bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Intratumoral Electroporation of Plasmid Encoded IL12 and Membrane-Anchored Anti-CD3 Increases Systemic Tumor Immunity
Authors: Han Mia , Nguyen Bianca , Lee Jack Y. , Browning Erica , Zhang Jun , Mukhopadhyay Anandaroop , Gujar Ravindra , Salazar Jon , Hermiz Reneta , Svenson Lauren , Rolig Annah S. , Redmond William L. , Algazi Alain P. , Daud Adil I. , Canton David A. , Twitty Christopher G.
Published: March 2024

Abstract
Intratumoral delivery of plasmid IL12 via electroporation (IT-tavo-EP) induces localized expression of IL12 leading to regression of treated and distant tumors with durable responses and minimal toxicity. A key driver in amplifying this local therapy into a systemic response is the magnitude and composition of immune infiltrate in the treated tumor. While intratumoral IL12 typically increases the density of CD3+ tumor-infiltrating lymphocytes (TIL), this infiltrate is composed of a broad range of T-cell subsets, including activated tumor-specific T cells, less functional bystander T cells, as well as suppressive T regulatory cells. To encourage a more favorable on-treatment tumor microenvironment (TME), we explored combining this IL12 therapy with an intratumoral polyclonal T-cell stimulator membrane-anchored anti-CD3 to productively engage a diverse subset of lymphocytes including the nonreactive and suppressive T cells. This study highlighted that combined intratumoral electroporation of IL12 and membrane-anchored anti-CD3 plasmids can enhance cytokine production, T-cell cytotoxicity, and proliferation while limiting the suppressive capacity within the TME. These collective antitumor effects not only improve regression of treated tumors but drive systemic immunity with control of nontreated contralateral tumors in vivo. Moreover, combination of IL12 and anti-CD3 restored the function of TIL isolated from a patient with melanoma actively progressing on programmed cell death protein 1 (PD-1) checkpoint inhibitor therapy.
Implications:
This DNA-encodable polyclonal T-cell stimulator (membrane-anchored anti-CD3 plasmid) may represent a key addition to intratumoral IL12 therapies in the clinic.
Data from Integrated Proteomics-Based Physical and Functional Mapping of AXL Kinase Signaling Pathways and Inhibitors Define Its Role in Cell Migration
Authors: Majumder Anurima , Hosseinian Sina , Stroud Mia , Adhikari Emma , Saller James J. , Smith Matthew A. , Zhang Guolin , Agarwal Shruti , Creixell Marc , Meyer Benjamin S. , Kinose Fumi , Bowers Kiah , Fang Bin , Stewart Paul A. , Welsh Eric A. , Boyle Theresa A. , Meyer Aaron S. , Koomen John M. , Haura Eric B.
Published: March 2024

Abstract
To better understand the signaling complexity of AXL, a member of the tumor-associated macrophage (TAM) receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein complexes using proximity-dependent biotinylation (BioID), effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration. Global phosphoproteomics show that AXL inhibition decreases phosphorylation of peptides involved in phosphatidylinositol-mediated signaling and cell adhesion/migration. Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT, and migration/invasion of these cells without reducing their viability, while bemcentinib exerts AXL-independent phenotypic effects on viability. Proteomic characterization of these TKIs demonstrates that they inhibit diverse targets in addition to AXL, with bemcentinib having the most off-targets. AXL and EGFR TKI cotreatment did not reverse resistance in cell line models of erlotinib resistance. However, a unique vulnerability was identified in one resistant clone, wherein combination of bemcentinib and erlotinib inhibited cell viability and signaling. We also show that AXL is overexpressed in approximately 30% to 40% of nonsmall but rarely in small cell lung cancer. Cell lines have a wide range of AXL expression, with basal activation detected rarely.
Implications:
Our study defines mechanisms of action of AXL in lung cancers which can be used to establish assays to measure drug targetable active AXL complexes in patient tissues and inform the strategy for targeting it's signaling as an anticancer therapy.
Data from Targeted Rejuvenation of Exhausted Chimeric Antigen Receptor T Cells Regresses Refractory Solid Tumors
Authors: Luo Qian , Napoleon John V. , Liu Xin , Zhang Boning , Zheng Suilan , Low Philip S.
Published: March 2024

Abstract
Chimeric antigen receptor (CAR) T-cell therapies have proven to be effective in treating hematologic malignancies but demonstrate only marginal efficacy in eradicating solid tumors. Although several mechanisms can account for these differences, a major cause is thought to derive from CAR T-cell exhaustion, where chronic exposure to tumor antigen can activate feedback pathways that suppress CAR T-cell cytotoxicity. We describe here a strategy to reverse this CAR T-cell exhaustion using a universal anti-fluorescein CAR that concurrently serves as (i) a cancer recognition receptor that enables engagement of multiple cancer cell clones upon addition of a cocktail of bispecific fluorescein-linked tumor-targeting ligands, and (ii) a drug-internalizing receptor that mediates uptake of a CAR T-cell activator comprised of fluorescein linked to an immune stimulant. By attaching a Toll-like receptor 7 agonist (TLR7–1A) to fluorescein, we enable the anti-fluorescein CAR to bind and internalize TLR7–1A, leading to both downregulation of exhaustion markers (i.e., PD-1, TIM3, LAG3) and reactivation of exhausted CAR-T cells without causing the toxicities commonly associated with systemic administration of TLR7 agonists. The resulting rejuvenated CAR-T cells are observed to regress otherwise refractory solid tumors. Moreover, because no other immune cells are altered by this treatment, the data demonstrate that the exhaustion state of the CAR-T cells constitutes a major property that determines the efficacies of CAR T-cell therapies in solid tumors.
Implications:
A novel strategy for rejuvenating exhausted CAR-T cells is described previously that promotes downregulation of exhaustion markers and renewed eradication of cancer cells in a tumor mass.
Data from Deregulation of AKT–mTOR Signaling Contributes to Chemoradiation Resistance in Lung Squamous Cell Carcinoma
Authors: Shen Changxian , Shyu Duan-Liang , Xu Min , Yang Linlin , Webb Amy , Duan Wenrui , Williams Terence M.
Published: March 2024

