bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Phase II and Biomarker Study of Ramucirumab, a Human Monoclonal Antibody Targeting the VEGF Receptor-2, as First-Line Monotherapy in Patients with Advanced Hepatocellular Cancer
Authors: Zhu Andrew X. , Finn Richard S. , Mulcahy Mary , Gurtler Jayne , Sun Weijing , Schwartz Jonathan D. , Dalal Rita P. , Joshi Adarsh , Hozak Rebecca R. , Xu Yihuan , Ancukiewicz Marek , Jain Rakesh K. , Nugent Francis W. , Duda Dan G. , Stuart Keith
Published: April 2023

Abstract
Purpose: To assess the efficacy and safety of the anti-VEGF receptor-2 (VEGFR-2) antibody ramucirumab as first-line therapy in patients with advanced hepatocellular carcinoma and explore potential circulating biomarkers.

Experimental Design: Adults with advanced hepatocellular carcinoma and no prior systemic treatment received ramucirumab 8 mg/kg every two weeks until disease progression or limiting toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients.

Results: Forty-two patients received ramucirumab. Median PFS was 4.0 months [95% confidence interval (CI), 2.6–5.7], ORR was 9.5% (95% CI, 2.7–22.6; 4/42 patients had a partial response), and median OS was 12.0 months (95% CI, 6.1–19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95% CI, 0.5–9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1–23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade ≥3 toxicities included hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%). There was one treatment-related death (gastrointestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2.

Conclusion: Ramucirumab monotherapy may confer anticancer activity in advanced hepatocellular carcinoma with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and sVEGFR-2 that are consistent with those seen with other anti-VEGF agents. Clin Cancer Res; 19(23); 6614–23. ©2013 AACR.
Data from Interleukin-32 Increases Human Gastric Cancer Cell Invasion Associated with Tumor Progression and Metastasis
Authors: Tsai Chung-Ying , Wang Chia-Siu , Tsai Ming-Ming , Chi Hsiang-Cheng , Cheng Wan-Li , Tseng Yi-Hsin , Chen Cheng-Yi , Lin Crystal D. , Wu Jun-I. , Wang Lu-Hai , Lin Kwang-Huei
Published: April 2023

Abstract
Purpose: The proinflammatory cytokine interleukin-32 (IL-32) is a novel tumor marker highly expressed in various human carcinomas, including gastric cancer. However, its effects on prognosis of patients with gastric cancer and cancer metastasis are virtually unknown at present. The main aim of this study was to explore the clinical significance of IL-32 in gastric cancer and further elucidate the molecular mechanisms underlying IL-32–mediated migration and invasion.

Experimental Design: Gastric cancer cells with ectopic expression or silencing of IL-32 were examined to identify downstream molecules and establish their effects on cell motility, invasion, and lung metastasis in vivo.

Results: IL-32 was significantly upregulated in gastric cancer and positively correlated with aggressiveness of cancer and poor prognosis. Ectopic expression of IL-32 induced elongated morphology and increased cell migration and invasion via induction of IL-8, VEGF, matrix metalloproteinase 2 (MMP2), and MMP9 expression via phosphor-AKT/phospho-glycogen synthase kinase 3β/active β-catenin as well as hypoxia-inducible factor 1α (HIF-1α) signaling pathways. Conversely, depletion of IL-32 in gastric cancer cells reversed these effects and decreased lung colonization in vivo. Examination of gene expression datasets in oncomine and staining of gastric cancer specimens demonstrated the clinical significance of IL-32 and its downstream molecules by providing information on their coexpression patterns.

Conclusions: IL-32 contributes to gastric cancer progression by increasing the metastatic potential resulting from AKT, β-catenin, and HIF-1α activation. Our results clearly suggest that IL-32 is an important mediator for gastric cancer metastasis and independent prognostic predictor of gastric cancer. Clin Cancer Res; 20(9); 2276–88. ©2014 AACR.
Data from Dual Blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) Pathways Synergistically Inhibits Rhabdomyosarcoma Cell Growth In Vitro and In Vivo
Authors: Renshaw Jane , Taylor Kathryn R. , Bishop Ryan , Valenti Melanie , De Haven Brandon Alexis , Gowan Sharon , Eccles Suzanne A. , Ruddle Ruth R. , Johnson Louise D. , Raynaud Florence I. , Selfe Joanna L. , Thway Khin , Pietsch Torsten , Pearson Andrew D. , Shipley Janet
Published: April 2023

Abstract
Purpose: To provide rationale for using phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathway inhibitors to treat rhabdomyosarcomas, a major cause of pediatric and adolescent cancer deaths.

