bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Sustained Minimal Residual Disease Negativity in Multiple Myeloma is Associated with Stool Butyrate and Healthier Plant-Based Diets
Authors: Shah Urvi A. , Maclachlan Kylee H. , Derkach Andriy , Salcedo Meghan , Barnett Kelly , Caple Julia , Blaslov Jenna , Tran Linh , Ciardiello Amanda , Burge Miranda , Shekarkhand Tala , Adintori Peter , Cross Justin , Pianko Matthew J. , Hosszu Kinga , McAvoy Devin , Mailankody Sham , Korde Neha , Hultcrantz Malin , Hassoun Hani , Tan Carlyn R. , Lu Sydney X. , Patel Dhwani , Diamond Benjamin , Shah Gunjan , Scordo Michael , Lahoud Oscar , Chung David J. , Landau Heather , Usmani Saad Z. , Giralt Sergio , Taur Ying , Landgren C. Ola , Block Gladys , Block Torin , Peled Jonathan U. , van den Brink Marcel R.M. , Lesokhin Alexander M.
Published: April 2023

AbstractPurpose:
Sustained minimal residual disease (MRD) negativity is associated with long-term survival in multiple myeloma. The gut microbiome is affected by diet, and in turn can modulate host immunity, for example through production of short-chain fatty acids including butyrate. We hypothesized that dietary factors affect the microbiome (abundance of butyrate-producing bacteria or stool butyrate concentration) and may be associated with multiple myeloma outcomes.
Experimental Design:
We examined the relationship of dietary factors (via a food frequency questionnaire), stool metabolites (via gas chromatography–mass spectrometry), and the stool microbiome (via 16S sequencing - α-diversity and relative abundance of butyrate-producing bacteria) with sustained MRD negativity (via flow cytometry at two timepoints 1 year apart) in myeloma patients on lenalidomide maintenance. The Healthy Eating Index 2015 score and flavonoid nutrient values were calculated from the food frequency questionnaire. The Wilcoxon rank sum test was used to evaluate associations with two-sided P < 0.05 considered significant.
Results:
At 3 months, higher stool butyrate concentration (P = 0.037), butyrate producers (P = 0.025), and α-diversity (P = 0.0035) were associated with sustained MRD negativity. Healthier dietary proteins, (from seafood and plants), correlated with butyrate at 3 months (P = 0.009) and sustained MRD negativity (P = 0.05). Consumption of dietary flavonoids, plant nutrients with antioxidant effects, correlated with stool butyrate concentration (anthocyanidins P = 0.01, flavones P = 0.01, and flavanols P = 0.02).
Conclusions:
This is the first study to demonstrate an association between a plant-based dietary pattern, stool butyrate production, and sustained MRD negativity in multiple myeloma, providing rationale to evaluate a prospective dietary intervention.
Data from Prediction of Response to Lenvatinib Monotherapy for Unresectable Hepatocellular Carcinoma by Machine Learning Radiomics: A Multicenter Cohort Study
Authors: Bo Zhiyuan , Chen Bo , Zhao Zhengxiao , He Qikuan , Mao Yicheng , Yang Yunjun , Yao Fei , Yang Yi , Chen Ziyan , Yang Jinhuan , Yu Haitao , Ma Jun , Wu Lijun , Chen Kaiyu , Wang Luhui , Wang Mingxun , Shi Zhehao , Yao Xinfei , Dong Yulong , Shi Xintong , Shan Yunfeng , Yu Zhengping , Wang Yi , Chen Gang
Published: April 2023

AbstractPurpose:
We aimed to construct machine learning (ML) radiomics models to predict response to lenvatinib monotherapy for unresectable hepatocellular carcinoma (HCC).
Experimental Design:
Patients with HCC receiving lenvatinib monotherapy at three institutions were retrospectively identified and assigned to training and external validation cohorts. Tumor response after initiation of lenvatinib was evaluated. Radiomics features were extracted from contrast-enhanced CT images. The K-means clustering algorithm was used to distinguish radiomics-based subtypes. Ten ML radiomics models were constructed and internally validated by 10-fold cross-validation. These models were subsequently verified in an external validation cohort.
Results:
A total of 109 patients were identified for analysis, namely, 74 in the training cohort and 35 in the external validation cohort. Thirty-two patients showed partial response, 33 showed stable disease, and 44 showed progressive disease. The overall response rate (ORR) was 29.4%, and the disease control rate was 59.6%. A total of 224 radiomics features were extracted, and 25 significant features were identified for further analysis. Two distant radiomics-based subtypes were identified by K-means clustering, and subtype 1 was associated with a higher ORR and longer progression-free survival (PFS). Among the 10 ML algorithms, AutoGluon displayed the highest predictive performance (AUC = 0.97), which was relatively stable in the validation cohort (AUC = 0.93). Kaplan–Meier analysis showed that responders had a better overall survival [HR = 0.21; 95% confidence interval (CI): 0.12–0.36; P < 0.001] and PFS (HR = 0.14; 95% CI: 0.09–0.22; P < 0.001) than nonresponders.
Conclusions:
Valuable ML radiomics models were constructed, with favorable performance in predicting the response to lenvatinib monotherapy for unresectable HCC.
Data from Response to Neoadjuvant Targeted Therapy in Operable Head and Neck Cancer Confers Survival Benefit
Authors: Mascarella Marco A. , Olonisakin Tolani F. , Rumde Purva , Vendra Varun , Nance Melonie A. , Kim Seungwon , Kubik Mark W. , Sridharan Shaum S. , Ferris Robert L. , Fenton Moon J. , Clayburgh Daniel R. , Ohr James P. , Joyce Sonali C. , Sen Malabika , Herman James G. , Grandis Jennifer R. , Zandberg Dan P. , Duvvuri Umamaheswar
Published: April 2023

