatory role of NQO1 in the mechanism of cell cycle progression at the G2/M phase through effects on c-Fos/CKS1 signaling pathway in cancer.

Citation Format: Eun-Taex Oh, Ha Gyeong Kim, Yunmi Cho, Heon Joo Park. NQO1/c-Fos/CKS1 signaling pathway regulates cell cycle progression at the G2/M phase [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 1427.
Abstract 1455: The glucocorticoid receptor-LEDGFp75 interaction in prostate cancer therapy cross-resistance
Authors: Sanchez-Hernandez Evelyn S. , Ochoa Pedro T. , Ortiz-Hernandez Greisha L. , Martinez Shannalee , Casiano Carlos
Published: April 2023

Prostate cancer (PCa) is the second leading cause of cancer deaths in the U.S., disproportionally affecting African American (AA) men. PCa patients with recurrent disease develop therapy resistance and fail to respond to both anti-androgen receptor signaling (ARSI) therapy and taxane-based chemotherapy. Glucocorticoid receptor, a transcription factor, has been implicated in resistance to ARSI (via the GR bypass), and docetaxel (DTX) therapies. However, the mechanisms underlying this GR-mediated therapy cross-resistance are poorly understood. Previously, we demonstrated that glucocorticoids, which are co-administered with current PCa therapies and activate GR signaling, upregulate the chemoresistance-associated transcription coactivator LEDGFp75 in PCa cells. We also identified consensus GR binding sites in the promoter region of the gene encoding LEDGFp75, suggesting it is a GR target gene. We hypothesized that GR transcriptionally upregulates LEDGFp75 and then interacts with this protein in the nucleus to promote DTX resistance in PCa cells. Genetic silencing of GR in a panel of DTX-sensitive and -resistant PCa cell lines decreased the expression of LEDGFp75 at both the protein and transcript levels, confirming its status as a candidate GR target gene. However, genetic silencing of LEDGFp75 had no effects on GR protein expression. Pharmacological inhibition of GR also decreased LEDGFp75 in DTX-sensitive cells. The effects of Exicorilant and Relacorilant (Corcept Therapeutics) were evaluated on LEDGFp75 protein expression levels. Immunoprecipitation and confocal microscopy studies revealed that GR and LEDGFp75 interact in the nucleus of PCa cells. Interestingly, upregulation of GR in enzalutamide resistant LNCaP cells correlated with LEDGFp75 upregulation, and GR silencing in these cells decreased this upregulation. These results suggested a possible role for GR and LEDGFp75 in PCa therapy cross-resistance. Further studies are underway to determine if co-targeting these two proteins genetically and pharmacologically attenuates both enzalutamide resistance and DTX resistance and other aggressive properties of PCa cells. In addition, RNAseq studies have been initiated to determine the degree of transcriptional overlap between GR and LEDGFp75 in chemoresistant PCa cells. Our goal is to link mechanistically the GR-LEDGFp75 transcriptional network to ARSI/taxane cross-resistance in PCa and target this network to attenuate therapy resistance.

Citation Format: Evelyn S. Sanchez-Hernandez, Pedro T. Ochoa, Greisha L. Ortiz-Hernandez, Shannalee Martinez, Carlos Casiano. The glucocorticoid receptor-LEDGFp75 interaction in prostate cancer therapy cross-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 1455.
Abstract 152: Robust establishment and expansion of human fallopian tube organoids in serum-free culture
Authors: Ho Victor , Chan Maggie , Chehal Manreet , Liang Alice , Eaves Allen , Louis Sharon , Stingl John
Published: April 2023