Experimental Design: The prevalence of PI3K/MAPK pathway activation in rhabdomyosarcoma clinical samples was assessed using immunohistochemistry. Compensatory signaling and cross-talk between PI3K/MAPK pathways was determined in rhabdomyosarcoma cell lines following p110α short hairpin RNA–mediated depletion. Pharmacologic inhibition of reprogrammed signaling in stable p110α knockdown lines was used to determine the target-inhibition profile inducing maximal growth inhibition. The in vitro and in vivo efficacy of inhibitors of TORC1/2 (AZD8055), MEK (AZD6244), and P13K/mTOR (NVP-BEZ235) was evaluated alone and in pairwise combinations.

Results: PI3K pathway activation was seen in 82.5% rhabdomyosarcomas with coactivated MAPK in 36% and 46% of alveolar and embryonal subtypes, respectively. p110α knockdown in cell lines over the short and long term was associated with compensatory expression of other p110 isoforms, activation of the MAPK pathway, and cross-talk to reactivate the PI3K pathway. Combinations of PI3K pathway and MAP–ERK kinase (MEK) inhibitors synergistically inhibited cell growth in vitro. Treatment of RD cells with AZD8055 plus AZD6244 blocked reciprocal pathway activation, as evidenced by reduced AKT/ERK/S6 phosphorylation. In vivo, the synergistic effect on growth and changes in pharmacodynamic biomarkers was recapitulated using the AZD8055/AZD6244 combination but not NVP-BEZ235/AZD6244. Pharmacokinetic analysis provided evidence of drug–drug interaction with both combinations.

Conclusions: Dual PI3K/MAPK pathway activation and compensatory signaling in both rhabdomyosarcoma subtypes predict a lack of clinical efficacy for single agents targeting either pathway, supporting a therapeutic strategy combining a TORC1/2 with a MEK inhibitor. Clin Cancer Res; 19(21); 5940–51. ©2013 AACR.
Data from Germline and Somatic Mutations in Homologous Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and Peritoneal Carcinomas
Authors: Pennington Kathryn P. , Walsh Tom , Harrell Maria I. , Lee Ming K. , Pennil Christopher C. , Rendi Mara H. , Thornton Anne , Norquist Barbara M. , Casadei Silvia , Nord Alexander S. , Agnew Kathy J. , Pritchard Colin C. , Scroggins Sheena , Garcia Rochelle L. , King Mary-Claire , Swisher Elizabeth M.
Published: April 2023

Abstract
Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain.

Experimental Design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway.

Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation.

Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials. Clin Cancer Res; 20(3); 764–75. ©2013 AACR.
Data from Frequent Overexpression of HMGA2 in Human Atypical Teratoid/Rhabdoid Tumor and Its Correlation with let-7a3/let-7b miRNA
Authors: Zhang Keqiang , Gao Hanlin , Wu Xiwei , Wang Jinhui , Zhou Wendi , Sun Guihua , Wang Jinghan , Wang Yafan , Mu Bing , Kim Charles , Chu Peiguo , Ho Donald M. , Ann David K. , Wong Tai-Tong , Yen Yun
Published: April 2023

Abstract
Purpose: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive pediatric malignancies characterized by biallelic inactivation of the SMARCB1 tumor suppressor gene. We searched for novel genomic aberrations by investigating the copy number and expression alterations of let-7a3/let-7b microRNA (miRNA) and correlated these with expression of high-mobility group AT-hook 2 (HMGA2) oncoprotein, a target of let-7 miRNA family, in 18 AT/RT samples to elucidate potential roles of HMGA2 in the pathogenesis of AT/RT.

Experimental Design: Genomic aberrations, let-7a3/let-7b miRNA and HMGA2 expression in AT/RT tissues were identified using quantitative PCR, reverse transcription PCR (RT-PCR), and immunohistochemistry. The impact of let-7b miRNA on HMGA2 expression and the malignant potential of human rhabdoid tumor cell G401 (SMARCB1−/−) were investigated by antisense inhibition and ectopic overexpression studies.