Abstract
Lung squamous cell carcinoma (LUSC) accounts for one of three of non–small cell lung carcinoma (NSCLC) and 30% of LUSC patients present with locally advanced, unresectable/medically inoperable disease, who are commonly treated with definitive chemoradiation. However, disease relapse in the radiation fields occurs in one of three cases. We aim to explore the underlying molecular mechanisms of chemoradiation resistance of LUSC. Patient-derived xenograft (PDX) models of LUSC were established in immunodeficient mice, followed by treatment with cisplatin in combination with clinically relevant courses of ionizing radiation (20, 30, and 40 Gy). The recurrent tumors were extracted for functional proteomics using reverse phase protein analysis (RPPA). We found that phospho-AKT-S473, phospho-AKT-T308, phospho-S6-S235/6, and phospho-GSK3β-S9 were upregulated in the chemoradiation-resistant 20 Gy + cisplatin and 40 Gy + cisplatin tumors compared with those in the control tumors. Ingenuity pathway analysis of the RPPA data revealed that AKT–mTOR signaling was the most activated signaling pathway in the chemoradiation-resistant tumors. Similarly, elevated AKT–mTOR signaling was observed in stable 40 Gy and 60 Gy resistant HARA cell lines compared with the parental cell line. Accordingly, pharmacologic inhibition of mTOR kinase by Torin2 significantly sensitized LUSC cell lines to ionizing radiation. In conclusion, using chemoradiation-resistant PDX models coupled with RPPA proteomics analysis, we revealed that deregulation of AKT–mTOR signaling may contribute to the chemoradiation resistance of LUSC.
Implications:
Clonal selection of subpopulations with high AKT–mTOR signaling in heterogeneous tumors may contribute to relapse of LUSC after chemoradiation. mTOR kinase inhibitors may be promising radiosensitizing agents in upfront treatment to prevent acquired resistance.
Data from Vitamin D Receptor Activation Attenuates Hippo Pathway Effectors and Cell Survival in Metastatic Neuroblastoma
Authors: Ladumor Yagnesh , Seong Bo Kyung Alex , Hallett Robin , Valencia-Sama Ivette , Adderley Teresa , Wang Yingying , Kee Lynn , Gont Alexander , Kaplan David R. , Irwin Meredith S.
Published: March 2024

Abstract
Survival for high-risk neuroblastoma remains poor. Most patients who recur, present with metastatic disease, and few targetable pathways that govern spread to distant sites are currently known. We previously developed a metastatic mouse model to select cells with enhanced ability to spread to the bone and brain and identified a signature based on differentially expressed genes, which also predicted patient survival. To discover new neuroblastoma therapies, we utilized the Connectivity Map to identify compounds that can reverse this metastatic transcriptional signature and found calcipotriol, a vitamin D3 analog, to be a compound that selectively targets cell lines with enhanced metastatic potential. Calcipotriol treatment of enhanced metastatic, but not parental, cells reduces proliferation and survival via vitamin D receptor (VDR) signaling, increases the expression of RASSF2, a negative regulator of the Hippo signaling pathway, and reduces the levels of the Hippo pathway effectors YAP and TAZ. RASSF2 is required for the effects of calcipotriol and for the reduction of levels and nuclear localization of YAP/TAZ. Migration of the enhanced metastatic cells and YAP/TAZ levels are reduced after calcipotriol treatment and YAP overexpression reduces calcipotriol sensitivity. Furthermore, metastatic cells that overexpress VDR also showed lower tumor burden in vivo.
Implications:
This newly identified link between VDR signaling and the Hippo pathway could inform treatment strategies for metastatic neuroblastoma.
Data from Combined Serum CA19-9 and miR-27a-3p in Peripheral Blood Mononuclear Cells to Diagnose Pancreatic Cancer
Authors: Wang Wan-Sheng , Liu Ling-Xiao , Li Guo-Ping , Chen Yi , Li Chang-Yu , Jin Da-Yong , Wang Xiao-Lin
Published: March 2024

Abstract
MicroRNAs are potentially very useful biomarkers in the diagnosis of cancer. We sought to identify specific microRNAs in peripheral blood mononuclear cells (PBMCs) whose levels might facilitate diagnosis of pancreatic cancer. We investigated PBMC microRNA expression in three independent cohorts [healthy, benign pancreatic/peripancreatic diseases (BPD), and pancreatic cancer], comprising a total of 352 participants. First, we used sequencing technology to identify differentially expressed microRNAs in PBMC of pancreatic cancer, BPD, and healthy controls (n = 20 in each group). Then the selected microRNAs were analyzed using the quantitative reverse transcriptase PCR assays in the remaining 292 samples. The predictive value of the microRNAs was evaluated by logistic regression models and the receiver operating characteristic curve (AUC). We found that miR-27a-3p level in PBMCs could discriminate pancreatic cancer from BPD with a sensitivity of 82.2% and specificity of 76.7% (AUC = 0.840; 95% CI, 0.787–0.885%). Combination of PBMC miR-27a-3p and serum CA19-9 levels provided a higher diagnostic accuracy with a sensitivity of 85.3% and specificity of 81.6% (AUC = 0.886; 95% CI, 0.837–0.923%). The satisfactory diagnostic performance of the panel persisted regardless of disease status (AUCs for tumor-node-metastasis stages I–III were 0.881, 0.884, and 0.893, respectively). PBMC miR-27a-3p level represents a potential marker for pancreatic cancer screening. A panel combining serum CA19-9 and PBMC miR-27a-3p level could have considerable clinical value in diagnosing pancreatic cancer. Cancer Prev Res; 6(4); 331–8. ©2013 AACR.
Data from The Chemopreventive Effect of Mifepristone on Mammary Tumorigenesis Is Associated with an Anti-invasive and Anti-inflammatory Gene Signature
Authors: Yuan Hongyan , Upadhyay Geeta , Lu Jin , Kopelovich Levy , Glazer Robert I.
Published: March 2024