AbstractPurpose:
Neoadjuvant targeted therapy provides a brief, preoperative window of opportunity that can be exploited to individualize cancer care based on treatment response. We investigated whether response to neoadjuvant therapy during the preoperative window confers survival benefit in patients with operable head and neck squamous cell carcinoma (HNSCC).
Patients and Methods:
A pooled analysis of treatment-naïve patients with operable HNSCC enrolled in one of three clinical trials from 2009 to 2020 (NCT00779389, NCT01218048, NCT02473731). Neoadjuvant regimens consisted of EGFR inhibitors (n = 83) or anti-ErbB3 antibody therapy (n = 9) within 28 days of surgery. Clinical to pathologic stage migration was compared with disease-free survival (DFS) and overall survival (OS) while adjusting for confounding factors using multivariable Cox regression. Circulating tumor markers validated in other solid tumor models were analyzed.
Results:
92 of 118 patients were analyzed; all patients underwent surgery following neoadjuvant therapy. Clinical to pathologic downstaging was more frequent in patients undergoing neoadjuvant targeted therapy compared with control cohort (P = 0.048). Patients with pathologic downstage migration had the highest OS [89.5%; 95% confidence interval (CI), 75.7–100] compared with those with no stage change (58%; 95% CI, 46.2–69.8) or upstage (40%; 95% CI, 9.6–70.4; P = 0.003). Downstage migration remained a positive prognostic factor for OS (HR, 0.22; 95% CI, 0.05–0.90) while adjusting for measured confounders. Downstage migration correlated with decreased circulating tumor markers, SOX17 and TAC1 (P = 0.0078).
Conclusions:
Brief neoadjuvant therapy achieved pathologic downstaging in a subset of patients and was associated with significantly better DFS and OS as well as decreased circulating methylated SOX17 and TAC1.
Data from Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial
Authors: Morgan Robert D. , Clamp Andrew R. , White Daniel J. , Price Marcus , Burghel George J. , Ryder W. David J. , Mahmood Reem D. , Murphy Alexander D. , Hasan Jurjees , Mitchell Claire L. , Salih Zena , Wheeler Chelsey , Buckley Emma , Truelove Joanna , King Georgia , Ainaoui Yasmina , Bhaskar Sanjeev S. , Shaw Joseph , Evans D. Gareth R. , Kilerci Bedirhan , Pearce Simon P. , Brady Gerard , Dive Caroline , O'Connor James P.B. , Wallace Andrew J. , Rothwell Dominic G. , Edmondson Richard J. , Jayson Gordon C.
Published: April 2023

AbstractPurpose:
A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown.
Patients and Methods:
Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies.
Results:
Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy.
Conclusions:
A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious.
Data from LAMC2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth
Authors: Erice Oihane , Narayanan Shruthi , Feliu Iker , Entrialgo-Cadierno Rodrigo , Malinova Antonia , Vicentini Caterina , Guruceaga Elizabeth , Delfino Pietro , Trajkovic-Arsic Marija , Moreno Haritz , Valencia Karmele , Blanco Ester , Macaya Irati , Öhlund Daniel , Khatri Purvesh , Lecanda Fernando , Scarpa Aldo , Siveke Jens T. , Corbo Vincenzo , Ponz-Sarvise Mariano , Vicent Silve
Published: April 2023

AbstractPurpose:
The identification of pancreatic ductal adenocarcinoma (PDAC) dysregulated genes may unveil novel molecular targets entering inhibitory strategies. Laminins are emerging as potential targets in PDAC given their role as diagnostic and prognostic markers. Here, we investigated the cellular, functional, and clinical relevance of LAMC2 and its regulated network, with the ultimate goal of identifying potential therapies.
Experimental Design:
LAMC2 expression was analyzed in PDAC tissues, a panel of human and mouse cell lines, and a genetically engineered mouse model. Genetic perturbation in 2D, 3D, and in vivo allograft and xenograft models was done. Expression profiling of a LAMC2 network was performed by RNA-sequencing, and publicly available gene expression datasets from experimental and clinical studies examined to query its human relevance. Dual inhibition of pharmacologically targetable LAMC2-regulated effectors was investigated.
Results:
LAMC2 was consistently upregulated in human and mouse experimental models as well as in human PDAC specimens, and associated with tumor grade and survival. LAMC2 inhibition impaired cell cycle, induced apoptosis, and sensitized PDAC to MEK1/2 inhibitors (MEK1/2i). A LAMC2-regulated network was featured in PDAC, including both classical and quasi-mesenchymal subtypes, and contained downstream effectors transcriptionally shared by the KRAS signaling pathway. LAMC2 regulated a functional FOSL1–AXL axis via AKT phosphorylation. Furthermore, genetic LAMC2 or pharmacological AXL inhibition elicited a synergistic antiproliferative effect in combination with MEK1/2is that was consistent across 2D and 3D human and mouse PDAC models, including primary patient-derived organoids.
Conclusions:
LAMC2 is a molecular target in PDAC that regulates a transcriptional network that unveils a dual drug combination for cancer treatment.
Supplementary Fig. S2 from Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers
Authors: Santarosa Manuela , Del Col Laura , Tonin Elena , Caragnano Angela , Viel Alessandra , Maestro Roberta
Published: April 2023