Results: The copy number of let-7a3/let-7b miRNA was substantially decreased in 4 of 11 AT/RT samples. A significantly inverse correlation between let-7a3/let-7b miRNA expression and HMGA2 mRNA expression was observed in AT/RT tissues (R = −0.34; P < 0.05). Immunohistochemistry analysis demonstrated that HMGA2 was highly overexpressed in 83.3% (15 of 18) of AT/RT tissues. Restoration of let-7 miRNA or knockdown of HMGA2 expression significantly suppressed proliferation and colony formation, and almost abolished the invasive potential of G401 cells.

Conclusion: Reduction of let-7a3/let-7b miRNA may be one of mechanisms leading to overexpression of HMGA2 in AT/RT tissues. HMGA2 oncoprotein plays critical roles in the pathogenesis of AT/RT development; and reconstitution of let-7 miRNA or knockdown of HMGA2 oncoprotein may provide a novel therapeutic strategy for the treatment of patients with AT/RT. Clin Cancer Res; 20(5); 1179–89. ©2014 AACR.
Data from The High-Affinity CXCR4 Antagonist BKT140 Is Safe and Induces a Robust Mobilization of Human CD34+ Cells in Patients with Multiple Myeloma
Authors: Peled Amnon , Abraham Michal , Avivi Irit , Rowe Jacob M. , Beider Katia , Wald Hanna , Tiomkin Lena , Ribakovsky Lena , Riback Yossi , Ramati Yaron , Aviel Sigal , Galun Eithan , Shaw Howard Laurence , Eizenberg Orly , Hardan Izhar , Shimoni Avichai , Nagler Arnon
Published: April 2023

Abstract
Purpose: CXCR4 plays an important role in the retention of stem cells within the bone marrow. BKT140 (4F-benzoyl-TN14003) is a 14-residue bio stable synthetic peptide, which binds CXCR4 with a greater affinity compared with plerixafor (4 vs. 84 nmol/L). Studies in mice demonstrated the efficient and superior mobilization and transplantation of stem cells collected with GCSF-BKT140, compared with those obtained when using stem cells obtained with each one of these mobilizing agent alone. These results have served as a platform for the present clinical phase I study.

Experimental Design: Eighteen patients with multiple myeloma who were preparing for their first autologous stem cell transplantation were included. Patients received a standard multiple myeloma mobilization regimen, consisting of 3 to 4 g/m2 cyclophosphamide (day 0), followed by granulocyte colony—stimulating factor (G-CSF) at 5 μg/kg/d starting on day 5 and administered between 8 and 10 pm until the end of stem cell collection. A single injection of BKT140 (0.006, 0.03, 0.1, 0.3, and 0.9 mg/kg) was administered subcutaneously on day 10 in the early morning, followed by G-CSF 12 hours later.

Results: BKT140 was well tolerated at all concentrations, and none of the patients developed grade 3 and 4 toxicity. A single administration of BKT140 at the highest dose, 0.9 mg/kg, resulted in a robust mobilization and collection of CD34+ cells (20.6 ± 6.9 × 106/kg), which were obtained through a single apheresis. All transplanted patients received ∼5.3 × 106 CD34+ cells/kg, which rapidly engrafted (n = 17). The median time to neutrophil and platelet recovery was 12 and 14 days, respectively, at the highest dose (0.9 mg/kg).

Conclusions: When combined with G-CSF, BKT140 is a safe and efficient stem cell mobilizer that enabled the collection of a high number of CD34+ cells in 1 and 2 aphaeresis procedures, resulting in successful engraftment. Clin Cancer Res; 20(2); 469–79. ©2013 AACR.
Data from GKN1–miR-185–DNMT1 Axis Suppresses Gastric Carcinogenesis through Regulation of Epigenetic Alteration and Cell Cycle
Authors: Yoon Jung Hwan , Choi Yoo Jin , Choi Won Suk , Ashktorab Hassan , Smoot Duane T. , Nam Suk Woo , Lee Jung Young , Park Won Sang
Published: April 2023

Abstract
Purpose: Gastrokine 1 (GKN1) functions to protect the gastric antral mucosa and promotes healing by facilitating restoration and proliferation after injury. GKN1 is downregulated in Helicobacter pylori–infected gastric epithelial cells and loss of GKN1 expression is closely associated with gastric carcinogenesis, but underlying mechanisms of the tumor-suppressing effects of GKN1 remain largely unknown.