Abstract
Progesterone receptor (PR) antagonists are potent antitumor agents in carcinogen and progestin-dependent mammary tumorigenesis models through both PR- and non-PR–mediated mechanisms. The PR antagonist mifepristone/RU486 has been used primarily as an abortifacient possessing high affinity for both the PR and glucocorticoid receptors (GR). To determine whether mifepristone would be effective as a chemopreventive agent, we assessed its effect on progestin/7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in wild-type (WT) and estrogen receptor-α–positive (ER+) transgenic mice expressing the dominant-negative Pax8PPARγ (Pax8) fusion protein. Mifepristone administered at a dose of 2.5 mg significantly delayed mammary tumorigenesis in WT, but not in Pax8 mice, whereas, a three-fold higher dose almost completely blocked tumorigenesis in both WT and Pax8 mice. The sensitivity of WT mice to 2.5 mg mifepristone correlated with an expression profile of 79 genes in tumors, 52 of which exhibited the opposite response in Pax8 mice, and corresponded primarily to the downregulation of genes associated with metabolism, inflammation, and invasion. These results suggest that the chemopreventive activity of mifepristone in WT mice correlates with a specific gene expression signature that is associated with multiple nuclear receptor signaling pathways. Cancer Prev Res; 5(5); 754–64. ©2012 AACR.
Data from Genes with Aberrant Expression in Murine Preneoplastic Intestine Show Epigenetic and Expression Changes in Normal Mucosa of Colon Cancer Patients
Authors: Leclerc Daniel , Lévesque Nancy , Cao Yuanhang , Deng Liyuan , Wu Qing , Powell Jasmine , Sapienza Carmen , Rozen Rima
Published: March 2024

Abstract
An understanding of early genetic/epigenetic changes in colorectal cancer would aid in diagnosis and prognosis. To identify these changes in human preneoplastic tissue, we first studied our mouse model in which Mthfr+/− BALB/c mice fed folate-deficient diets develop intestinal tumors in contrast to Mthfr+/+ BALB/c mice fed control diets. Transcriptome profiling was performed in normal intestine from mice with low or high tumor susceptibility. We identified 12 upregulated and 51 downregulated genes in tumor-prone mice. Affected pathways included retinoid acid synthesis, lipid and glucose metabolism, apoptosis and inflammation. We compared murine candidates from this microarray analysis, and murine candidates from an earlier strain-based comparison, with a set of human genes that we had identified in previous methylome profiling of normal human colonic mucosa, from colorectal cancer patients and controls. From the extensive list of human methylome candidates, our approach uncovered five orthologous genes that had shown changes in murine expression profiles (PDK4, SPRR1A, SPRR2A, NR1H4, and PYCARD). The human orthologs were assayed by bisulfite-pyrosequencing for methylation at 14 CpGs. All CpGs exhibited significant methylation differences in normal mucosa between colorectal cancer patients and controls; expression differences for these genes were also observed. PYCARD and NR1H4 methylation differences showed promise as markers for presence of polyps in controls. We conclude that common pathways are disturbed in preneoplastic intestine in our animal model and morphologically normal mucosa of patients with colorectal cancer, and present an initial version of a DNA methylation-based signature for human preneoplastic colon. Cancer Prev Res; 6(11); 1171–81. ©2013 AACR.
Data from DNA Methylation Levels at Chromosome 8q24 in Peripheral Blood Are Associated with 8q24 Cancer Susceptibility Loci
Authors: Barry Kathryn Hughes , Moore Lee E. , Sampson Joshua , Yan Liying , Meyer Ann , Oler Andrew J. , Chung Charles C. , Wang Zhaoming , Yeager Meredith , Amundadottir Laufey , Berndt Sonja I.
Published: March 2024

Abstract
Chromosome 8q24 has emerged as an important region for genetic susceptibility to various cancers, but little is known about the contribution of DNA methylation at 8q24. To evaluate variability in DNA methylation levels at 8q24 and the relationship with cancer susceptibility single nucleotide polymorphisms (SNPs) in this region, we quantified DNA methylation levels in peripheral blood at 145 CpG sites nearby 8q24 cancer susceptibility SNPs or MYC using pyrosequencing among 80 Caucasian men in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. For the 60 CpG sites meeting quality control, which also demonstrated temporal stability over a 5-year period, we calculated pairwise Spearman correlations for DNA methylation levels at each CpG site with 42 8q24 cancer susceptibility SNPs. To account for multiple testing, we adjusted P values into q values reflecting the false discovery rate (FDR). In contrast to the MYC CpG sites, most sites nearby the SNPs demonstrated good reproducibility, high methylation levels, and moderate-high between-individual variation. We observed 10 statistically significant (FDR < 0.05) CpG site–SNP correlations. These included correlations between an intergenic CpG site at Chr8:128393157 and the prostate cancer SNP rs16902094 (ρ = −0.54; P = 9.7 × 10−7; q = 0.002), a PRNCR1 CpG site at Chr8:128167809 and the prostate cancer SNP rs1456315 (ρ = 0.52; P = 1.4 × 10−6; q = 0.002), and two POU5F1B CpG sites and several prostate/colorectal cancer SNPs (for Chr8:128498051 and rs6983267, ρ = 0.46; P = 2.0 × 10−5; q = 0.01). This is the first report of correlations between blood DNA methylation levels and cancer susceptibility SNPs at 8q24, suggesting that DNA methylation at this important susceptibility locus may contribute to cancer risk. Cancer Prev Res; 7(12); 1282–92. ©2014 AACR.
Data from Gene Expression Profiling Predicts the Development of Oral Cancer
Authors: Saintigny Pierre , Zhang Li , Fan You-Hong , El-Naggar Adel K. , Papadimitrakopoulou Vassiliki A. , Feng Lei , Lee J. Jack , Kim Edward S. , Ki Hong Waun , Mao Li
Published: March 2024

