bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Microtubule-Associated Protein-tau is a Bifunctional Predictor of Endocrine Sensitivity and Chemotherapy Resistance in Estrogen Receptor–Positive Breast Cancer
Authors: Andre Fabrice , Hatzis Christos , Anderson Keith , Sotiriou Christos , Mazouni Chafika , Mejia Jaime , Wang Bailiang , Hortobagyi Gabriel N. , Symmans W. Fraser , Pusztai Lajos
Published: April 2023

Abstract
Purpose: The clinical outcome for patients with breast cancer is influenced by the metastatic competence of the cancer and its sensitivity to endocrine therapy and chemotherapy. A molecular marker may be prognostic of outcome or predictive of response to therapy, or a combination of both.

Experimental Design: We examined separately the prognostic and predictive values of tau mRNA expression in estrogen receptor (ER)–positive primary breast cancers in three patient cohorts. We used gene expression data from 209 untreated patients to assess the pure prognostic value of tau, data from 267 patients treated with adjuvant tamoxifen to assess predictive value for endocrine therapy, and data from 82 patients treated with preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide (paclitaxel/FAC) to assess predictive value for chemotherapy response. Wilcoxon rank sum test was used to compare tau expression between different outcome groups.

Results: Higher tau mRNA expression showed borderline nonsignificant association with better prognosis in the absence of systemic adjuvant therapy. Higher tau mRNA expression was significantly associated with no recurrence (at 5 and 10 years, P = 0.005 and P = 0.05, respectively) in patients treated with tamoxifen, indicating a predictive value for endocrine therapy. Tau expression was significantly lower in patients who achieved pathologic complete response to paclitaxel/FAC chemotherapy (P < 0.001).

Conclusion: This study suggests that high tau mRNA expression in ER-positive breast cancer indicates an endocrine-sensitive but chemotherapy-resistant disease. In contrast, low tau expression identifies a subset of ER-positive cancers that have poor prognosis with tamoxifen alone and may benefit from taxane-containing chemotherapy.
Data from DNA Methylation in Serum and Tumors of Cervical Cancer Patients
Authors: Widschwendter Andreas , Müller Hannes M. , Fiegl Heidi , Ivarsson Lennart , Wiedemair Annemarie , Müller-Holzner Elisabeth , Goebel Georg , Marth Christian , Widschwendter Martin
Published: April 2023

Abstract
Purpose: Promoter hypermethylation has been recognized to play an important role in carcinogenesis. Numerous studies have demonstrated tumor-specific alterations, such as aberrant promoter hypermethylation, in DNA recovered from plasma or serum of patients with various malignancies. The aim of this study was to investigate the methylation status of various genes in cervical cancer patients and their association with clinicopathological characteristics and outcome of the disease.

Experimental Design: The methylation status of CALCA, hTERT, MYOD1, PGR (progesterone receptor), and TIMP3 was investigated in serum samples from 93 cervical cancer patients and 19 corresponding tissue samples using the MethyLight technique.

Results: Aberrant promoter hypermethylation was detected in any of these genes in 87% (81 of 93) of the serum samples studied. Methylation of MYOD1 was detected more frequently in advanced stage. All of the genes found to be methylated in serum samples were also methylated in the corresponding tissue sample, except in one patient. Patients with unmethylated MYOD1 serum DNA had significantly better disease-free (P = 0.04) and overall survival (P = 0.02) in comparison with patients with methylated MYOD1.

Conclusions: To the best of our knowledge, this is, thus far, the largest study investigating aberrant promoter hypermethylation in serum samples from cancer patients and the first study investigating methylation patterns in sera of cervical cancer patients. Our results suggest that serological detection of MYOD1 promoter hypermethylation may be of potential use as a prognostic marker for discriminating cervical cancer patients at high risk for lymph node metastasis or relapse. Additional studies, including a panel of additional genes, are necessary to elucidate the role of aberrant methylation in serum as a tool for surveillance of cervical cancer.
Data from Novel Blood Biomarkers of Human Urinary Bladder Cancer
Authors: Osman Iman , Bajorin Dean F. , Sun Tung-Tien , Zhong Hong , Douglas Diah , Scattergood Joseph , Zheng Run , Han Mark , Marshall K. Wayne , Liew Choong-Chin
Published: April 2023

Abstract
Purpose: Recent data indicate that cDNA microarray gene expression profile of blood cells can reflect disease states and thus have diagnostic value. We tested the hypothesis that blood cell gene expression can differentiate between bladder cancer and other genitourinary cancers as well as between bladder cancer and healthy controls.

Experimental Design: We used Affymetrix U133 Plus 2.0 GeneChip (Affymetrix, Santa Clara, CA) to profile circulating blood total RNA from 35 patients diagnosed with one of three types of genitourinary cancer [bladder cancer (n = 16), testicular cancer (n = 10), and renal cell carcinoma (n = 9)] and compared their cDNA profiles with those of 10 healthy subjects. We then verified the expression levels of selected genes from the Affymetrix results in a larger number of bladder cancer patients (n = 40) and healthy controls (n = 27).