Experimental Design: AGS, MKN1, MKN28 gastric cancer cells and HFE-145 immortalized non-neoplastic gastric mucosal cells were transfected with GKN1 or shGKN1. We conducted molecular and functional studies of GKN1 and miR-185 and investigated the mechanisms of alteration. We also analyzed epigenetic alterations in 80 gastric cancer tissues.

Results: Restoration of GKN1 protein suppressed gastric cancer cell growth by inducing endogenous miR-185 that directly targets epigenetic effectors DNMT1 and EZH2 in gastric cancer cells. In addition, ectopic expression of GKN1 upregulated Tip60 and downregulated HDAC1 in an miR-185–independent manner, thereby inducing cell-cycle arrest by regulating cell-cycle proteins in gastric cancer cells. Notably, GKN1 expression was inversely correlated with DNMT1 and EZH2 expression in a subset of 80 gastric cancer tissues and various gastric cancer cell lines. Interestingly, it was found that GKN1 exerted a synergistic anti-cancerous effect with 5-fluorouracil on tumor cell growth, which suggests a possible therapeutic intervention method for gastric cancer.

Conclusion: Our results show that GKN1 has an miR-185–dependent and -independent mechanism for chromatic and DNA epigenetic modification, thereby regulating the cell cycle. Thus, the loss of GKN1 function contributes to malignant transformation and proliferation of gastric epithelial cells in gastric carcinogenesis. Clin Cancer Res; 19(17); 4599–610. ©2013 AACR.
Data from Elevated TNFR1 and Serotonin in Bone Metastasis Are Correlated with Poor Survival following Bone Metastasis Diagnosis for Both Carcinoma and Sarcoma Primary Tumors
Authors: Chiechi Antonella , Novello Chiara , Magagnoli Giovanna , Petricoin Emanuel F. , Deng Jianghong , Benassi Maria S. , Picci Piero , Vaisman Iosif , Espina Virginia , Liotta Lance A.
Published: April 2023

Abstract
Purpose: There is an urgent need for therapies that will reduce the mortality of patients with bone metastasis. In this study, we profiled the protein signal pathway networks of the human bone metastasis microenvironment. The goal was to identify sets of interacting proteins that correlate with survival time following the first diagnosis of bone metastasis.

Experimental Design: Using Reverse Phase Protein Microarray technology, we measured the expression of 88 end points in the bone microenvironment of 159 bone metastasis tissue samples derived from patients with primary carcinomas and sarcomas.

Results: Metastases originating from different primary tumors showed similar levels of cell signaling across tissue types for the majority of proteins analyzed, suggesting that the bone microenvironment strongly influences the metastatic tumor signaling profiles. In a training set (72 samples), TNF receptor 1, alone (P = 0.0013) or combined with serotonin (P = 0.0004), TNFα (P = 0.0214), and RANK (P = 0.0226), was associated with poor survival, regardless of the primary tumor of origin. Results were confirmed by (i) analysis of an independent validation set (71 samples) and (ii) independent bioinformatic analysis using a support vector machine learning model. Spearman rho analysis revealed a highly significant number of interactions intersecting with ERα S118, serotonin, TNFα, RANKL, and matrix metalloproteinase in the bone metastasis signaling network, regardless of the primary tumor. The interaction network pattern was significantly different in the short versus long survivors.

Conclusions: TNF receptor 1 and neuroendocrine-regulated protein signal pathways seem to play an important role in bone metastasis and may constitute a novel drug-targetable mechanism of seed-soil cross talk in bone metastasis. Clin Cancer Res; 19(9); 2473–85. ©2013 AACR.
Data from Increased CDA Expression/Activity in Males Contributes to Decreased Cytidine Analog Half-Life and Likely Contributes to Worse Outcomes with 5-Azacytidine or Decitabine Therapy
Authors: Mahfouz Reda Z. , Jankowska Ania , Ebrahem Quteba , Gu Xiaorong , Visconte Valeria , Tabarroki Ali , Terse Pramod , Covey Joseph , Chan Kenneth , Ling Yonghua , Engelke Kory J. , Sekeres Mikkael A. , Tiu Ramon , Maciejewski Jaroslaw , Radivoyevitch Tomas , Saunthararajah Yogen
Published: April 2023

Abstract
Purpose: The cytidine analogs 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), produce a molecular epigenetic effect, depletion of DNA-methyltransferase 1 (DNMT1). This action is S-phase dependent. Hence, genetic factors that decrease the half-lives of these drugs could impact efficacy. Documentation of such impact, and elucidation of underlying mechanisms, could lead to improved clinical application.