Supplementary Fig. S2 from Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers
Supplementary Data from Identification of Common Predictive Markers of In vitro Response to the Mek Inhibitor Selumetinib (AZD6244; ARRY-142886) in Human Breast Cancer and Non–Small Cell Lung Cancer Cell Lines
Authors: Garon Edward B. , Finn Richard S. , Hosmer Wylie , Dering Judy , Ginther Charles , Adhami Shahriar , Kamranpour Naeimeh , Pitts Sharon , Desai Amrita , Elashoff David , French Tim , Smith Paul , Slamon Dennis J.
Published: April 2023

Supplementary Data from Identification of Common Predictive Markers of In vitro Response to the Mek Inhibitor Selumetinib (AZD6244; ARRY-142886) in Human Breast Cancer and Non–Small Cell Lung Cancer Cell Lines
Supplementary Table 1 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer
Authors: Ohori Hisatsugu , Yamakoshi Hiroyuki , Tomizawa Masaki , Shibuya Masatoshi , Kakudo Yuichi , Takahashi Atsuko , Takahashi Shin , Kato Satoshi , Suzuki Takao , Ishioka Chikashi , Iwabuchi Yoshiharu , Shibata Hiroyuki
Published: April 2023

Supplementary Table 1 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer
Supplementary Fig. S1 from Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors
Authors: Baird Richard D. , Kitzen Jos , Clarke Paul A. , Planting Andre , Reade Sarah , Reid Alison , Welsh Lyndsey , López Lázaro Luis , de las Heras Begona , Judson Ian R. , Kaye Stan B. , Eskens Ferry , Workman Paul , deBono Johann S. , Verweij Jaap
Published: April 2023

Supplementary Fig. S1 from Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors
Supplementary Figure 1 from Sensitivity to the Aromatase Inhibitor Letrozole Is Prolonged After a “Break” in Treatment
Authors: Sabnis Gauri , Goloubeva Olga , Gilani Rabia , Macedo Luciana , Brodie Angela
Published: April 2023

Supplementary Figure 1 from Sensitivity to the Aromatase Inhibitor Letrozole Is Prolonged After a “Break” in Treatment
Supplementary Table 1 from Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice
Authors: Matsunaka Toshihiro , Miyamoto Shin'ichi , Shitara Kenya , Ochiai Atsushi , Chiba Tsutomu
Published: April 2023

Supplementary Table 1 from Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice
Supplementary Figure Legends from Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides
Authors: de Wolf Cornelia , Jansen Robert , Yamaguchi Hiroaki , de Haas Marcel , van de Wetering Koen , Wijnholds Jan , Beijnen Jos , Borst Piet
Published: April 2023

Supplementary Figure Legends from Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides
Supplementary Fig. S2 from Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides
Authors: de Wolf Cornelia , Jansen Robert , Yamaguchi Hiroaki , de Haas Marcel , van de Wetering Koen , Wijnholds Jan , Beijnen Jos , Borst Piet
Published: April 2023

Supplementary Fig. S2 from Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides
Supplementary Data from Garcinol Potentiates TRAIL-Induced Apoptosis through Modulation of Death Receptors and Antiapoptotic Proteins
Authors: Prasad Sahdeo , Ravindran Jayaraj , Sung Bokyung , Pandey Manoj K. , Aggarwal Bharat B.
Published: April 2023

Supplementary Data from Garcinol Potentiates TRAIL-Induced Apoptosis through Modulation of Death Receptors and Antiapoptotic Proteins
Supplementary Figure 1 from Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway
Authors: Handrick René , Ontikatze Teona , Bauer Kerstin-Daniela , Freier Florian , Rübel Amelie , Dürig Jan , Belka Claus , Jendrossek Verena
Published: April 2023

Supplementary Figure 1 from Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway
Supplementary Figures 1-4 from Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells
Authors: Cui Jian , Wang Qingyang , Wang Jing , Lv Ming , Zhu Ning , Li Yan , Feng Jiannan , Shen Beifen , Zhang Jiyan
Published: April 2023

Supplementary Figures 1-4 from Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells
Adobe PDF - Supplementary_Data.pdf from BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy
Authors: Kremmidiotis Gabriel , Leske Annabell F. , Lavranos Tina C. , Beaumont Donna , Gasic Jelena , Hall Allison , O'Callaghan Michael , Matthews Clayton A. , Flynn Bernard
Published: April 2023

Adobe PDF - Supplementary_Data.pdf from BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy
Supplementary Figure 2 from Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands
Authors: Wood Tabitha E. , Dalili Shadi , Simpson Craig D. , Sukhai Mahadeo A. , Hurren Rose , Anyiwe Kika , Mao Xinliang , Suarez Saiz Fernando , Gronda Marcela , Eberhard Yanina , MacLean Neil , Ketela Troy , Reed John C. , Moffat Jason , Minden Mark D. , Batey Robert A. , Schimmer Aaron D.
Published: April 2023

Supplementary Figure 2 from Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands
Supplementary Data from Development of Candidate Genomic Markers to Select Breast Cancer Patients for Dasatinib Therapy
Authors: Moulder Stacy , Yan Kai , Huang Fei , Hess Kenneth R. , Liedtke Cornelia , Lin Feng , Hatzis Christos , Hortobagyi Gabriel N. , Symmans W. Fraser , Pusztai Lajos
Published: April 2023

Supplementary Data from Development of Candidate Genomic Markers to Select Breast Cancer Patients for Dasatinib Therapy
Supplementary Fig. S1 legend from Induction of programmed cell death in ErbB2/HER2-expressing cancer cells by targeted delivery of apoptosis-inducing factor
Authors: Mahmud Hayat , Dälken Benjamin , Wels Winfried S.
Published: April 2023