Results: Blood gene expression profiles distinguished bladder cancer patients from healthy controls and from testicular and renal cancer patients. Differential expression of a combined set of seven gene transcripts (insulin-like growth factor–binding protein 7, sorting nexin 16, chondroitin sulfate proteoglycan 6, and cathepsin D, chromodomain helicase DNA-binding protein 2, nell-like 2, and tumor necrosis factor receptor superfamily member 7) was able to discriminate bladder cancer from control samples with a sensitivity of 83% (95% confidence interval, 67-93%) and a specificity of 93% (95% confidence interval, 76-99%).

Conclusion: We have shown that the gene expression profile of circulating blood cells can distinguish bladder cancer from other types of genitourinary cancer and healthy controls and can be used to identify novel blood markers for bladder cancer.
Data from A Pilot Study of Volume Measurement as a Method of Tumor Response Evaluation to Aid Biomarker Development
Authors: Zhao Binsheng , Oxnard Geoffrey R. , Moskowitz Chaya S. , Kris Mark G. , Pao William , Guo Pingzhen , Rusch Valerie M. , Ladanyi Marc , Rizvi Naiyer A. , Schwartz Lawrence H.
Published: April 2023

Abstract
Purpose: Tissue biomarker discovery is potentially limited by conventional tumor measurement techniques, which have an uncertain ability to accurately distinguish sensitive and resistant tumors. Semiautomated volumetric measurement of computed tomography imaging has the potential to more accurately capture tumor growth dynamics, allowing for more exact separation of sensitive and resistant tumors and a more accurate comparison of tissue characteristics.

Experimental Design: Forty-eight patients with early stage non–small cell lung cancer and clinical characteristics of sensitivity to gefitinib were studied. High-resolution computed tomography was done at baseline and after 3 weeks of gefitinib. Tumors were then resected and molecularly profiled. Unidimensional and volumetric measurements were done using a semiautomated algorithm. Measurement changes were evaluated for their ability to differentiate tumors with and without sensitizing mutations.

Results: Forty-four percent of tumors had epidermal growth factor receptor–sensitizing mutations. Receiver operating characteristic curve analysis showed that volumetric measurement had a higher area under the curve than unidimensional measurement for identifying tumors harboring sensitizing mutations (P = 0.009). Tumor volume decrease of >24.9% was the imaging criteria best able to classify tumors with and without sensitizing mutations (sensitivity, 90%; specificity, 89%).

Conclusions: Volumetric tumor measurement was better than unidimensional tumor measurement at distinguishing tumors based on presence or absence of a sensitizing mutation. Use of volume-based response assessment for the development of tissue biomarkers could reduce contamination between sensitive and resistant tumor populations, improving our ability to identify meaningful predictors of sensitivity. Clin Cancer Res; 16(18); 4647–53. ©2010 AACR.
Data from The Coamplification Pattern of the MYCN Amplicon Is an Invariable Attribute of Most MYCN-Amplified Human Neuroblastomas
Authors: Weber Axel , Starke Sven , Bergmann Eckhard , Christiansen Holger
Published: April 2023

Abstract
Purpose: Fifteen percent to 20% of human neuroblastomas show amplification of the MYCN oncogene physiologically located at chromosome 2p24-25, indicating an aggressive subtype of human neuroblastoma with a poor clinical outcome. Recent findings revealed that the structure of the amplicon differs interindividually and that coamplification of genes in telomeric proximity to MYCN might play a relevant role in neuroblastoma development and response to treatment, respectively. We now asked if the amplicon structure is an invariable attribute of an individual tumor or if the coamplification pattern could change during progress or in case of recurrent disease.

Experimental Design: We used a previously described multiplex PCR approach to analyze the coamplification status of MYCN-amplified human neuroblastomas (n = 33) in tumor tissue at the time of initial diagnosis and in consecutive tissue specimens at later time points after initial treatment or from relapsing disease. The MYCN copy number per haploid genome (Mcn/hg) in these specimens was determined in a separate duplex PCR.

Results: In 32 of the 33 investigated tumors, the amplicon structure showed no changes after initial chemotherapy and in recurrent disease. Mcn/hg showed a decrease after initial treatment (n = 23), whereas we found a significant increase in recurrent disease (n = 10).

Conclusion: Our data indicate that the initial determined structure of the 2p24-25 amplicon is a consistent attribute in the great majority of the individual MYCN-amplified neuroblastomas and shows no plasticity during or after chemotherapy. Observed changes in the Mcn/hg over the course of disease are in line with preexisting cell culture findings.
Data from Genome-Wide Screening of Genomic Alterations and Their Clinicopathologic Implications in Non–Small Cell Lung Cancers
Authors: Kim Tae-Min , Yim Seon-Hee , Lee Jung-Sook , Kwon Mi-Seon , Ryu Jae-Wook , Kang Hyun-Mi , Fiegler Heike , Carter Nigel P. , Chung Yeun-Jun
Published: April 2023

Abstract
Purpose: Although many genomic alterations have been observed in lung cancer, their clinicopathologic significance has not been thoroughly investigated. This study screened the genomic aberrations across the whole genome of non–small cell lung cancer cells with high-resolution and investigated their clinicopathologic implications.