Experimental design: Cytidine deaminase (CDA) rapidly inactivates 5-azacytidine/decitabine. The effect of CDA SNP A79C and gender on CDA expression, enzyme activity, and drug pharmacokinetics/pharmacodynamics was examined in mice and humans, and the impact on overall survival (OS) was evaluated in 5-azacytidine/decitabine-treated patients with MDS (n = 90) and cytarabine-treated patients with acute myeloid leukemia (AML) (n = 76).

Results: By high-performance liquid chromatography (HPLC), plasma CDA activity was decreased as expected in individuals with the SNP A79C. Interestingly and significantly, there was an even larger decrease in females than in males. Explaining this decrease, liver CDA expression was significantly lower in female versus male mice. As expected, decitabine plasma levels, measured by mass spectrometry, were significantly higher in females. In mathematical modeling, the detrimental impact of shorter drug half-life (e.g., in males) was greater in low compared with high S-phase fraction disease (e.g., MDS vs. AML), because in high S-phase fraction disease, even a short exposure treats a major portion of cells. Accordingly, in multivariate analysis, OS was significantly worse in male versus female patients with MDS treated with 5-azacytidine/decitabine.

Conclusions: Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy. Clin Cancer Res; 19(4); 938–48. ©2012 AACR.
Data from Phase I/II Trial of Orteronel (TAK-700)—an Investigational 17,20-Lyase Inhibitor—in Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Dreicer Robert , MacLean David , Suri Ajit , Stadler Walter M. , Shevrin Daniel , Hart Lowell , MacVicar Gary R. , Hamid Omid , Hainsworth John , Gross Mitchell E. , Shi Yuanjun , Webb Iain J. , Agus David B.
Published: April 2023

Abstract
Purpose: The androgen receptor pathway remains active in men with prostate cancer whose disease has progressed following surgical or medical castration. Orteronel (TAK-700) is an investigational, oral, nonsteroidal, selective, reversible inhibitor of 17,20-lyase, a key enzyme in the production of androgenic hormones.

Experimental Design: We conducted a phase I/II study in men with progressive, chemotherapy-naïve, metastatic castration-resistant prostate cancer, and serum testosterone <50 ng/dL. In the phase I part, patients received orteronel 100 to 600 mg twice daily or 400 mg twice a day plus prednisone 5 mg twice a day. In phase II, patients received orteronel 300 mg twice a day, 400 mg twice a day plus prednisone, 600 mg twice a day plus prednisone, or 600 mg once a day without prednisone.

Results: In phase I (n = 26), no dose-limiting toxicities were observed and 13 of 20 evaluable patients (65%) achieved ≥50% prostate-specific antigen (PSA) decline from baseline at 12 weeks. In phase II (n = 97), 45 of 84 evaluable patients (54%) achieved a ≥50% decline in PSA and at 12 weeks, substantial mean reductions from baseline in testosterone (−7.5 ng/dL) and dehydroepiandrosterone-sulfate (−45.3 μg/dL) were observed. Unconfirmed partial responses were reported in 10 of 51 evaluable phase II patients (20%). Decreases in circulating tumor cells were documented. Fifty-three percent of phase II patients experienced grade ≥3 adverse events irrespective of causality; most common were fatigue, hypokalemia, hyperglycemia, and diarrhea.