Abstract
Patients with oral premalignant lesion (OPL) have a high risk of developing oral cancer. Although certain risk factors, such as smoking status and histology, are known, our ability to predict oral cancer risk remains poor. The study objective was to determine the value of gene expression profiling in predicting oral cancer development. Gene expression profile was measured in 86 of 162 OPL patients who were enrolled in a clinical chemoprevention trial that used the incidence of oral cancer development as a prespecified endpoint. The median follow-up time was 6.08 years and 35 of the 86 patients developed oral cancer over the course. Gene expression profiles were associated with oral cancer–free survival and used to develop multivariate predictive models for oral cancer prediction. We developed a 29-transcript predictive model which showed marked improvement in terms of prediction accuracy (with 8% predicting error rate) over the models using previously known clinicopathologic risk factors. On the basis of the gene expression profile data, we also identified 2,182 transcripts significantly associated with oral cancer risk–associated genes (P value < 0.01; univariate Cox proportional hazards model). Functional pathway analysis revealed proteasome machinery, MYC, and ribosomal components as the top gene sets associated with oral cancer risk. In multiple independent data sets, the expression profiles of the genes can differentiate head and neck cancer from normal mucosa. Our results show that gene expression profiles may improve the prediction of oral cancer risk in OPL patients and the significant genes identified may serve as potential targets for oral cancer chemoprevention. Cancer Prev Res; 4(2); 218–29. ©2011 AACR.
Data from MAPRE1 as a Plasma Biomarker for Early-Stage Colorectal Cancer and Adenomas
Authors: Taguchi Ayumu , Rho Jung-hyun , Yan Qingxiang , Zhang Yuzheng , Zhao Yang , Xu Hanwen , Tripathi Satyendra Chandra , Wang Hong , Brenner Dean E. , Kucherlapati Melanie , Kucherlapati Raju , Boutin Adam T. , Wang Y. Alan , DePinho Ronald A. , Feng Ziding , Lampe Paul D. , Hanash Samir M.
Published: March 2024

Abstract
Blood-based biomarkers for early detection of colorectal cancer could complement current approaches to colorectal cancer screening. We previously identified the APC-binding protein MAPRE1 as a potential colorectal cancer biomarker. Here, we undertook a case–control validation study to determine the performance of MAPRE1 in detecting early colorectal cancer and colon adenoma and to assess the potential relevance of additional biomarker candidates. We analyzed plasma samples from 60 patients with adenomas, 30 with early colorectal cancer, 30 with advanced colorectal cancer, and 60 healthy controls. MAPRE1 and a set of 21 proteins with potential biomarker utility were assayed using high-density antibody arrays, and carcinoembryonic antigen (CEA) was assayed using ELISA. The biologic significance of the candidate biomarkers was also assessed in colorectal cancer mouse models. Plasma MAPRE1 levels were significantly elevated in both patients with adenomas and patients with colorectal cancer compared with controls (P < 0.0001). MAPRE1 and CEA together yielded an area under the curve of 0.793 and a sensitivity of 0.400 at 95% specificity for differentiating early colorectal cancer from controls. Three other biomarkers (AK1, CLIC1, and SOD1) were significantly increased in both adenoma and early colorectal cancer patient plasma samples and in plasma from colorectal cancer mouse models at preclinical stages compared with controls. The combination of MAPRE1, CEA, and AK1 yielded sensitivities of 0.483 and 0.533 at 90% specificity and sensitivities of 0.350 and 0.467 at 95% specificity for differentiating adenoma and early colorectal cancer, respectively, from healthy controls. These findings suggest that MAPRE1 can contribute to the detection of early-stage colorectal cancer and adenomas together with other biomarkers. Cancer Prev Res; 8(11); 1112–9. ©2015 AACR.
Data from (3-Chloroacetyl)-indole, a Novel Allosteric AKT Inhibitor, Suppresses Colon Cancer Growth In Vitro and In Vivo
Authors: Kim Dong Joon , Reddy Kanamata , Kim Myoung Ok , Li Yan , Nadas Janos , Cho Yong-Yeon , Kim Jong-Eun , Shim Jung-Hyun , Song Nu Ry , Carper Andria , Lubet Ronald A. , Bode Ann M. , Dong Zigang
Published: March 2024