Experimental Design: One-megabase resolution array comparative genomic hybridization was applied to 29 squamous cell carcinomas and 21 adenocarcinomas of the lung. Tumor and normal tissues were microdissected and the extracted DNA was used directly for hybridization without genomic amplification. The recurrent genomic alterations were analyzed for their association with the clinicopathologic features of lung cancer.

Results: Overall, 36 amplicons, 3 homozygous deletions, and 17 minimally altered regions common to many lung cancers were identified. Among them, genomic changes on 13q21, 1p32, Xq, and Yp were found to be significantly associated with clinical features such as age, stage, and disease recurrence. Kaplan-Meier survival analysis revealed that genomic changes on 10p, 16q, 9p, 13q, 6p21, and 19q13 were associated with poor survival. Multivariate analysis showed that alterations on 6p21, 7p, 9q, and 9p remained as independent predictors of poor outcome. In addition, significant correlations were observed for three pairs of minimally altered regions (19q13 and 6p21, 19p13 and 19q13, and 8p12 and 8q11), which indicated their possible collaborative roles.

Conclusions: These results show that our approach is robust for high-resolution mapping of genomic alterations. The novel genomic alterations identified in this study, along with their clinicopathologic implications, would be useful to elucidate the molecular mechanisms of lung cancer and to identify reliable biomarkers for clinical application.
Data from High WT1 Expression Is Associated with Very Poor Survival of Patients with Osteogenic Sarcoma Metastasis
Authors: Srivastava Alok , Fuchs Bruno , Zhang Kunbo , Ruan Ming , Halder Chandralekha , Mahlum Eric , Weber Kristin , Bolander Mark E. , Sarkar Gobinda
Published: April 2023

Abstract
Purpose: Although metastasis is the primary determinant of poor survival of patients with osteogenic sarcoma, some patients live much longer than others, indicating metastatic heterogeneity underlying survival outcome. The purpose of the investigation was to identify genes underlying survival outcome of patients with osteogenic sarcoma metastasis.

Experimental Design: We have used microarray to first compare mRNA expression between normal bone and osteogenic sarcoma specimens, identified genes overexpressed in osteogenic sarcoma, and compared expression of the selected gene between a poorly metastatic (SAOS) and two highly metastatic cell lines (LM8 and 143B). Finally, expression of the selected gene was assessed by immunostaining of osteogenic sarcoma samples with known survival outcome.

Results: Microarray analysis revealed 5.3-fold more expression of WT1 mRNA in osteogenic sarcoma compared with normal bone and >2-fold overexpression in 143B and LM8 cells compared with SAOS. Furthermore, WT1 mRNA was absent in normal bone (10 of 10) by reverse transcription-PCR but present in osteogenic sarcoma–derived cell lines (5 of 8). One hundred percent (42 of 42) of low-grade osteogenic sarcoma specimens expressed no WT1 as determined by immunostaining; however, 24% (12 of 49) of the high-grade specimens showed intense staining. Mean survival of patients with high-grade metastatic osteogenic sarcoma but low WT1 staining (27 of 37) was 96.5 ± 129.3 months, whereas mean survival of patients with high-grade metastatic osteogenic sarcoma having intense staining (10 of 37) was 18.3 ± 12.3 months (P > 0.0143). All splice variants of WT1 mRNA, including a hitherto unknown variant (lacking exons 4 and 5), were found to be expressed in osteogenic sarcoma.

Conclusion: WT1 seems to be associated with very poor survival of patients with osteogenic sarcoma metastasis.
Data from Close and Stable Relationship between Proliferation and a Hypoxia Metagene in Aromatase Inhibitor–Treated ER-Positive Breast Cancer
Authors: Ghazoui Zara , Buffa Francesca M. , Dunbier Anita K. , Anderson Helen , Dexter Tim , Detre Simone , Salter Janine , Smith Ian E. , Harris Adrian L. , Dowsett Mitchell
Published: April 2023

Abstract
Purpose: The majority of breast cancer patients who have estrogen receptor positive (ER+) tumors whose proliferation is reduced after estrogen deprivation by aromatase inhibitors (AI). This study investigates any link between proliferation and hypoxia, a major determinant of tumor biology, and defines the effect of estrogen deprivation on hypoxia-associated genes.

Methods: Genome-wide expression profiles were obtained from tumor biopsies from 81 ER+ postmenopausal patients, before and after 2 weeks' anastrozole treatment. A hypoxia metagene was developed by identifying genes clustered with classical hypoxia-regulated genes, excluding those associated with proliferation. Proliferation was measured by Ki67 and a proliferation metagene derived from two published breast cancer data sets.

Results: Hypoxia and proliferation metagenes were associated at baseline (Pearson correlation coefficient, r = 0.67, P < 10−4) and after 2 weeks (r = 0.71, P < 10−4). Hypoxia metagene at baseline was associated with 2-week Ki67 (r = 0.43, P = 0.0002) and more weakly with poor 2-week Ki67 change consistent with a weak association with AI resistance. Hypoxia metagene was significantly downregulated with AI. This downregulation was significantly associated with change in the proliferation metagene and with Ki67 but, importantly, not with the substantial change in expression of classical estrogen-dependent genes.