High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of epithelial ovarian cancer. Despite its name, HGSOC originates in the fallopian tube (FT), but metastasizes quickly in the adnexal region and is the most lethal gynecological cancer worldwide. Organoid culture is emerging as a powerful model for studying normal FT cell biology and ovarian cancer. To standardize primary human FT and HGSOC organoid culture, we have developed GyneCult Fallopian Tube Organoid Medium (FTOM), an optimized serum-free medium and a workflow that supports robust and representative FT organoid culture from freshly isolated or cryopreserved primary human FT cells. FT cultures were initiated by seeding 4000 dissociated single cells directly into 20 µL Corning® Matrigel® domes and overlaying them with FT Organoid Medium. After seeding, cultures were maintained with full-medium changes every 3 - 4 days and were split either in a passage ratio of 1:3, or at 4,000 cells per 20 µL of Matrigel®, as single cells every 8 - 14 days. Cultures were analyzed by immunocytochemistry (ICC) to detect secretory markers keratin 7 (KRT7), oviductal glycoprotein 1 (OVGP1), and PAX8, as well as ciliated cell markers acetylated alpha tubulin (TUBA1A) and FOXJ1. Across all donor samples, approximately 16 ± 8% (mean ± SD) of dissociated EpCAM+ FT cells formed 50 - 300 µm diameter cystic organoids within 14 days (n = 8). Cultures can be maintained for at least 5 passages with 14 - 20 cumulative population doublings, at 3 - 4 doublings per passage. ICC analysis confirmed that organoids contain both polarized KRT7+ OVGP1+ PAX8+ secretory cells and acetylated TUBA1A+ FOXJ1+ ciliated cells, indicating multilineage capacity (n = 5). We also tested the compatibility of GyneCult FTOM for growing HGSOC samples, and we observed that 1 of the 3 tumor samples tested generated organoids with a solid and irregular shaped morphology. These cells could undergo a minimum of 5 cumulative population doublings over 5 passages, at 0.5 - 2 doublings per passage; this performance is in line with recently published HGSOC organoid culture methods. These results demonstrate that GyneCult Fallopian Tube Organoid Medium is a robust medium for initiating and culturing FT epithelium as organoids and is a valuable tool for studying FT biology, with the capacity to support HGSOC organoid culture.

Citation Format: Victor Ho, Maggie Chan, Manreet Chehal, Alice Liang, Allen Eaves, Sharon Louis, John Stingl. Robust establishment and expansion of human fallopian tube organoids in serum-free culture [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 152.
Abstract 1687: ATPase copper transporting beta (ATP7B) contributes to acquired docetaxel resistance in human prostate cancer
Authors: Song Liankun , Nguyen Vyvyan , Xie Jun , Tippin Matthew , Truong Le TP , Blair Christopher A. , Wang Beverly , Uchio Edward , Zi Xiaolin
Published: April 2023

Docetaxel has been the standard first-line chemotherapy for lethal metastatic prostate cancer (mPCa) since 2004, but the resistance to docetaxel treatment is common. The molecular mechanisms of docetaxel resistance remain largely unknown and could be amenable to interventions that mitigate resistance. We have recently discovered that several docetaxel resistant mPCa cell lines exhibit less uptake of cellular copper and express markedly higher levels of ATP7B protein without significant changes in the protein expression levels of other copper transporters, such as ATPase copper transporting alpha (ATP7A) and high affinity copper uptake protein 1 (CTR1). Knock-down of ATP7B by silencing RNAs sensitized docetaxel resistant-mPCa cells to the growth inhibitory and apoptotic effects of docetaxel. Importantly, deletions of ATP7B in mPCa tissues predict significantly better survival of patients after their first chemotherapy than those with wild-type ATP7B (P = 0.0006). In addition, Disulfiram (DSF), an FDA approved drug for treatment of alcohol dependence, in combination with copper, significantly enhanced the in vivo antitumor effects of docetaxel in a docetaxel resistant xenograft tumor model. Our analyses also revealed that DSF and copper engaged with ATP7B to decrease protein levels of COMM domain-containing protein 1 (COMMD1), S-phase kinase associated protein 2 (Skp2) and clusterin and markedly increase protein expression of cyclin-dependent kinase inhibitor 1 (p21/WAF1). Taken together, our results suggest that ATP7B is a clinically relevant and key target for improving the efficacy of docetaxel for treatment of mPCa.