Conclusions: 17,20-Lyase inhibition by orteronel was tolerable and results in declines in PSA and testosterone, with evidence of radiographic responses. Clin Cancer Res; 20(5); 1335–44. ©2014 AACR.
Data from Contribution of Abcc4-Mediated Gastric Transport to the Absorption and Efficacy of Dasatinib
Authors: Furmanski Brian D. , Hu Shuiying , Fujita Ken-ichi , Li Lie , Gibson Alice A. , Janke Laura J. , Williams Richard T. , Schuetz John D. , Sparreboom Alex , Baker Sharyn D.
Published: April 2023

Abstract
Purpose: Several oral multikinase inhibitors are known to interact in vitro with the human ATP-binding cassette transporter ABCC4 (MRP4), but the in vivo relevance of this interaction remains poorly understood. We hypothesized that host ABCC4 activity may influence the pharmacokinetic profile of dasatinib and subsequently affect its antitumor properties.

Experimental Design: Transport of dasatinib was studied in cells transfected with human ABCC4 or the ortholog mouse transporter, Abcc4. Pharmacokinetic studies were done in wild-type and Abcc4-null mice. The influence of Abcc4 deficiency on dasatinib efficacy was evaluated in a model of Ph+ acute lymphoblastic leukemia by injection of luciferase-positive, p185(BCR-ABL)-expressing Arf(−/−) pre-B cells.

Results: Dasatinib accumulation was significantly changed in cells overexpressing ABCC4 or Abcc4 compared with control cells (P < 0.001). Deficiency of Abcc4 in vivo was associated with a 1.75-fold decrease in systemic exposure to oral dasatinib, but had no influence on the pharmacokinetics of intravenous dasatinib. Abcc4 was found to be highly expressed in the stomach, and dasatinib efflux from isolated mouse stomachs ex vivo was impaired by Abcc4 deficiency (P < 0.01), without any detectable changes in gastric pH. Abcc4-null mice receiving dasatinib had an increase in leukemic burden, based on bioluminescence imaging, and decreased overall survival compared with wild-type mice (P = 0.048).

Conclusions: This study suggests that Abcc4 in the stomach facilitates the oral absorption of dasatinib, and it possibly plays a similar role for other orally administered substrates, such as acetylsalicylic acid. This phenomenon also provides a mechanistic explanation for the malabsorption of certain drugs following gastric resection. Clin Cancer Res; 19(16); 4359–70. ©2013 AACR.
Data from Improved Differentiation of Benign and Malignant Breast Tumors with Multiparametric 18Fluorodeoxyglucose Positron Emission Tomography Magnetic Resonance Imaging: A Feasibility Study
Authors: Pinker Katja , Bogner Wolfgang , Baltzer Pascal , Karanikas Georgios , Magometschnigg Heinrich , Brader Peter , Gruber Stephan , Bickel Hubert , Dubsky Peter , Bago-Horvath Zsuzsanna , Bartsch Rupert , Weber Michael , Trattnig Siegfried , Helbich Thomas H.
Published: April 2023

Abstract
Purpose: To assess whether multiparametric 18fluorodeoxyglucose positron emission tomography magnetic resonance imaging (MRI) (MP 18FDG PET-MRI) using dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted imaging (DWI), three-dimensional proton MR spectroscopic imaging (3D 1H-MRSI), and 18FDG-PET enables an improved differentiation of benign and malignant breast tumors.

Experimental Design: Seventy-six female patients (mean age, 55.7 years; range, 25–86 years) with an imaging abnormality (BI-RADS 0, 4–5) were included in this Institutional Review Board (IRB)-approved study. Patients underwent fused PET-MRI of the breast with 18FDG-PET/CT and MP MRI at 3T. The likelihood of malignancy was assessed for all single parameters, for MP MRI with two/three parameters, and for MP 18FDG PET-MRI. Histopathology was used as the standard of reference. Appropriate statistical tests were used to assess sensitivity, specificity, and diagnostic accuracy for each assessment combination.

Results: There were 53 malignant and 23 benign breast lesions. MP 18FDG PET-MRI yielded a significantly higher area under the cure (AUC) of 0.935 than DCE-MRI (AUC, 0.86; P = 0.044) and the combination of DCE-MRI and another parameter (AUC, 0.761–0.826; P = 0.013–0.020). MP 18FDG PET-MRI showed slight further improvement to MP MRI with three parameters (AUC, 0.925; P = 0.317). Using MP 18FDG PET-MRI there would have been a reduction of the unnecessary breast biopsies recommended by MP imaging with one or two parameters (P = 0.002–0.011).