Conclusions: Hypoxia metagene is closely associated with proliferation before and after AI treatment. The downregulation of hypoxia metagene after AI therapy is most likely the result of changes in proliferation. There may be a weak effect of hypoxia metagene on de novo resistance to AIs. These findings are important to consider in coapplication of antiproliferative agents with antiangiogenic or antihypoxia agents. Clin Cancer Res; 17(9); 3005–12. ©2011 AACR.
Data from IL-4R Drives Dedifferentiation, Mitogenesis, and Metastasis in Rhabdomyosarcoma
Authors: Hosoyama Tohru , Aslam Mohammed Imran , Abraham Jinu , Prajapati Suresh I. , Nishijo Koichi , Michalek Joel E. , Zarzabal Lee Ann , Nelon Laura D. , Guttridge Denis C. , Rubin Brian P. , Keller Charles
Published: April 2023

Abstract
Purpose: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. The alveolar subtype of rhabdomyosarcoma (ARMS) is a paradigm for refractory and incurable solid tumors because more than half of the children at diagnosis have either regional lymph node or distant metastases. These studies follow our previous observation that Interleukin-4 receptor α (IL-4Rα) is upregulated in both human and murine ARMS, and that the IL-4R signaling pathway may be a target for abrogating tumor progression.

Experimental Design: By in vitro biochemical and cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of IL-4 and IL-13 in IL-4R–mediated mitogenesis, myodifferentiation, and tumor progression.

Results: IL-4 and IL-13 ligands accelerated tumor cell growth and activated STAT6, Akt, or MAPK signaling pathways in the human RMS cell lines, RD and Rh30, as well as in mouse primary ARMS cell cultures. IL-4 and IL-13 treatment also decreased protein expression of myogenic differentiation factors MyoD and Myogenin, indicating a loss of muscle differentiation. Using a genetically engineered mouse model of ARMS, we have shown that inhibition of IL-4R signaling pathway with a neutralizing antibody has a profound effect on the frequency of lymph node and pulmonary metastases, resulting in significant survival extension in vivo.

Conclusions: Our results indicate that an IL-4R-dependent signaling pathway regulates tumor cell progression in RMS, and inhibition of this pathway could be a promising adjuvant therapeutic approach. Clin Cancer Res; 17(9); 2757–66. ©2011 AACR.
Data from Insulin-like Growth Factor 2 Expression Modulates Taxol Resistance and Is a Candidate Biomarker for Reduced Disease-Free Survival in Ovarian Cancer
Authors: Huang Gloria S. , Brouwer-Visser Jurriaan , Ramirez Marissa J. , Kim Christine H. , Hebert Tiffany M. , Lin Juan , Arias-Pulido Hugo , Qualls Clifford R. , Prossnitz Eric R. , Goldberg Gary L. , Smith Harriet O. , Horwitz Susan Band
Published: April 2023

Abstract
Purpose: This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors.

Experimental Design: The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phospho-AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. A type 1 IGF receptor (IGF1R) inhibitor, NVP-AEW541, and IGF2 small interfering RNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors and analyzed in relation to clinical/pathologic factors using the χ2 or Fisher's exact tests. The influence of IGF2 expression on survival was studied with Cox regression.

Results: Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (P < 0.001) and tumor grade (P < 0.01) and reduced disease-free survival (P < 0.05).

Conclusions: IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance. Clin Cancer Res; 16(11); 2999–3010. ©2010 AACR.
Data from Pharmacokinetic–Pharmacodynamic Analysis of Vismodegib in Preclinical Models of Mutational and Ligand-Dependent Hedgehog Pathway Activation
Authors: Wong Harvey , Alicke Bruno , West Kristina A. , Pacheco Patricia , La Hank , Januario Tom , Yauch Robert L. , de Sauvage Frederic J. , Gould Stephen E.
Published: April 2023

Abstract
Purpose: Vismodegib (GDC-0449) is a potent and selective inhibitor of the Hedgehog (Hh) pathway that shows antitumor activity in preclinical models driven by mutational or ligand-dependent activation of the Hh pathway. We wished to characterize the pharmacokinetic–pharmacodynamic (PK/PD) relationship of vismodegib in both model systems to guide optimal dose and schedule for vismodegib in the clinic.

Experimental Design: Preclinical efficacy and PK/PD studies were carried out with vismodegib in a Ptch+/− allograft model of medulloblastoma exhibiting mutational activation of the Hh pathway and patient-derived colorectal cancer (CRC) xenograft models exhibiting ligand-dependent pathway activation. Inhibition of the hedgehog pathway was related to vismodegib levels in plasma and to antitumor efficacy using an integrated population-based PK/PD model.