Supplementary Fig. S1 legend from Induction of programmed cell death in ErbB2/HER2-expressing cancer cells by targeted delivery of apoptosis-inducing factor
Supplementary Fig. from MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance
Authors: Moriyama Taiki , Ohuchida Kenoki , Mizumoto Kazuhiro , Yu Jun , Sato Norihiro , Nabae Toshinaga , Takahata Shunichi , Toma Hiroki , Nagai Eishi , Tanaka Masao
Published: April 2023

Supplementary Fig. from MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance
Supplementary Data from Natural Immunity Enhances the Activity of a DR5 Agonistic Antibody and Carboplatin in the Treatment of Ovarian Cancer
Authors: El-Gazzar Ahmed , Perco Paul , Eckelhart Eva , Anees Mariam , Sexl Veronika , Mayer Bernd , Liu Yanxin , Mikulits Wolfgang , Horvat Reinhard , Pangerl Thomas , Zheng Dexian , Krainer Michael
Published: April 2023

Supplementary Data from Natural Immunity Enhances the Activity of a DR5 Agonistic Antibody and Carboplatin in the Treatment of Ovarian Cancer
Supplementary Figures 1-2 from Peroxisome Proliferator-Activated Receptor-γ Activation Inhibits Tumor Metastasis by Antagonizing Smad3-Mediated Epithelial-Mesenchymal Transition
Authors: Reka Ajaya Kumar , Kurapati Himabindu , Narala Venkata R. , Bommer Guido , Chen Jun , Standiford Theodore J. , Keshamouni Venkateshwar G.
Published: April 2023

Supplementary Figures 1-2 from Peroxisome Proliferator-Activated Receptor-γ Activation Inhibits Tumor Metastasis by Antagonizing Smad3-Mediated Epithelial-Mesenchymal Transition
Data from Genome-wide DNA copy number predictors of lapatinib sensitivity in tumor-derived cell lines
Authors: Greshock Joel , Cheng Jie , Rusnak David , Martin Anne Marie , Wooster Richard , Gilmer Tona , Lee Kwan , Weber Barbara L. , Zaks Tal
Published: April 2023

Abstract
A common aim of pharmacogenomic studies that use genome-wide assays on panels of cancers is the unbiased discovery of genomic alterations that are associated with clinical outcome and drug response. Previous studies of lapatinib, a selective dual-kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2 tyrosine kinases, have shown predictable relationships between the activity of these target genes and response. Under the hypothesis that additional genes may play a role in drug sensitivity, a predictive model for lapatinib response was constructed from genome-wide DNA copy number data from 24 cancer cell lines. An optimal predictive model which consists of aberrations at nine distinct genetic loci, includes gains of HER2, EGFR, and loss of CDKN2A. This model achieved an area under the receiver operating characteristic curve of ∼0.85 (80% confidence interval, 0.70–0.98; P < 0.01), and correctly classified the sensitivity status of 8 of 10 head and neck cancer cell lines. This study shows that biomarkers predictive for lapatinib sensitivity, including the previously described copy number gains of EGFR and HER2, can be discovered using novel genomic assays in an unbiased manner. Furthermore, these results show the utility of DNA copy number profiles in pharmacogenomic studies. [Mol Cancer Ther 2008;7(4):935–43]
Data from Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma
Authors: Ding Yan , Boguslawski Elissa A. , Berghuis Bree D. , Young John J. , Zhang Zhongfa , Hardy Kim , Furge Kyle , Kort Eric , Frankel Arthur E. , Hay Rick V. , Resau James H. , Duesbery Nicholas S.
Published: April 2023

Abstract
We hypothesized that signaling through multiple mitogen-activated protein kinase (MAPK) kinase (MKK) pathways is essential for the growth and vascularization of soft-tissue sarcomas, which are malignant tumors derived from mesenchymal tissues. We tested this using HT-1080, NCI, and Shac fibrosarcoma-derived cell lines and anthrax lethal toxin (LeTx), a bacterial toxin that inactivates MKKs. Western blots confirmed that LeTx treatment reduced the levels of phosphorylated extracellular signal-regulated kinase and p38 MAPK in vitro. Although short treatments with LeTx only modestly affected cell proliferation, sustained treatment markedly reduced cell numbers. LeTx also substantially inhibited the extracellular release of angioproliferative factors including vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor. Similar results were obtained with cell lines derived from malignant fibrous histiocytomas, leiomyosarcomas, and liposarcomas. In vivo, LeTx decreased MAPK activity and blocked fibrosarcoma growth. Growth inhibition correlated with decreased cellular proliferation and extensive necrosis, and it was accompanied by a decrease in tumor mean vessel density as well as a reduction in serum expression of angioproliferative cytokines. Vital imaging using high-resolution ultrasound enhanced with contrast microbubbles revealed that the effects of LeTx on tumor perfusion were remarkably rapid (<24 h) and resulted in a marked reduction of perfusion within the tumor but not in nontumor tissues. These results are consistent with our initial hypothesis and lead us to propose that MKK inhibition by LeTx is a broadly effective strategy for targeting neovascularization in fibrosarcomas and other similar proliferative lesions. [Mol Cancer Ther 2008;7(3):648–58]
Data from UBE1L causes lung cancer growth suppression by targeting cyclin D1
Authors: Feng Qing , Sekula David , Guo Yongli , Liu Xi , Black Candice C. , Galimberti Fabrizio , Shah Sumit J. , Sempere Lorenzo F. , Memoli Vincent , Andersen Jesper B. , Hassel Bret A. , Dragnev Konstantin , Dmitrovsky Ethan
Published: April 2023