Abstract
Indole-3-carbinol (I3C) is produced in Brassica vegetables such as broccoli and cabbage and has been shown to inhibit proliferation and induce apoptosis in various cancer cells, including breast, prostate, colon, and leukemia. However, only high doses of I3C were shown to inhibit cell proliferation (IC50 = 200–300 μmol/L). Our goal here was to develop a more potent antitumor agent by modifying the structure of I3C. We created I3C derivatives and found that (3-chloroacetyl)-indole (3CAI) more strongly inhibited colon cancer cell growth than I3C. In addition, by screening 85 kinases in a competitive kinase assay, we found that 3CAI was a specific AKT inhibitor. AKT is a serine/threonine kinase that plays a pivotal role in promoting transformation and chemoresistance by inducing proliferation and inhibiting apoptosis. Therefore, AKT is regarded as a critical target for cancer therapy. 3ICA, a derivative of I3C, is a potent and specific AKT inhibitor. This compound showed significant inhibition of AKT in an in vitro kinase assay and suppressed expression of AKT direct downstream targets such as mTOR and GSK3β as well as induced growth inhibition and apoptosis in colon cancer cells. In addition, oral administration of this potent AKT inhibitor suppressed cancer cell growth in an in vivo xenograft mouse model. Cancer Prev Res; 4(11); 1842–51. ©2011 AACR.
Data from Phospho-Sulindac (OXT-328) Combined with Difluoromethylornithine Prevents Colon Cancer in Mice
Authors: Mackenzie Gerardo G. , Ouyang Nengtai , Xie Gang , Vrankova Kvetoslava , Huang Liqun , Sun Yu , Komninou Despina , Kopelovich Levy , Rigas Basil
Published: March 2024

Abstract
The nonsteroidal anti-inflammatory drug (NSAID) sulindac and the ornithine decarboxylase (ODC) antagonist difluoromethylornithine (DFMO), individually and together, are effective inhibitors of colon carcinogenesis. However, chronic use of sulindac is associated with significant side effects. We evaluated the chemopreventive efficacy of phospho-sulindac (P-S, OXT-328), an apparently safe derivative of sulindac, together with DFMO, in HT-29 human colon cancer xenografts. Nude mice were divided into four groups as follows: group 1 received vehicle (corn oil); group 2 received P-S (100 mg/kg/d) by oral gavage; group 3 received DFMO (2% in drinking water); and group 4 received P-S (100 mg/kg/d) by gavage plus DFMO (2% in drinking water; P-S/DFMO). Eighteen days after implantation, compared with controls, tumor volume was inhibited 65.9% by P-S, 52.9% by DFMO, and 70.9% by P-S/DFMO (P < 0.01 for all). P-S/DFMO reduced cell proliferation 27.1% and increased apoptosis 38.9% compared with controls (P < 0.05 for both). Compared with controls, P-S reduced the levels of thioredoxin-1 (Trx-1) and thioredoxin reductase (TrxR), whereas DFMO reduced polyamine content (putrescine and spermidine) and TrxR levels. Importantly, P-S/DFMO decreased putrescine and spermidine levels and the expression of Trx-1, TrxR, and cyclooxygenase (COX) 2. Of these molecular targets, TrxR most consistently correlated with tumor growth. Study results show that P-S/DFMO is an efficacious drug combination for colon cancer prevention and also show the safety of P-S, which may overcome the limiting side effects of conventional sulindac. P-S/DFMO has an intricate mechanism of action extending beyond polyamines and including the thioredoxin system, an emerging regulator of chemoprevention. P-S/DFMO merits further evaluation. Cancer Prev Res; 4(7); 1052–60. ©2011 AACR.
Data from Targeting FACT Complex Suppresses Mammary Tumorigenesis in Her2/neu Transgenic Mice
Authors: Koman Igor E. , Commane Mairead , Paszkiewicz Geraldine , Hoonjan Bhupinder , Pal Srabani , Safina Alfiya , Toshkov Ilya , Purmal Andrei A. , Wang Dan , Liu Song , Morrison Carl , Gudkov Andrei V. , Gurova Katerina V.
Published: March 2024

Abstract
Development of safe and effective tumor-preventive treatments for high-risk patient populations and therapies for early-stage cancer remains a critical need in oncology. We have recently discovered compound with anticancer activity, Curaxin-137, which modulates several important signaling pathways involved in even the very early stages of cancer. In tumor cells, Curaxin-137 inhibits NF-κB- and HSF1-dependent transcription (prosurvival pathways) and activates p53 (a proapoptotic pathway) without inducing DNA damage. These effects result from chromatin trapping and inhibition of activity of the FACT (facilitates chromatin transcription) complex by Curaxin-137. FACT has not been previously implicated in cancer, but we found that its subunits are overexpressed in breast cancer. On the basis of this background, we tested whether Curaxin-137 could suppress tumorigenesis in MMTV-neu transgenic mice, which spontaneously develop mammary carcinoma due to steroid receptor–regulated expression of the Her2 proto-oncogene. We found that chronic administration of Curaxin-137 in a preventive regimen to MMTV-neu mice did not cause any detectable changes in normal organs and tissues, yet inhibited tumor onset, delayed tumor progression, and prolonged survival of mice in a dose-dependent manner. Curaxin-137 induced changes in FACT, altered NF-κB localization, and activated p53 in tumor cells as expected from its defined mechanism of action. These results support further investigation of Curaxin-137 as a potential preventive and/or early-stage therapeutic agent for breast cancer. Cancer Prev Res; 5(8); 1025–35. ©2012 AACR.
Data from Cryptotanshinone Inhibits Lymphatic Endothelial Cell Tube Formation by Suppressing VEGFR-3/ERK and Small GTPase Pathways
Authors: Luo Yan , Chen Wenxing , Zhou Hongyu , Liu Lei , Shen Tao , Alexander J. Steven , Zheng Shizhong , Lu Yin , Huang Shile
Published: March 2024