Results: Oral dosing of vismodegib caused tumor regressions in the Ptch+/− allograft model of medulloblastoma at doses ≥25 mg/kg and tumor growth inhibition at doses up to 92 mg/kg dosed twice daily in two ligand-dependent CRC models, D5123, and 1040830. Analysis of Hh pathway activity and PK/PD modeling reveals that vismodegib inhibits Gli1 with a similar IC50 in both the medulloblastoma and D5123 models (0.165 μmol/L ±11.5% and 0.267 μmol/L ±4.83%, respectively). Pathway modulation was linked to efficacy using an integrated PK/PD model revealing a steep relationship where > 50% of the activity of vismodegib is associated with >80% repression of the Hh pathway.

Conclusions: These results suggest that even small reductions in vismodegib exposure can lead to large changes in antitumor activity and will help guide proper dose selection for vismodegib in the clinic. Clin Cancer Res; 17(14); 4682–92. ©2011 AACR.
Data from CD44 Expression Predicts Local Recurrence after Radiotherapy in Larynx Cancer
Authors: de Jong Monique C. , Pramana Jimmy , van der Wal Jacqueline E. , Lacko Martin , Peutz-Kootstra Carine J. , de Jong Jos M. , Takes Robert P. , Kaanders Johannes H. , van der Laan Bernard F. , Wachters Jasper , Jansen Jeroen C. , Rasch Coen R. , van Velthuysen Marie-Louise F. , Grénman Reidar , Hoebers Frank J. , Schuuring Ed , van den Brekel Michiel W. , Begg Adrian C.
Published: April 2023

Abstract
Purpose: To find molecular markers from expression profiling data to predict recurrence of laryngeal cancer after radiotherapy.

Experimental Design: We generated gene expression data on pre-treatment biopsies from 52 larynx cancer patients. Patients developing a local recurrence were matched for T-stage, subsite, treatment, gender and age with non-recurrence patients. Candidate genes were then tested by immunohistochemistry on tumor material from a second series of 76 patients. Both series comprised early stage cancer treated with radiotherapy alone. Finally, gene expression data of eight larynx cancer cell lines with known radiosensitivity were analyzed.

Results: Nineteen patients with a local recurrence were matched with 33 controls. Gene sets for hypoxia, proliferation and intrinsic radiosensitivity did not correlate with recurrence, whereas expression of the putative stem cell marker CD44 did. In a supervised analysis, probes for all three splice variants of CD44 on the array appeared in the top 10 most significantly correlated with local recurrence. Immunohistochemical analysis of CD44 expression on the independent validation series confirmed CD44's predictive potential. In 8 larynx cancer cell lines, CD44 gene expression did not correlate with intrinsic radiosensitivity although it did correlate significantly with plating efficiency, consistent with a relationship with stem cell content.

Conclusions: CD44 was the only biological factor tested which significantly correlated with response to radiotherapy in early stage larynx cancer patients, both at the mRNA and protein levels. Further studies are needed to confirm this and to assess how general these findings are for other head and neck tumor stages and sites. Clin Cancer Res; 16(21); 5329–38. ©2010 AACR.
Data from Phase I Study of Decitabine in Combination with Vorinostat in Patients with Advanced Solid Tumors and Non-Hodgkin's Lymphomas
Authors: Stathis Anastasios , Hotte Sebastien J. , Chen Eric X. , Hirte Holger W. , Oza Amit M. , Moretto Patricia , Webster Sheila , Laughlin Anne , Stayner Lee-Anne , McGill Shauna , Wang Lisa , Zhang Wen-jiang , Espinoza-Delgado Igor , Holleran Julianne L. , Egorin Merrill J. , Siu Lillian L.
Published: April 2023

Abstract
Purpose: This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat.

Patients and Methods: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied.

Results: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m2/day on days 1 to 5 and vorinostat 200 mg three times a day on days 6 to 12. The MTD on the concurrent schedule was decitabine 10 mg/m2/day on days 1 to 5 with vorinostat 200 mg twice a day on days 3 to 9. However, the sequential schedule of decitabine 10 mg/m2/day on days 1 to 5 and vorinostat 200 mg twice a day on days 6 to 12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12 of 42 (29%) patients evaluable for toxicity. The most common grade 3 or higher adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for 4 cycles or more was observed in 11 of 38 (29%) evaluable patients.

Conclusion: The combination of decitabine with vorinostat is tolerable on both concurrent and sequential schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types. Clin Cancer Res; 17(6); 1582–90. ©2011 AACR.
Data from Prognostic Utility of Anti-EBV Antibody Testing for Defining NPC Risk among Individuals from High-Risk NPC Families
Authors: Yu Kelly J. , Hsu Wan-Lun , Pfeiffer Ruth M. , Chiang Chun-Ju , Wang Cheng-Ping , Lou Pei-Jen , Cheng Yu-Juen , Gravitt Patti , Diehl Scott R. , Goldstein Alisa M. , Chen Chien-Jen , Hildesheim Allan
Published: April 2023

Abstract
Purpose: Epstein–Barr virus (EBV) infection and a family history of nasopharyngeal carcinoma (NPC) are associated with NPC risk. We examined the risk associated with EBV markers and their clinical utility to identify NPC susceptibles within high-risk NPC families.