Citation Format: Liankun Song, Vyvyan Nguyen, Jun Xie, Matthew Tippin, Le TP Truong, Christopher A. Blair, Beverly Wang, Edward Uchio, Xiaolin Zi. ATPase copper transporting beta (ATP7B) contributes to acquired docetaxel resistance in human prostate 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 1687.
Abstract 1704: Interferon inducible ADAR1 is essential for the survival of oral squamous cell carcinoma
Authors: Yee Pei San , Chai Annie Wai Yeeng , Yee Shi Mun , Ooi Shi Yin , Tan Yee Hua , Garnett Mathew , Ng Siew Kit , Cheong Sok Ching
Published: April 2023

Treating oral squamous cell carcinoma (OSCC) remains challenging due to limited knowledge of the critical genes that could affect cell survival in OSCC. We have previously utilized genome-wide CRISPR-Cas9 knockout functional screens to explore the genetic vulnerabilities of OSCC and identified Adenosine deaminase acting on RNA (ADAR1) as one of the top fitness genes. ADAR1 is an interferon-stimulated gene (ISG) that catalyses adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA), which suppresses dsRNA sensing mechanism from triggering cell death. ADAR1 gene encodes for two isoforms, the constitutively expressed P110 and the interferon-inducible P150. Given that deleting ADAR1 severely impacts OSCC viability, we aimed to elucidate key molecular mechanisms underlying this gene dependency which may provide opportunities for developing better treatment strategies. Here, we validated ADAR1 dependency via competitive co-culture assay using single-guide RNA (sgRNA) knockout in selected OSCC cell lines. We also confirmed that sgRNA-mediated ADAR1 knockout resulted in prominent cell lethality through increased apoptosis and inhibition of colony formation. Cell lethality is evident in ADAR1 KO cells in conjunction with the phosphorylation of a dsRNA sensor, protein kinase R (PKR) which regulates cell death mechanism. In ADAR1-less dependent cells, IFN-β treatment increased the expression of ISGs including ADAR1, and sensitized the cells to ADAR1 KO-induced cell death. Overexpression of ADAR1-P150 but not ADAR1-P110 rescued cell lethality in ADAR1-depleted cells, suggesting that ADAR1-P150 is required for OSCC survival. We also demonstrate that the deaminase function of ADAR1 is important in conferring survival to a subset of OSCC lines. In addition to PKR, the melanoma differentiation-associated protein 5 (MDA5) dsRNA sensor is also important in mediating ADAR1 KO-induced cell lethality OSCC and co-deleting both PKR and MDA5 enabled the partial rescue of cell death compared to when each gene was knocked out individually. Collectively, our results uncover the essentiality of IFN-inducible ADAR1-P150 for OSCC survival, and reveal that the activation of PKR and MDA5 dsRNA sensing pathways underlie the cell lethality caused by ADAR1 deletion.

Citation Format: Pei San Yee, Annie Wai Yeeng Chai, Shi Mun Yee, Shi Yin Ooi, Yee Hua Tan, Mathew Garnett, Siew Kit Ng, Sok Ching Cheong. Interferon inducible ADAR1 is essential for the survival of oral squamous cell carcinoma [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 1704.
Abstract 1705: SPOP: An essential gene for normal and prostate tumor cells
Authors: Rizwan Kinza , Skapura Darlene , Mason Cammy , Coarfa Cristian , Mitsiades Nicholas , Young Damian , Kaochar Salma
Published: April 2023

Background: Prostate cancer (PC) is the single most common and second-most lethal cancer in men, with over 268,000 estimated cases and over 34,500 estimated deaths in the US in 2022. The Speckle-Type POZ protein (SPOP) mutant subclass of PC accounts for 10% to 15% of all primary PC cases. SPOP is an adaptor for Cullin3/Ring (CUL3-RING)-type E3 ubiquitin ligase complexes and provides substrate specificity. The Cancer Genome Atlas (TCGA) studies show that SPOP is the most frequently mutated gene in primary prostate cancer (PC). Interestingly, PC-associated SPOP mutations are always missense and occur in a heterozygous fashion. The current gap in knowledge is the lack of understanding of the role of wildtype SPOP in PC.