Abstract
Cryptotanshinone (CPT), isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism remains to be defined. Here, we show that CPT inhibited lymphangiogenesis in an in vitro model (tube formation). This effect was partly attributed to inhibiting expression of VEGF receptor 3 (VEGFR-3) in murine lymphatic endothelial cells (LEC), as overexpression of VEGFR-3 conferred resistance to CPT inhibition of the tube formation, whereas downregulation of VEGFR-3 mimicked the effect of CPT, blocking the tube formation. Furthermore, CPT inhibited phosphorylation of the extracellular signal–related kinase 1/2 (ERK1/2). Overexpression of VEGFR-3 attenuated CPT inhibition of ERK1/2 phosphorylation, whereas downregulation of VEGFR-3 inhibited ERK1/2 phosphorylation in LECs. Expression of constitutively active MKK1 resulted in activation of ERK1/2 and partially prevented CPT inhibition of LEC tube formation. In addition, CPT also inhibited protein expression and activities of Rac1 and Cdc42 but not RhoA. Expression of constitutively active Rac1 and Cdc42 concurrently, but not Rac1 or Cdc42 alone, conferred resistance to CPT inhibition of LEC tube formation. Taken together, the results suggest that CPT inhibits LEC tube formation, in part, by inhibiting VEGFR-3–mediated ERK1/2 phosphorylation and, in part, by inhibiting expression of the small GTPases. Cancer Prev Res; 4(12); 2083–91. ©2011 AACR.
Data from Kaempferol Targets RSK2 and MSK1 to Suppress UV Radiation-Induced Skin Cancer
Authors: Yao Ke , Chen Hanyong , Liu Kangdong , Langfald Alyssa , Yang Ge , Zhang Yi , Yu Dong Hoon , Kim Myoung Ok , Lee Mee-Hyun , Li Haitao , Bae Ki Beom , Kim Hong-Gyum , Ma Wei-Ya , Bode Ann M. , Dong Ziming , Dong Zigang
Published: March 2024

Abstract
Solar UV (SUV) irradiation is a major factor in skin carcinogenesis, the most common form of cancer in the United States. The MAPK cascades are activated by SUV irradiation. The 90 kDa ribosomal S6 kinase (RSK) and mitogen and stress-activated protein kinase (MSK) proteins constitute a family of protein kinases that mediate signal transduction downstream of the MAPK cascades. In this study, phosphorylation of RSK and MSK1 was upregulated in human squamous cell carcinoma (SCC) and SUV-treated mouse skin. Kaempferol, a natural flavonol, found in tea, broccoli, grapes, apples, and other plant sources, is known to have anticancer activity, but its mechanisms and direct target(s) in cancer chemoprevention are unclear. Kinase array results revealed that kaempferol inhibited RSK2 and MSK1. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and inhibits their respective kinase activities. Mechanistic investigations showed that kaempferol suppresses RSK2 and MSK1 kinase activities to attenuate SUV-induced phosphorylation of cAMP-responsive element binding protein (CREB) and histone H3 in mouse skin cells. Kaempferol was a potent inhibitor of SUV-induced mouse skin carcinogenesis. Further analysis showed that skin from the kaempferol-treated group exhibited a substantial reduction in SUV-induced phosphorylation of CREB, c-Fos, and histone H3. Overall, our results identify kaempferol as a safe and novel chemopreventive agent against SUV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1. Cancer Prev Res; 7(9); 958–67. ©2014 AACR.
Data from Temporal and Spatial Evolution of Somatic Chromosomal Alterations: A Case-Cohort Study of Barrett's Esophagus
Authors: Li Xiaohong , Galipeau Patricia C. , Paulson Thomas G. , Sanchez Carissa A. , Arnaudo Jessica , Liu Karen , Sather Cassandra L. , Kostadinov Rumen L. , Odze Robert D. , Kuhner Mary K. , Maley Carlo C. , Self Steven G. , Vaughan Thomas L. , Blount Patricia L. , Reid Brian J.
Published: March 2024

Abstract
All cancers are believed to arise by dynamic, stochastic somatic genomic evolution with genome instability, generation of diversity, and selection of genomic alterations that underlie multistage progression to cancer. Advanced esophageal adenocarcinomas have high levels of somatic copy number alterations. Barrett's esophagus is a risk factor for developing esophageal adenocarcinoma, and somatic chromosomal alterations (SCA) are known to occur in Barrett's esophagus. The vast majority (∼95%) of individuals with Barrett's esophagus do not progress to esophageal adenocarcinoma during their lifetimes, but a small subset develop esophageal adenocarcinoma, many of which arise rapidly even in carefully monitored patients without visible endoscopic abnormalities at the index endoscopy. Using a well-designed, longitudinal case-cohort study, we characterized SCA as assessed by single-nucleotide polymorphism arrays over space and time in 79 “progressors” with Barrett's esophagus as they approach the diagnosis of cancer and 169 “nonprogressors” with Barrett's esophagus who did not progress to esophageal adenocarcinoma over more than 20,425 person-months of follow-up. The genomes of nonprogressors typically had small localized deletions involving fragile sites and 9p loss/copy neutral LOH that generate little genetic diversity and remained relatively stable over prolonged follow-up. As progressors approach the diagnosis of cancer, their genomes developed chromosome instability with initial gains and losses, genomic diversity, and selection of SCAs followed by catastrophic genome doublings. Our results support a model of differential disease dynamics in which nonprogressor genomes largely remain stable over prolonged periods, whereas progressor genomes evolve significantly increased SCA and diversity within four years of esophageal adenocarcinoma diagnosis, suggesting a window of opportunity for early detection. Cancer Prev Res; 7(1); 114–27. ©2013 AACR.
Data from Genetic Variants Associated with the Risk of Chronic Obstructive Pulmonary Disease with and without Lung Cancer
Authors: de Andrade Mariza , Li Yan , Marks Randolph S. , Deschamps Claude , Scanlon Paul D. , Olswold Curtis L. , Jiang Ruoxiang , Swensen Stephen J. , Sun Zhifu , Cunningham Julie M. , Wampfler Jason A. , Limper Andrew H. , Midthun David E. , Yang Ping
Published: March 2024