Conclusion: This feasibility study shows that MP 18FDG PET-MRI enables an improved differentiation of benign and malignant breast tumors when several MRI and PET parameters are combined. MP 18FDG PET-MRI may lead to a reduction in unnecessary breast biopsies. Clin Cancer Res; 20(13); 3540–9. ©2014 AACR.
Data from Phase I Trial of a New Schedule of Romidepsin in Patients with Advanced Cancers
Authors: Amiri-Kordestani Laleh , Luchenko Victoria , Peer Cody J. , Ghafourian Kambiz , Reynolds James , Draper Deb , Frye Robin , Woo Sue , Venzon David , Wright John , Skarulis Monica , Figg William D. , Fojo Tito , Bates Susan E. , Piekarz Richard L.
Published: April 2023

Abstract
Purpose: Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers.

Experimental Design: Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes.

Results: Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m2 on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors–defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21–112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases.

Conclusions: A romidepsin dose of 7 mg/m2 administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors. Clin Cancer Res; 19(16); 4499–507. ©2013 AACR.
Data from The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas
Authors: Gini Beatrice , Zanca Ciro , Guo Deliang , Matsutani Tomoo , Masui Kenta , Ikegami Shiro , Yang Huijun , Nathanson David , Villa Genaro R. , Shackelford David , Zhu Shaojun , Tanaka Kazuhiro , Babic Ivan , Akhavan David , Lin Kelly , Assuncao Alvaro , Gu Yuchao , Bonetti Bruno , Mortensen Deborah S. , Xu Shuichan , Raymon Heather K. , Cavenee Webster K. , Furnari Frank B. , James C. David , Kroemer Guido , Heath James R. , Hege Kristen , Chopra Rajesh , Cloughesy Timothy F. , Mischel Paul S.
Published: April 2023

Abstract
Purpose: mTOR pathway hyperactivation occurs in approximately 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here, we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacologic strategy to overcome it.

Experimental Design: We conducted in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin-resistant signaling and blocking glioblastoma growth and a novel single-cell technology—DNA Encoded Antibody Libraries—was used to identify mechanisms of resistance.

Results: Here, we show that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling, block mTORC2 signaling, and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2–induced cell death.

Conclusions: These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it. Clin Cancer Res; 19(20); 5722–32. ©2013 AACR.
Data from Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma
Authors: Atefi Mohammad , Avramis Earl , Lassen Amanda , Wong Deborah J.L. , Robert Lidia , Foulad David , Cerniglia Michael , Titz Bjoern , Chodon Thinle , Graeber Thomas G. , Comin-Anduix Begonya , Ribas Antoni
Published: April 2023

Abstract
Purpose: PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study, we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition.

Experimental Design: Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors (BRAFi). The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated.

Results: No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN, or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, whereas the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines, the effects of BRAF, MEK, and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INFγ. In PD-L1–exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines.

Conclusions: In melanoma cell lines, including BRAFi-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1–exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies. Clin Cancer Res; 20(13); 3446–57. ©2014 AACR.
Data from Neoadjuvant Imatinib in Advanced Primary or Locally Recurrent Dermatofibrosarcoma Protuberans: A Multicenter Phase II DeCOG Trial with Long-term Follow-up
Authors: Ugurel Selma , Mentzel Thomas , Utikal Jochen , Helmbold Peter , Mohr Peter , Pföhler Claudia , Schiller Meinhard , Hauschild Axel , Hein Rüdiger , Kämpgen Eckhardt , Kellner Ivonne , Leverkus Martin , Becker Jürgen C. , Ströbel Philip , Schadendorf Dirk
Published: April 2023

Abstract
Purpose: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor. COL1A1–PDGFB gene fusion is frequent in DFSP, rendering tumor cell proliferation and survival dependent on PDGFRβ (platelet-derived growth factor receptor β) signaling. This trial investigated imatinib as neoadjuvant treatment of DFSP, including long-term follow-up.

Experimental Design: The primary endpoint of this multicenter phase II trial was response; secondary endpoints were safety, tumor relapse, and response biomarkers. Patients with advanced primary or locally recurrent DFSP and measurable disease by RECIST (response evaluation criteria in solid tumors) were eligible and received imatinib 600 mg/d until definitive surgery with histopathologic proof of tumor-free margins.