Abstract
UBE1L is the E1-like ubiquitin-activating enzyme for the IFN-stimulated gene, 15-kDa protein (ISG15). The UBE1L-ISG15 pathway was proposed previously to target lung carcinogenesis by inhibiting cyclin D1 expression. This study extends prior work by reporting that UBE1L promotes a complex between ISG15 and cyclin D1 and inhibited cyclin D1 but not other G1 cyclins. Transfection of the UBE1L-ISG15 deconjugase, ubiquitin-specific protein 18 (UBP43), antagonized UBE1L-dependent inhibition of cyclin D1 and ISG15-cyclin D1 conjugation. A lysine-less cyclin D1 species was resistant to these effects. UBE1L transfection reduced cyclin D1 protein but not mRNA expression. Cycloheximide treatment augmented this cyclin D1 protein instability. UBE1L knockdown increased cyclin D1 protein. UBE1L was independently retrovirally transduced into human bronchial epithelial and lung cancer cells. This reduced cyclin D1 expression and clonal cell growth. Treatment with the retinoid X receptor agonist bexarotene induced UBE1L and reduced cyclin D1 immunoblot expression. A proof-of-principle bexarotene clinical trial was independently examined for UBE1L, ISG15, cyclin D1, and Ki-67 immunohistochemical expression profiles in pretreatment versus post-treatment tumor biopsies. Increased UBE1L with reduced cyclin D1 and Ki-67 expression occurred in human lung cancer when a therapeutic bexarotene intratumoral level was achieved. Thus, a mechanism for UBE1L-mediated growth suppression was found by UBE1L-ISG15 preferentially inhibiting cyclin D1. Molecular therapeutic implications are discussed. [Mol Cancer Ther 2008;7(12):3780–8]
Data from Targeted drug delivery to mesothelioma cells using functionally selected internalizing human single-chain antibodies
Authors: An Feng , Drummond Daryl C. , Wilson Shannon , Kirpotin Dmitri B. , Nishimura Stephen L. , Broaddus V. Courtney , Liu Bin
Published: April 2023

Abstract
Mesothelioma is a malignancy of the mesothelium and current treatments are generally ineffective. One promising area of anticancer drug development is to explore tumor susceptibility to targeted therapy. To achieve efficient, targeted intracellular delivery of therapeutic agents to mesothelioma cells, we selected a naive human single-chain (scFv) phage antibody display library directly on the surface of live mesothelioma cells to identify internalizing antibodies that target mesothelioma-associated cell surface antigens. We have identified a panel of internalizing scFvs that bind to mesothelioma cell lines derived from both epithelioid (M28) and sarcomatous (VAMT-1) types of this disease. Most importantly, these antibodies stain mesothelioma cells in situ and therefore define a panel of clinically represented tumor antigens. We have further exploited the internalizing function of these scFvs to achieve targeted intracellular drug delivery to mesothelioma cells. We showed that scFv-targeted immunoliposomes were efficiently and specifically taken up by both epithelioid and sarcomatous mesothelioma cells, but not control cells, and immunoliposomes encapsulating the small-molecule drug topotecan caused targeted killing of both types of mesothelioma cells in vitro. [Mol Cancer Ther 2008;7(3):569–78]
Data from A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells
Authors: Zhang Tao , Hamza Adel , Cao Xianhua , Wang Bing , Yu Shuwen , Zhan Chang-Guo , Sun Duxin
Published: April 2023

Abstract
Pancreatic cancer is an aggressive disease with multiple biochemical and genetic alterations. Thus, a single agent to hit one molecular target may not be sufficient to treat this disease. The purpose of this study is to identify a novel Hsp90 inhibitor to disrupt protein-protein interactions of Hsp90 and its cochaperones for down-regulating many oncogenes simultaneously against pancreatic cancer cells. Here, we reported that celastrol disrupted Hsp90-Cdc37 interaction in the superchaperone complex to exhibit antitumor activity in vitro and in vivo. Molecular docking and molecular dynamic simulations showed that celastrol blocked the critical interaction of Glu33 (Hsp90) and Arg167 (Cdc37). Immunoprecipitation confirmed that celastrol (10 μmol/L) disrupted the Hsp90-Cdc37 interaction in the pancreatic cancer cell line Panc-1. In contrast to classic Hsp90 inhibitor (geldanamycin), celastrol (0.1-100 μmol/L) did not interfere with ATP binding to Hsp90. However, celastrol (1-5 μmol/L) induced Hsp90 client protein degradation (Cdk4 and Akt) by 70% to 80% and increased Hsp70 expression by 12-fold. Celastrol induced apoptosis in vitro and significantly inhibited tumor growth in Panc-1 xenografts. Moreover, celastrol (3 mg/kg) effectively suppressed tumor metastasis by more than 80% in RIP1-Tag2 transgenic mouse model with pancreatic islet cell carcinogenesis. The data suggest that celastrol is a novel Hsp90 inhibitor to disrupt Hsp90-Cdc37 interaction against pancreatic cancer cells. [Mol Cancer Ther 2008;7(1):162–70]
Data from Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib
Authors: Williamson Mark J. , Blank Jonathan L. , Bruzzese Frank J. , Cao Yueying , Daniels J. Scott , Dick Lawrence R. , Labutti Jason , Mazzola Anne M. , Patil Ashok D. , Reimer Corinne L. , Solomon Marjorie S. , Stirling Matthew , Tian Yuan , Tsu Christopher A. , Weatherhead Gabriel S. , Zhang Julie X. , Rolfe Mark
Published: April 2023