Abstract
Chronic obstructive pulmonary disease (COPD) is a strong risk factor for lung cancer. Published studies about variations of genes encoding glutathione metabolism, DNA repair, and inflammatory response pathways in susceptibility to COPD were inconclusive. We evaluated 470 single-nucleotide polymorphisms (SNP) from 56 genes of these three pathways in 620 cases and 893 controls to identify susceptibility markers for COPD risk, using existing resources. We assessed SNP- and gene-level effects adjusting for sex, age, and smoking status. Differential genetic effects on disease risk with and without lung cancer were also assessed; cumulative risk models were established. Twenty-one SNPs were found to be significantly associated with risk of COPD (P < 0.01); gene-based analyses confirmed two genes (GCLC and GSS) and identified three additional genes (GSTO2, ERCC1, and RRM1). Carrying 12 high-risk alleles may increase risk by 2.7-fold; eight SNPs altered COPD risk without lung cancer by 3.1-fold and 4 SNPs altered the risk with lung cancer by 2.3-fold. Our findings indicate that multiple genetic variations in the three selected pathways contribute to COPD risk through GCLC, GSS, GSTO2, ERCC1, and RRM1 genes. Functional studies are needed to elucidate the mechanisms of these genes in the development of COPD, lung cancer, or both. Cancer Prev Res; 5(3); 365–73. ©2011 AACR.
Data from Salivary microRNAs Show Potential as a Noninvasive Biomarker for Detecting Resectable Pancreatic Cancer
Authors: Xie Zijun , Yin Xiaoyu , Gong Bo , Nie Wenjing , Wu Bin , Zhang Xuchao , Huang Jian , Zhang Pingyou , Zhou Zhiwei , Li Zijun
Published: March 2024

Abstract
Early surgery is vital in the treatment of pancreatic cancer, which is often fatal. However, there is currently no useful noninvasive biomarker to screen for pancreatic cancer. Studies have documented that many salivary molecules can be used to detect systemic diseases. We investigated whether salivary miRNAs are useful biomarkers for detecting resectable pancreatic cancer. Using an Agilent microarray, salivary miRNAs were profiled from saliva samples of 8 patients with resectable pancreatic cancer and 8 healthy controls. Candidate biomarkers identified in the profiles were subjected to validation using quantitative PCR and an independent sample set of 40 patients with pancreatic cancer, 20 with benign pancreatic tumors (BPT), and 40 healthy controls. The validated salivary miRNA biomarkers were evaluated within three discriminatory categories: pancreatic cancer versus healthy control, pancreatic cancer versus BPT, and pancreatic cancer versus noncancer (healthy control + BPT). miR-3679-5p showed significant downregulation in the pancreatic cancer group within the three categories (P = 0.008, 0.007, and 0.002, respectively), whereas miR-940 showed significant upregulation in pancreatic cancer (P = 0.006, 0.004, and 0.0001, respectively). Logistic regression models combining the two salivary miRNAs were able to distinguish resectable pancreatic cancer within the three categories, showing sensitivities of 72.5%, 62.5%, and 70.0% and specificities of 70.0%, 80.0%, and 70.0%, respectively. Salivary miR-3679-5p and miR-940 possess good discriminatory power to detect resectable pancreatic cancer, with reasonable specificity and sensitivity. This report provides a new method for the early detection of pancreatic cancer and other systemic diseases by assessing salivary miRNAs. Cancer Prev Res; 8(2); 165–73. ©2014 AACR.
Data from Combination of Chemopreventive Agents in Nanoparticles for Cancer Prevention
Authors: Yang Chung S. , Wang Hong , Hu Bing
Published: March 2024

Abstract
Carcinogenesis involves multiple genetic and epigenetic alterations, and a single chemopreventive agent may not be sufficient to prevent these events. Therefore, the use of a combination of agents is an attractive approach for cancer chemoprevention. In this issue of the journal, Prabhu and colleagues examined a combination of aspirin, curcumin, and sulforaphane for the prevention of pancreatic cancer in hamsters (beginning page 1015). The novelty of this work is that when aspirin and curcumin were incorporated in nanoparticles and administered orally, in combination with sulforaphane, the effective dosages were decreased by 10-fold in comparison with the free form mixture. In this commentary, the possible mechanisms of synergistic action among multiple chemopreventive agents and the use of stable nanoparticles for oral delivery are discussed. Also discussed is the importance of measuring tissue levels of the chemopreventive agents to understand the mode of action of these nanoparticles and to avoid toxicity. Cancer Prev Res; 6(10); 1011–4. ©2013 AACR.
Data from Kava Blocks 4-(Methylnitrosamino)-1-(3-pyridyl)-1-Butanone–Induced Lung Tumorigenesis in Association with Reducing O6-methylguanine DNA Adduct in A/J Mice
Authors: Leitzman Pablo , Narayanapillai Sreekanth C. , Balbo Silvia , Zhou Bo , Upadhyaya Pramod , Shaik Ahmad Ali , O'Sullivan M. Gerard , Hecht Stephen S. , Lu Junxuan , Xing Chengguo
Published: March 2024