Experimental Design: We evaluated antibody titers against viral capsid antigen (VCA) IgA, EBV nuclear antigen-1 (EBNA1) IgA, and DNase among unaffected relatives of NPC cases from 358 multiplex families in Taiwan. Incident NPC cases were identified via linkage to the National Cancer Registry. Clinical examinations of 924 individuals were also done to identify occult, asymptomatic NPC. Baseline EBV serology was used to estimate NPC risk using rate ratios with 95% CI. Associated sensitivity/specificity and receiver operating characteristic (ROC) curves were calculated.

Results: A total of 2,444 unaffected individuals with 15,519 person-years (6.5 years median follow-up) yielded 14 incident NPC cases (nearly 11 times the general population rate). The absolute rate of NPC among anti-EBV EBNA1 IgA seropositives using a standard positivity cutoff versus an optimized cutoff point defined by ROC analyses was 265/100,000 person-years with a 4.7-fold increased risk of NPC (95% CI: 1.4–16) and 166/100,000 person-years with a 6.6-fold increase (95% CI: 1.5–61), respectively. Sensitivity and specificity using the optimized positivity cutoff points were 85.7% and 51.2%, respectively. It is estimated that active evaluation of 49% of individuals from high-risk NPC families seropositive for this marker could lead to earlier detection of up to 86% of NPC cases. Risks associated with the other three EBV markers were weaker.

Conclusions: Future efforts are needed to identify susceptibility markers among high-risk NPC families that maximize both sensitivity and specificity. Clin Cancer Res; 17(7); 1906–14. ©2011 AACR.
Data from Targeted Gene Silencing Using RGD-Labeled Chitosan Nanoparticles
Authors: Han Hee Dong , Mangala Lingegowda S. , Lee Jeong Won , Shahzad Mian M.K. , Kim Hye Sun , Shen Deyu , Nam Eun Ji , Mora Edna M. , Stone Rebecca L. , Lu Chunhua , Lee Sun Joo , Roh Ju Won , Nick Alpa M. , Lopez-Berestein Gabriel , Sood Anil K.
Published: April 2023

Abstract
Purpose: This study aimed to develop an Arg-Gly-Asp (RGD) peptide-labeled chitosan nanoparticle (RGD-CH-NP) as a novel tumor targeted delivery system for short interfering RNA (siRNA).

Experimental Design: RGD peptide conjugated with chitosan by thiolation reaction was confirmed by proton-NMR (H-NMR). Binding of RGD-CH-NP with ανβ3 integrin was examined by flow cytometry and fluorescence microscopy. Antitumor efficacy was examined in orthotopic mouse models of ovarian carcinoma.

Results: We show that RGD-CH-NP loaded with siRNA significantly increased selective intratumoral delivery in orthotopic animal models of ovarian cancer. In addition, we show targeted silencing of multiple growth-promoting genes (POSTN, FAK, and PLXDC1) along with therapeutic efficacy in the SKOV3ip1, HeyA8, and A2780 models using siRNA incorporated into RGD-CH-NP (siRNA/RGD-CH-NP). Furthermore, we show in vivo tumor vascular targeting using RGD-CH-NP by delivering PLXDC1-targeted siRNA into the ανβ3 integrin–positive tumor endothelial cells in the A2780 tumor-bearing mice. This approach resulted in significant inhibition of tumor growth compared with controls.

Conclusions: This study shows that RGD-CH-NP is a novel and highly selective delivery system for siRNA with the potential for broad applications in human disease. Clin Cancer Res; 16(15); 3910–22. ©2010 AACR.
Data from Oncogenic B-RAF Signaling in Melanoma Impairs the Therapeutic Advantage of Autophagy Inhibition
Authors: Armstrong Jane L. , Corazzari Marco , Martin Shaun , Pagliarini Vittoria , Falasca Laura , Hill David S. , Ellis Nicola , Al Sabah Salim , Redfern Christopher P.F. , Fimia Gian Maria , Piacentini Mauro , Lovat Penny E.
Published: April 2023

Abstract
Purpose: Metastatic melanoma is characterized by extremely poor survival rates and hence novel therapies are urgently required. The ability of many anticancer drugs to activate autophagy, a lysosomal-mediated catabolic process which usually promotes cell survival, suggests targeting the autophagy pathway may be a novel means to augment therapy.

Experimental Design: Autophagy and apoptosis were assessed in vitro in human melanoma cell lines in response to clinically achievable concentrations of the endoplasmic reticulum (ER) stress-inducing drugs fenretinide or bortezomib, and in vivo using a s.c. xenograft model.