Abstract
Strains within the genus Salinospora have been shown to produce complex natural products having antibiotic and antiproliferative activities. The biochemical basis for the cytotoxic effects of salinosporamide A has been linked to its ability to inhibit the proteasome. Synthetically accessible salinosporamide A (ML858) was used to determine its biochemical and biological activities and to compare its effects with those of bortezomib. ML858 and bortezomib show time- and concentration-dependent inhibition of the proteasome in vitro. However, unlike bortezomib, which is a reversible inhibitor, ML858 covalently binds to the proteasome, resulting in the irreversible inhibition of 20S proteasome activity. ML858 was equipotent to bortezomib in cell-based reporter stabilization assays, but due to intramolecular instability is less potent in long-term assays. ML858 failed to maintain levels of proteasome inhibition necessary to achieve efficacy in tumor models responsive to bortezomib. Our results show that ML858 and bortezomib exhibit different kinetic and pharmacologic profiles and suggest that additional characterization of ML858 is warranted before its therapeutic potential can be fully appreciated. [Mol Cancer Ther 2006;5(12):3052–61]
Data from Efficacy of the Multi-Kinase Inhibitor Enzastaurin Is Dependent on Cellular Signaling Context
Authors: Kuo Wen-Liang , Liu Jing , Mauceri Helena , Vokes Everett E. , Weichselbaum Ralph , Rosner Marsha Rich , Cohen Ezra Eddy Wyssam
Published: April 2023

Abstract
The number of targeted small molecules being developed in oncology is increasing rapidly. Many of these are designed to inhibit multiple kinases, and thus the mechanisms of responsiveness and predictive biomarkers can be difficult to discern. In fact, with few exceptions, multi-kinase inhibitors are developed with limited mechanism-based patient selection. Enzastaurin is a multi-kinase inhibitor being studied in several malignancies that we hypothesized would be active in squamous cell carcinoma of the head and neck, because it inhibits classic and novel protein kinase C isoforms. Indeed, enzastaurin reduced the growth of SQ-20B and CAL27 tumor xenografts, decreased proliferation in these cell lines, inhibited putative target phosphorylation, and induced cell cycle arrest. Gene expression arrays confirmed that expression of cell cycle genes, including cyclins D and E, were significantly altered by exposure to enzastaurin. However, testing a panel of squamous cell carcinoma of the head and neck cell lines revealed variable sensitivity to enzastaurin, which correlated significantly with baseline cyclin D1 protein expression. Moreover, sensitivity and resistance could be reversed, respectively, by expression or depletion of cyclin D1. Furthermore, analysis of sensitive and resistant cell lines revealed distinct differences in cyclin D1 regulation. Enzastaurin modulated cyclin D1 synthesis through an Akt-regulated pathway in the former, whereas high-level CCND1 gene amplification was present in the latter. These results underscore the critical relevance of cellular signaling context in developing cancer therapies in general and suggest that enzastaurin in particular would be most effective in tumors where baseline cyclin D1 expression is low to moderate and physiologically regulated. Mol Cancer Ther; 9(10); 2814–24. ©2010 AACR.
Data from Epidermal Growth Factor Receptor–Targeted Radioimmunotherapy of Human Head and Neck Cancer Xenografts Using 90Y-Labeled Fully Human Antibody Panitumumab
Authors: Liu Zhaofei , Liu Yan , Jia Bing , Zhao Huiyun , Jin Xiaona , Li Fang , Chen Xiaoyuan , Wang Fan
Published: April 2023

Abstract
Panitumumab (ABX-EGF or Vectibix), the first fully human monoclonal antibody targeting epidermal growth factor receptor (EGFR), was approved by the Food and Drug Administration for treatment of patients with metastatic colorectal cancer. Here, we report for the first time the radioimmunotherapy (RIT) of EGFR-positive human head and neck cancer in a nude mouse model using pure β− emitter 90Y-labeled panitumumab. Biodistribution and planar γ-imaging studies were carried out with 111In-DOTA-panitumumab. The RIT efficacy of 90Y-DOTA-panitumumab was evaluated in UM-SCC-22B tumor model. CD31, Ki67, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, and H&E staining were done on UM-SCC-22B tumor sections after treatment. The tumor uptake of 111In-DOTA-panitumumab in UM-SCC-22B tumor-bearing nude mice was 26.10 ± 4.93, 59.11 ± 7.22, 44.57 ± 9.80, 40.38 ± 7.76, and 14.86 ± 7.23 % injected dose per gram of tissue at 4, 24, 72, 120, and 168 hours after injection, respectively. Immunotherapy with cold panitumumab (four doses of 10 mg/kg) did not cause significant antitumor effect. RIT with a single dose of 100 μCi 90Y-DOTA-panitumumab caused significant tumor growth delay and improved the survival in UM-SCC-22B tumor model. A single dose of 200 μCi 90Y-DOTA-panitumumab led to almost complete tumor regression (tumor volumes were 34.83 ± 11.11 mm3 and 56.02 ± 39.95 mm3 on days 0 and 46 after treatment, respectively). Histopathologic analysis of tumors and normal organs further validated the therapeutic efficacy and limited systemic toxicity of 90Y-DOTA-panitumumab. The high tumor uptake and prolonged tumor retention, as well as effective therapy, reveal that 90Y-DOTA-panitumumab may be a promising radioimmunotherapeutic agent to treat EGFR-positive solid tumors. Mol Cancer Ther; 9(8); 2297–308. ©2010 AACR.
Data from Natural product derivative Bis(4-fluorobenzyl)trisulfide inhibits tumor growth by modification of β-tubulin at Cys 12 and suppression of microtubule dynamics
Authors: Xu Wanhong , Xi Biao , Wu Jieying , An Haoyun , Zhu Jenny , Abassi Yama , Feinstein Stuart C. , Gaylord Michelle , Geng Baoqin , Yan Huifang , Fan Weimin , Sui Meihua , Wang Xiaobo , Xu Xiao
Published: April 2023