Methods: By utilizing prostate specific SPOP knockout (KO) mice, we recently reported increased levels of AR and MYC protein and increased cellular turnover (both proliferation and apoptosis) in the prostate luminal epithelium compared to wildtype prostates. We now characterized these mice for the expression of Cre protein and SPOP mRNA at different age using immunohistochemistry and RNA in situ hybridization. Furthermore, we performed RNA-sequencing analysis in the SPOP knockout mice and matched control littermates. Moreover, we performed RNA-seq in LNCaP, LNCaP-Abl, and RWPE1 cells following SPOP inhibition via siRNA targeting SPOP. Finally, we compared our SPOP inhibition signature from in vitro cell lines and prostate specific SPOP knockout murine model to gain insights about the role of wildtype SPOP protein in the prostate epithelium.

Result: Using our Spopfl/fl;PBCre+ model, we observed SPOP floxed cells are rapidly lost and the murine prostate epithelium was repopulated with SPOP wildtype carrying cells. Similarly, knockdown (KD) of SPOP through siRNA treatment in a panel of PC cell lines resulted in a significant reduction in cell viability. These observations suggest that SPOP is important for the normal prostate cell viability. Further transcriptomic profiling of SPOP KO (from transgenic murine model) as well as siSPOP treated in vitro prostate cell lines revealed a significant reduction in the transcriptional activity of the AR.

Conclusion: Our data illustrate for the first time a critical role for SPOP in the growth and survival of the prostate epithelium and prostate cancer cell. Our findings further validates SPOP as a important therapeutic target for the treatment of prostate cancer.

Citation Format: Kinza Rizwan, Darlene Skapura, Cammy Mason, Cristian Coarfa, Nicholas Mitsiades, Damian Young, Salma Kaochar. SPOP: An essential gene for normal and prostate tumor 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 1705.
Abstract 1759: Targeting adaptation to cancer treatment by drug combinations
Authors: Luna Augustin , Wang Heping , Yan Gonghong , Li Xubin , Babur Ozgun , Mills Gordon Mills B. , Sander Chris , Korkut Anil
Published: April 2023

Adaptation of tumors to therapeutic interventions contributes to dismal long-term patient outcomes. Adaptation to therapy involves co-action of functionally related proteins that together activate cell survival programs and compensate for the therapeutic impact. Oncogenic dependencies to such adaptive events, however, can generate new therapeutic vulnerabilities that can be targeted with drug combinations. The precision medicine approaches in which targeted drugs are matched to pre-existing genomic aberrations fail to address the adaptive responses and resulting vulnerabilities. Here, we provide the mathematical formulation, implementation and validation of the TargetScore method. The TargetScore identifies collective adaptive responses to targeted interventions as concurrent changes of phospho-proteins that are connected within a signaling network. Based on the adaptive responses, the method predicts drug-induced vulnerabilities. Using TargetScore, we inferred the adaptive responses with short-term (i.e., days) stress and long-term (i.e., months) acquired resistance to inhibitors of anti-apoptotic mediators, MCL1 and BCL2. With experiments guided by the predictions, we identified synergistic interactions between inhibitors of PARP, SHP2, and MCL1 in breast cancer cells. TargetScore is readily applicable to existing precision oncology efforts by matching targeted drug combinations to emerging molecular signatures under therapeutic stress.

Citation Format: Augustin Luna, Heping Wang, Gonghong Yan, Xubin Li, Ozgun Babur, Gordon Mills B. Mills, Chris Sander, Anil Korkut. Targeting adaptation to cancer treatment by drug combinations [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 1759.
Abstract 1888: IAE0972, A novel EGFR/IL10 immunocytokine of monovalent anti-EGFR antibody fused with IL10 homodimer
Authors: Yin Liusong , Jiang Xiaoling , Wu Chongbing , Chen Zi
Published: April 2023