Results: Autophagy was activated in response to fenretinide or bortezomib in B-RAF wild-type cells, shown by increased conversion of LC3 to the autophagic vesicle-associated form (LC3-II) and redistribution to autophagosomes and autolysosomes, increased acidic vesicular organelle formation and autophagic vacuolization. In contrast, autophagy was significantly reduced in B-RAF–mutated melanoma cells, an effect attributed partly to oncogenic B-RAF. Rapamycin treatment was unable to stimulate LC3-II accumulation or redistribution in the presence of mutated B-RAF, indicative of de-regulated mTORC1-dependent autophagy. Knockdown of Beclin-1 or ATG7 sensitized B-RAF wild-type cells to fenretinide- or bortezomib-induced cell death, demonstrating a pro-survival function of autophagy. In addition, autophagy was partially reactivated in B-RAF–mutated cells treated with the BH3 mimetic ABT737 in combination with fenretinide or bortezomib, suggesting autophagy resistance is partly mediated by abrogated Beclin-1 function.

Conclusions: Our findings suggest inhibition of autophagy in combination with ER stress-inducing agents may represent a means by which to harness autophagy for the therapeutic benefit of B-RAF wild-type melanoma. Clin Cancer Res; 17(8); 2216–26. ©2011 AACR.
Data from Functional Roles of Src and Fgr in Ovarian Carcinoma
Authors: Kim Hye-Sun , Han Hee Dong , Armaiz-Pena Guillermo N. , Stone Rebecca L. , Nam Eun Ji , Lee Jeong-Won , Shahzad Mian M. K. , Nick Alpa M. , Lee Sun Joo , Roh Ju-Won , Nishimura Masato , Mangala Lingegowda S. , Bottsford-Miller Justin , Gallick Gary E. , Lopez-Berestein Gabriel , Sood Anil K.
Published: April 2023

Abstract
Purpose:Src is an attractive target because it is overexpressed in a number of malignancies, including ovarian cancer. However, the effect of Src silencing on other Src family kinases (SFKs) is not known. We hypothesized that other SFK members could compensate for the lack of Src activity.

Experimental Design: Cell viability after either Src or Fgr silencing was examined in ovarian cancer cell lines by MTT assay. Expression of SFKs after Src silencing in ovarian cancer cells was examined by real-time reverse transcriptase (RT)-PCR. Therapeutic effect of in vivo Src and/or Fgr silencing was examined using siRNA incorporated into chitosan nanoparticles (siRNA/CH-NP). Microvessel density, cell proliferation, and apoptosis markers were determined by immunohistochemical staining in ovarian tumor tissues.

Results:Src silencing enhanced cytotoxicity of docetaxel in both SKOV3ip1 and HeyA8 cells. In addition, Src silencing using siRNA/CH-NP in combination with docetaxel resulted in significant inhibition of tumor growth compared with control siRNA/CH-NP (81.8% reduction in SKOV3ip1, P = 0.017; 84.3% reduction in HeyA8, P < 0.005). These effects were mediated by decreased tumor cell proliferation and angiogenesis, and increased tumor cell apoptosis. Next, we assessed the effects of Src silencing on other SFK members in ovarian cancer cell lines. Src silencing resulted in significantly increased Fgr levels. Dual Src and Fgr silencing in vitro resulted in increased apoptosis that was mediated by increased caspase and AKT activity. In addition, dual silencing of Src and Fgr in vivo using siRNA/CH-NP resulted in the greatest reduction in tumor growth compared with silencing of either Src or Fgr alone in the HeyA8 model (68.8%, P < 0.05).

Conclusions: This study demonstrates that, in addition to Src, Fgr plays a biologically significant role in ovarian cancer growth and might represent an important target. Clin Cancer Res; 17(7); 1713–21. ©2011 AACR.
Data from Anti-GD3 Chimeric sFv-CD28/T-Cell Receptor ζ Designer T Cells for Treatment of Metastatic Melanoma and Other Neuroectodermal Tumors
Authors: Lo Agnes S.Y. , Ma Qiangzhong , Liu David L. , Junghans Richard P.
Published: April 2023

Abstract
Purpose: The aims of this study are to compare antitumor activities of two generations of GD3-specific chimeric antigen receptors (CAR) in human primary T lymphocytes in vitro and to evaluate the antitumor efficacy of using a combination of systemic infusion of interleukin-2 (IL2) and designer T cells to eradicate subcutaneous established GD3+ melanoma in nude mice.

Experimental Design: Antitumor activities were compared for two generations of designer T cells, the progenitor first-generation with immunoglobulin T-cell receptor (TCR) with Signal 1 and the second-generation designer T cells with Signal 1+2. Osmotic IL2 pumps were used to deliver the maximum tolerated dose of IL2 to enhance the antitumor effects of designer T cells on subcutaneous established melanoma in nude mice.

Results: Melanoma is associated with high expression of ganglioside GD3, which has been targeted with modest effect in antibody therapies. We previously showed that an anti-GD3 CAR (sFv-TCRζ) will recruit T cells to target this non–T-dependent antigen, with potent killing of melanoma cells. Here, we report the addition of a CD28 costimulation domain to create a second-generation CAR, called Tandem for two signals. We show that this Tandem sFv-CD28/TCRζ receptor on T cells confers advantages of improved cytokine secretion, cytotoxicity, proliferation, and clonal expansion on tumor contact versus the same CAR without costimulation. In an adoptive transfer model using established melanoma tumors, designer T cells with CD28 showed a 50% rate of complete remissions but only where IL2 was supplemented.