Abstract
Bis(4-fluorobenzyl)trisulfide (BFBTS) is a synthetic molecule derived from a bioactive natural product, dibenzyltrisulfide, found in a subtropical shrub, Petiveria allieacea. BFBTS has potent anticancer activities to a broad spectrum of tumor cell lines with IC50 values from high nanomolar to low micromolar and showed equal anticancer potency between tumor cell lines overexpressing multidrug-resistant gene, MDR1 (MCF7/adr line and KBv200 line), and their parental MCF7 line and KB lines. BFBTS inhibited microtubule polymerization dynamics in MCF7 cells, at a low nanomolar concentration of 54 nmol/L, while disrupting microtubule filaments in cells at low micromolar concentration of 1 μmol/L. Tumor cells treated with BFBTS were arrested at G2-M phase, conceivably resulting from BFBTS-mediated antimicrotubule activities. Mass spectrometry studies revealed that BFBTS bound and modified β-tubulin at residue Cys12, forming β-tubulin-SS-fluorobenzyl. The binding site differs from known antimicrotubule agents, suggesting that BFBTS functions as a novel antimicrotubule agent. BFBTS at a dose of 25 mg/kg inhibited tumor growth with relative tumor growth rates of 19.91%, 18.5%, and 23.42% in A549 lung cancer, Bcap-37 breast cancer, and SKOV3 ovarian cancer xenografts, respectively. Notably, BFBTS was more potent against MDR1-overexpressing MCF7/adr breast cancer xenografts with a relative tumor growth rate of 12.3% than paclitaxel with a rate of 43.0%. BFBTS displays a novel antimicrotubule agent with potentials for cancer therapeutics. [Mol Cancer Ther 2009;8(12):3318–30]
Data from Development of Candidate Genomic Markers to Select Breast Cancer Patients for Dasatinib Therapy
Authors: Moulder Stacy , Yan Kai , Huang Fei , Hess Kenneth R. , Liedtke Cornelia , Lin Feng , Hatzis Christos , Hortobagyi Gabriel N. , Symmans W. Fraser , Pusztai Lajos
Published: April 2023

Abstract
Patient selection is important for targeted therapies, yet phase I/II trials are often underpowered for developing predictors of drug response. The goal of this research was to define genomic predictors for dasatinib that could be prospectively tested in early-phase clinical trials.

Gene expression profiles of dasatinib-sensitive and dasatinib-resistant cell lines (n = 23) were compared to develop a dasatinib-sensitivity index (modified DS index). A Src pathway activity index (revised Src index) was defined using genes induced by the Src transfection of mammary epithelial cells and was optimized to be reproducible across cell lines and human specimens. A dasatinib target index was devised using the weighted sum of 19 kinases that bind to dasatinib with variable affinity. The performance of these prediction models was assessed in independent cell lines with known dasatinib sensitivity. The feasibility of applying these genomic tests to human samples was evaluated on 133 biopsies of primary breast cancers.

The modified DS index showed 90% accuracy in independent breast cancer cell lines (n = 12) and the target index, but not the revised Src index signature, also distinguished dasatinib-sensitive and dasatinib-resistant cells (P = 0.0024). The genomic predictors showed acceptable reproducibility in replicate cell line and human gene expression data. When all three predictors were applied to the same 133 patient samples, the predictors identified different patient subsets as potentially sensitive.

We defined three conceptually different potential predictors of dasatinib response that were reproducible across cell lines and human data. These candidate markers are being tested in a clinical trial to determine their utility. Mol Cancer Ther; 9(5); 1120–7. ©2010 AACR.
Data from The nonsteroidal anti-inflammatory drug tolfenamic acid inhibits BT474 and SKBR3 breast cancer cell and tumor growth by repressing erbB2 expression
Authors: Liu Xinyi , Abdelrahim Maen , Abudayyeh Ala , Lei Ping , Safe Stephen
Published: April 2023

Abstract
Tolfenamic acid (TA) is a nonsteroidal anti-inflammatory drug that inhibits pancreatic cancer cell and tumor growth through decreasing expression of specificity protein (Sp) transcription factors. TA also inhibits growth of erbB2-overexpressing BT474 and SKBR3 breast cancer cells; however, in contrast to pancreatic cancer cells, TA induced down-regulation of erbB2 but not Sp proteins. TA-induced erbB2 down-regulation was accompanied by decreased erbB2-dependent kinase activities, induction of p27, and decreased expression of cyclin D1. TA also decreased erbB2 mRNA expression and promoter activity, and this was due to decreased mRNA stability in BT474 cells and, in both cell lines, TA decreased expression of the YY1 and AP-2 transcription factors required for basal erbB2 expression. In addition, TA also inhibited tumor growth in athymic nude mice in which BT474 cells were injected into the mammary fat pad. TA represents a novel and promising new anticancer drug that targets erbB2 by decreasing transcription of this oncogene. [Mol Cancer Ther 2009;8(5):OF1–11]
Data from Novel benzylidene-thiazolidine-2,4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells
Authors: Beharry Zanna , Zemskova Marina , Mahajan Sandeep , Zhang Fengxue , Ma Jian , Xia Zuping , Lilly Michael , Smith Charles D. , Kraft Andrew S.
Published: April 2023