Abstract
We previously reported the chemopreventive potential of kava against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- and benzo(a)pyrene (BaP)–induced lung tumorigenesis in A/J mice during the initiation and postinitiation stages. In this study, we investigated the tumorigenesis-stage specificity of kava, the potential active compounds, and the underlying mechanisms in NNK-induced lung tumorigenesis in A/J mice. In the first experiment, NNK-treated mice were given diets containing kava at a dose of 5 mg/g of diet during different periods. Kava treatments covering the initiation stage reduced the multiplicity of lung adenomas by approximately 99%. A minimum effective dose is yet to be defined because kava at two lower dosages (2.5 and 1.25 mg/g of diet) were equally effective as 5 mg/g of diet in completely inhibiting lung adenoma formation. Daily gavage of kava (one before, during, and after NNK treatment) completely blocked lung adenoma formation as well. Kavalactone-enriched fraction B fully recapitulated kava's chemopreventive efficacy, whereas kavalactone-free fractions A and C were much less effective. Mechanistically, kava and fraction B reduced NNK-induced DNA damage in lung tissues with a unique and preferential reduction in O6-methylguanine (O6-mG), the highly tumorigenic DNA damage by NNK, correlating and predictive of efficacy on blocking lung adenoma formation. Taken together, these results demonstrate the outstanding efficacy of kava in preventing NNK-induced lung tumorigenesis in A/J mice with high selectivity for the initiation stage in association with the reduction of O6-mG adduct in DNA. They also establish the knowledge basis for the identification of the active compound(s) in kava. Cancer Prev Res; 7(1); 86–96. ©2013 AACR.
Data from Basal Cell Carcinoma Chemoprevention with Nonsteroidal Anti-inflammatory Drugs in Genetically Predisposed PTCH1+/− Humans and Mice
Authors: Tang Jean Y. , Aszterbaum Michelle , Athar Mohammad , Barsanti Franco , Cappola Carol , Estevez Nini , Hebert Jennifer , Hwang Jimmy , Khaimskiy Yefim , Kim Arianna , Lu Ying , So Po-Lin , Tang Xiuwei , Kohn Michael A. , McCulloch Charles E. , Kopelovich Levy , Bickers David R. , Epstein Ervin H.
Published: March 2024

Abstract
In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1+/− mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1+/−) patients with the basal cell nevus syndrome. In Ptch1+/− mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (Pdifference = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1+/− mice and had a significant anti-BCC effect in humans with less severe disease. Cancer Prev Res; 3(1); OF1–11
Data from Curcumin Modulates MicroRNA-203–Mediated Regulation of the Src-Akt Axis in Bladder Cancer
Authors: Saini Sharanjot , Arora Sumit , Majid Shahana , Shahryari Varahram , Chen Yi , Deng Guoren , Yamamura Soichiro , Ueno Koji , Dahiya Rajvir
Published: March 2024

Abstract
Bladder cancer is often associated with recurrence and progression to invasive metastatic disease that have palliative therapeutic options. The use of traditional chemotherapeutic agents for bladder cancer management often suffers from toxicity and resistance concerns. This emphasizes the need for development of safer, natural, nontoxic compounds as chemotherapeutic/chemopreventive agents. Curcumin (diferuloylmethane) is a natural compound that has been known to possess anticancer properties in various cancers, including bladder cancer. However, the biological targets of curcumin are not well defined. Recently, it has been proposed that curcumin may mediate epigenetic modulation of expression of microRNAs (miRNA). In this article, we define for the first time, that curcumin directly induces a tumor-suppressive miRNA, miR-203, in bladder cancer. miR-203 is frequently downregulated in bladder cancer due to DNA hypermethylation of its promoter. We studied the functional significance of miR-203 in bladder cancer cell lines and found that miR-203 has tumor suppressive properties. Also, we define Akt2 and Src as novel miR-203 targets in bladder cancer. Curcumin induces hypomethylation of the miR-203 promoter and subsequent upregulation of miR-203 expression. This leads to downregulation of miR-203 target genes Akt2 and Src that culminates in decreased proliferation and increased apoptosis of bladder cancer cells. This is the first report that shows a direct effect of curcumin on inducing epigenetic changes at a miRNA promoter with direct biological consequences. Our study suggests that curcumin may offer a therapeutic advantage in the clinical management of refractory bladder cancer over other standard treatment modalities. Cancer Prev Res; 4(10); 1698–709. ©2011 AACR.
Data from Noninvasive Detection of Candidate Molecular Biomarkers in Subjects with a History of Insulin Resistance and Colorectal Adenomas
Authors: Zhao Chen , Ivanov Ivan , Dougherty Edward R. , Hartman Terryl J. , Lanza Elaine , Bobe Gerd , Colburn Nancy H. , Lupton Joanne R. , Davidson Laurie A. , Chapkin Robert S.
Published: March 2024

Abstract
We have developed novel molecular methods using a stool sample, which contains intact sloughed colon cells, to quantify colonic gene expression profiles. In this study, our goal was to identify diagnostic gene sets (combinations) for the noninvasive classification of different phenotypes. For this purpose, the effects of a legume-enriched, low glycemic index, high fermentable fiber diet was evaluated in subjects with four possible combinations of risk factors, including insulin resistance and a history of adenomatous polyps. In a randomized crossover design controlled feeding study, each participant (a total of 23; 5–12 per group) consumed the experimental diet (1.5 cups of cooked dry beans) and a control diet (isocaloric average American diet) for 4 weeks with a 3-week washout period between diets. Using prior biological knowledge, the complexity of feature selection was reduced to perform an exhaustive search on all allowable feature (gene) sets of size 3, and among these, 27 had (unbiased) error estimates of 0.15 or less. Linear discriminant analysis was successfully used to identify the best single genes and two- to three-gene combinations for distinguishing subjects with insulin resistance, a history of polyps, or exposure to a chemoprotective legume-rich diet. These results support our premise that gene products (RNA) isolated from stool have diagnostic value in terms of assessing colon cancer risk.