Exhaustion of immune cells in the tumor microenvironment has been found and confirmed in many tumor cases, accounting for the major problems of current PD1/L1-oriented immunotherapy. There are two types of exhausted T cells present in the tumor microenvironment: progenitor exhausted T cells and terminally exhausted T cells. Data from various mouse syngeneic tumor models suggest that the dominance of progenitor exhausted T cells will be replaced by terminally exhausted T cells as the tumor progresses. The PD1/PDL1 antibodies mainly act on progenitor exhausted T cells and can develop acquired resistance as terminally exhausted T cells become the dominant cells in the tumor microenvironment. Recently, there are studies demonstrating that IL10 can restore the oxidative phosphorylation metabolism of terminally exhausted T cells and restore their potent killing activities of tumor cells. We therefore designed IAE0972, a novel EGFR/IL10 immunocytokine to solve the problems of immune cell exhaustion in current immunotherapy. It is a monovalent anti-EGFR antibody fused with IL10 homodimer. The anti-EGFR antibody can specifically enrich IAE0972 in tumor microenvironment, so that IL10 can reinvigorate antigen specific CD8+ T cells and facilitate its proliferation, while preserving the tumor cell proliferation inhibition activities of EGFR antibody. The design of monovalent form anti-EGFR antibody can also avoid the skin toxicity problem. In this study, we studied the target binding activity, CD8+ T cell activation activity and cancer cell proliferation inhibition activity of IAE0972. We also observed a much higher anti-tumor efficacy of IAE0972 in a MC38 syngeneic tumor model compared with that of Cetuximab. In addition, the molecule has a very good safety profile with MTD over 6 mg/kg and no skin toxicities, which is about 300-fold higher than that of cytokine drugs. In summary, IAE0972 is an innovative EGFR/IL10 immunocytokine with robust preclinical anti-tumor efficacy and favorable safety profile, which has the potential to address acquired resistance of current immunotherapy. IAE0972 is the first EGFR/IL10 immunocytokine with IND approval from both FDA and NMPA. The indications of IAE0972 include colorectal cancer, head and neck squamous cell carcinoma, squamous non-small cell lung cancer, and other EGFR positive tumors. A Phase I/IIa clinical trial to evaluate the safety, tolerability and preliminary efficacy of IAE0972 in patients with locally advanced or metastatic malignant tumors is on-going (NCT05396339).

Citation Format: Liusong Yin, Xiaoling Jiang, Chongbing Wu, Zi Chen. IAE0972, A novel EGFR/IL10 immunocytokine of monovalent anti-EGFR antibody fused with IL10 homodimer [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 1888.
Abstract 200: Patient-derived cervical cancer organoids as a pre-clinical model predicting drug and radiation response
Authors: Oh Ju Hee , Seol Hyang Sook , Choi Eun Hye , Lee Yong Jae Lee , Lee Jung-Yun , Kim Sang Wun , Kim Sunghoon , Kim Young Tae , Kim Hyun Ki , Lee Young Joo , Nam Eun Ji
Published: April 2023

Objective: Advanced cervical cancer is still difficult to treat and in the case of recurrent cancer, it is desirable to utilize personalized treatment rather than uniform treatment because the type of recurrence is different for each individual. Therefore, this study aimed to establish patients-derived organoid platform to determine the effects of chemotherapy, radiation therapy, and targeted therapy in cervical cancer.

Methods: We established organoids from four patients with various types of cervical cancer. The histopathological and gene profiles of these organoid models were compared to determine their characteristics and the maintenance of the patient phenotype. Each type of organoid was also subjected to anticancer drug screening and radiation therapy to evaluate its sensitivity.

Results: We established patient-derived organoids recapitulated the main elements of the original patient tumors, including the DNA copy number and mutational profile. We screened seven drugs that showed growth inhibition in cervical cancer organoids using two analytical tools (individual drugs and an FDA-approved drug library). Moreover, squamous cell carcinoma and villoglandular carcinoma showed significant response to radiation therapy, however, adenocarcinoma and large-cell neuroendocrine carcinoma showed relative resistance to radiation therapy.

Conclusion: Our results showed patient-derived cervical cancer organoid can be used as a pre-clinical model for drug and radiation sensitivity test. These findings suggest that patient-derived cervical cancer organoids could be used as a personalized medicine confirmation tool and to improve treatment options for patients with various subtypes of cervical cancer.

Citation Format: Ju Hee Oh, Hyang Sook Seol, Eun Hye Choi, Yong Jae Lee Lee, Jung-Yun Lee, Sang Wun Kim, Sunghoon Kim, Young Tae Kim, Hyun Ki Kim, Young Joo Lee, Eun Ji Nam. Patient-derived cervical cancer organoids as a pre-clinical model predicting drug and radiation response [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 200.