Abstract
The Pim protein kinases play important roles in cancer development and progression, including prostate tumors and hematologic malignancies. To investigate the potential role of these enzymes as anticancer drug targets, we have synthesized novel benzylidene-thiazolidine-2,4-diones that function as potent Pim protein kinase inhibitors. With IC50 values in the nanomolar range, these compounds block the ability of Pim to phosphorylate peptides and proteins in vitro and, when added to DU145 prostate cancer cells overexpressing Pim, inhibit the ability of this enzyme to phosphorylate a known substrate, the BH3 protein BAD. When added to prostate cancer cell lines, including PC3, DU145, and CWR22Rv1, and human leukemic cells, MV4;11, K562, and U937 cells, these compounds induce G1-S cell cycle arrest and block the antiapoptotic effect of the Pim protein kinase. The cell cycle arrest induced by these compounds is associated with an inhibition of cyclin-dependent kinase 2 and activity and translocation of the Pim-1 substrate p27Kip1, a cyclin-dependent kinase 2 inhibitory protein, to the nucleus. Furthermore, when added to leukemic cells, these compounds synergize with the mammalian target of rapamycin inhibitor rapamycin to decrease the phosphorylation level of the translational repressor 4E-BP1 at sites phosphorylated by mammalian target of rapamycin. Combinations of rapamycin and the benzylidene-thiazolidine-2,4-diones synergistically block the growth of leukemic cells. Thus, these agents represent novel Pim inhibitors and point to an important role for the Pim protein kinases in cell cycle control in multiple types of cancer cells. [Mol Cancer Ther 2009;8(6):1473–83]
Data from Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer
Authors: Liu Dong , Kojima Toru , Ouchi Masaaki , Kuroda Shinji , Watanabe Yuichi , Hashimoto Yuuri , Onimatsu Hideki , Urata Yasuo , Fujiwara Toshiyoshi
Published: April 2023

Abstract
A phase I dose-escalation study of telomerase-specific oncolytic adenovirus, OBP-301 (Telomelysin), is now under way in the United States to assess feasibility and to characterize its pharmacokinetics in patients with advanced solid tumors. The present preclinical study investigates whether OBP-301 and a chemotherapeutic agent that is commonly used for lung cancer treatment, gemcitabine, are able to enhance antitumor effects in vitro and in vivo. The antitumor effects of OBP-301 infection and gemcitabine were evaluated by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt assay. In vivo antitumor effects of intratumoral injection of OBP-301 in combination with systemic administration of gemcitabine were assessed on nu/nu mice s.c. xenografted with human lung tumors. OBP-301 infection combined with gemcitabine resulted in very potent synergistic cytotoxicity in human lung cancer cells. The three human lung cancer cell lines treated with OBP-301 for 24 hours tended to accumulate in S phase compared with controls. The proportion of cells in S phase increased from 43.85% to 56.41% in H460 cells, from 46.72% to 67.09% in H322 cells, and from 38.22% to 57.67% in H358 cells. Intratumoral injection of OBP-301 combined with systemic administration of gemcitabine showed therapeutic synergism in human lung tumor xenografts. Our data suggest that the combination of OBP-301 and gemcitabine enhances the antitumor effects against human lung cancer. We also found that the synergistic mechanism may be due to OBP-301–mediated cell cycle accumulation in S phase. These results have important implications for the treatment of human lung cancer.[Mol Cancer Ther 2009;8(4):980–7]
Data from Biochemical Characterization of AMG 102: A Neutralizing, Fully Human Monoclonal Antibody to Human and Nonhuman Primate Hepatocyte Growth Factor
Authors: Burgess Teresa L. , Sun Jan , Meyer Susanne , Tsuruda Trace S. , Sun Jilin , Elliott Gary , Chen Qing , Haniu Mitsuru , Barron Will F. , Juan Todd , Zhang Ke , Coxon Angela , Kendall Richard L.
Published: April 2023

Abstract
AMG 102 is a fully human monoclonal antibody that selectively targets and neutralizes hepatocyte growth factor/scatter factor (HGF/SF). A detailed biochemical and functional characterization of AMG 102 was done to support its clinical development for the treatment of cancers dependent on signaling through the HGF/SF:c-Met pathway. In competitive equilibrium binding experiments, AMG 102 bound to human and cynomolgus monkey HGF with affinities of approximately 19 pmol/L and 41 pmol/L, respectively. However, AMG 102 did not detect mouse or rabbit HGF on immunoblots. Immunoprecipitation experiments showed that AMG 102 preferentially bound to the mature, active form of HGF, and incubation of AMG 102/HGF complexes with kallikrein protease indicated that AMG 102 had no apparent effect on proteolytic processing of the inactive HGF precursor. AMG 102 inhibited human and cynomolgus monkey HGF-induced c-Met autophosphorylation in PC3 cells with IC50 values of 0.12 nmol/L and 0.24 nmol/L, respectively. AMG 102 also inhibited cynomolgus monkey HGF-induced migration of human MDA-MB-435 cells but not rat HGF-induced migration of mouse 4T1 cells. Epitope-mapping studies of recombinant HGF molecules comprising human/mouse chimeras and human-to-mouse amino acid substitutions showed that amino acid residues near the NH2-terminus of the β-chain are critical for AMG 102 binding. Bound AMG 102 protected one trypsin protease cleavage site near the NH2-terminus of the β-chain of human HGF, further substantiating the importance of this region for AMG 102 binding. Currently, AMG 102 is in phase II clinical trials in a variety of solid tumor indications. Mol Cancer Ther; 9(2); 400–9