Conclusions: As a reagent for clinical development, the second-generation product is shown to have superior properties to warrant its preference for clinical designer T-cell immunotherapy for melanoma and other tumors. Systemic IL2 was required for optimal activity in an established tumor model. Clin Cancer Res; 16(10); 2769–80. ©2010 AACR.
Data from AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer
Authors: Hickinson D. Mark , Klinowska Teresa , Speake Georgina , Vincent John , Trigwell Cath , Anderton Judith , Beck Sarah , Marshall Gayle , Davenport Sara , Callis Rowena , Mills Elizabeth , Grosios Konstantina , Smith Paul , Barlaam Bernard , Wilkinson Robert W. , Ogilvie Donald
Published: April 2023

Abstract
Purpose: To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo.

Experimental Design: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors.

Results: In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC50, 4 nmol/L), erbB2 (IC50, 3 nmol/L), and erbB3 (IC50, 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non–small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.

Conclusions: AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2. Clin Cancer Res; 16(4); 1159–69
Data from Evaluation of a 30-Gene Paclitaxel, Fluorouracil, Doxorubicin, and Cyclophosphamide Chemotherapy Response Predictor in a Multicenter Randomized Trial in Breast Cancer
Authors: Tabchy Adel , Valero Vicente , Vidaurre Tatiana , Lluch Ana , Gomez Henry , Martin Miguel , Qi Yuan , Barajas-Figueroa Luis Javier , Souchon Eduardo , Coutant Charles , Doimi Franco D. , Ibrahim Nuhad K. , Gong Yun , Hortobagyi Gabriel N. , Hess Kenneth R. , Symmans W. Fraser , Pusztai Lajos
Published: April 2023

Abstract
Purpose: We examined in a prospective, randomized, international clinical trial the performance of a previously defined 30-gene predictor (DLDA-30) of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide (T/FAC) chemotherapy, and assessed if DLDA-30 also predicts increased sensitivity to FAC-only chemotherapy. We compared the pCR rates after T/FAC versus FACx6 preoperative chemotherapy. We also did an exploratory analysis to identify novel candidate genes that differentially predict response in the two treatment arms.

Experimental Design: Two hundred and seventy-three patients were randomly assigned to receive either weekly paclitaxel × 12 followed by FAC × 4 (T/FAC, n = 138), or FAC × 6 (n = 135) neoadjuvant chemotherapy. All patients underwent a pretreatment fine-needle aspiration biopsy of the tumor for gene expression profiling and treatment response prediction.

Results: The pCR rates were 19% and 9% in the T/FAC and FAC arms, respectively (P < 0.05). In the T/FAC arm, the positive predictive value (PPV) of the genomic predictor was 38% [95% confidence interval (95% CI), 21-56%], the negative predictive value was 88% (95% CI, 77-95%), and the area under the receiver operating characteristic curve (AUC) was 0.711. In the FAC arm, the PPV was 9% (95% CI, 1-29%) and the AUC was 0.584. This suggests that the genomic predictor may have regimen specificity. Its performance was similar to a clinical variable–based predictor nomogram.

Conclusions: Gene expression profiling for prospective response prediction was feasible in this international trial. The 30-gene predictor can identify patients with greater than average sensitivity to T/FAC chemotherapy. However, it captured molecular equivalents of clinical phenotype. Next-generation predictive markers will need to be developed separately for different molecular subsets of breast cancers. Clin Cancer Res; 16(21); 5351–61. ©2010 AACR.
Data from Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements
Authors: Hayes D. Neil , Lucas Amy S. , Tanvetyanon Tawee , Krzyzanowska Monika K. , Chung Christine H. , Murphy Barbara A. , Gilbert Jill , Mehra Ranee , Moore Dominic T. , Sheikh Arif , Hoskins Janelle , Hayward Michele C. , Zhao Ni , O'Connor Wendi , Weck Karen E. , Cohen Roger B. , Cohen Ezra E.W.
Published: April 2023

Abstract
Purpose: A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC).

Experimental Design: Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed.

Results: Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The most common adverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug.

Conclusions: Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome. Clin Cancer Res; 18(7); 2056–65. ©2012 AACR.
Data from Phase I and Pharmacokinetic Study of CT-322 (BMS-844203), a Targeted Adnectin Inhibitor of VEGFR-2 Based on a Domain of Human Fibronectin
Authors: Tolcher Anthony W. , Sweeney Christopher J. , Papadopoulos Kyri , Patnaik Amita , Chiorean Elena G. , Mita Alain C. , Sankhala Kamalesh , Furfine Eric , Gokemeijer Jochem , Iacono Lisa , Eaton Cheryl , Silver Bruce A. , Mita Monica
Published: April 2023

Abstract
Purpose: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain–based targeted biologic (Adnectin) to enter clinical studies.

Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies.

Results: Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti–CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease.

Conclusions: CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics. Cancer Res; 17(2); 363–71. ©2011 AACR. Clin Cancer Res; 17(2); 363–71. ©2011 AACR.