Results: Sixteen patients received imatinib, and 14 patients were evaluable for all endpoints. Median treatment duration was 3.1 months; median tumor shrinkage was 31.5%. Best overall response was 7.1% complete response (CR), 50.0% partial response (PR), 35.7% stable disease, and 7.1% progressive disease (PD). Toxicity was moderate with 25.0% grade 3 and 4 events. During a median follow-up of 6.4 years, one patient developed secondary resistance to imatinib but responded to second-line sunitinib. This patient also presented local recurrence, distant metastasis, and death from DFSP. Exploratory analysis showed that response to imatinib was associated with decreased tumor cellularity and formation of strong hyalinic fibrosis. Weak PDGFRB phosphorylation and pigmented-type DFSP were associated with nonresponse. Additional to PDGFRB, the kinases EGFR and insulin receptor were found activated in a high percentage of DFSPs.

Conclusion: The neoadjuvant use of imatinib 600 mg/d in DFSP is efficacious and well tolerated. Long-term follow-up results do not definitely support smaller surgical margins after successful imatinib pretreatment, and presume that secondary resistance to imatinib might promote accelerated disease progression. Clin Cancer Res; 20(2); 499–510. ©2013 AACR.
Data from Characteristics and Clinical Impacts of the Immune Environments in Colorectal and Renal Cell Carcinoma Lung Metastases: Influence of Tumor Origin
Authors: Remark Romain , Alifano Marco , Cremer Isabelle , Lupo Audrey , Dieu-Nosjean Marie-Caroline , Riquet Marc , Crozet Lucile , Ouakrim Hanane , Goc Jeremy , Cazes Aurélie , Fléjou Jean-François , Gibault Laure , Verkarre Virginie , Régnard Jean-François , Pagès Olivier-Nicolas , Oudard Stéphane , Mlecnik Bernhard , Sautès-Fridman Catherine , Fridman Wolf-Herman , Damotte Diane
Published: April 2023

Abstract
Purpose: If immune cells are involved in tumor surveillance and have a prognostic impact in most primary tumors, little is known about their significance in metastases. Because patients' survival is heterogeneous, even at metastatic stages, we hypothesized that immune cells may be involved in the control of metastases. We therefore characterized the tumor immune microenvironment and its prognostic value in colorectal and renal cell carcinoma (RCC) metastases, and compared it to primary tumors.

Experimental Design: We analyzed by immunohistochemistry (n = 192) and qPCR (n = 32) the immune environments of colorectal carcinoma and RCC lung metastases.

Results: Metastases from colorectal carcinoma and RCC have different immune infiltrates. Higher densities of DC-LAMP+ mature dendritic cells (P < 0.0001) and lower densities of NKp46+ NK cells (P < 0.0001) were observed in colorectal carcinoma as compared to RCC metastases, whereas densities of T cells were similar. High densities of CD8+ and DC-LAMP+ cells correlated with longer overall survival (OS) in colorectal carcinoma (P = 0.008) and shorter OS in RCC (P < 0.0001). High NK-cell densities were associated with improved survival in RCC (P = 0.002) but not in colorectal carcinoma. Densities of immune cells correlated significantly from primary to relapsing metastases for the same patient. A TH1 orientation was found in colorectal carcinoma metastases, whereas a heterogeneous immune gene expression was found in RCC metastases.

Conclusions: Our results show a major prognostic value of the immune pattern (CD8+/DC-LAMP+ cell densities) in colorectal carcinoma and RCC, reproducible from primary to metastatic tumors, although with opposite clinical impacts, and highlight the role of the tumor cell in shaping its immune environment. Clin Cancer Res; 19(15); 4079–91. ©2013 AACR.
Data from It Takes Two to Tango: Dual Inhibition of PI3K and MAPK in Rhabdomyosarcoma
Authors: Jahangiri Arman , Weiss William A.
Published: April 2023

Abstract
The PI3K/AKT/mTOR and RAS/RAF/MAPK pathways play essential roles in rhabdomyosarcoma. Singular targeting of each pathway is ineffective due to extensive cross-talk and compensatory feedback between these two pathways. Dual blockade with inhibitors of PI3K and MAPK in combination synergistically inhibits growth of rhabdomyosarcoma both in vitro and in vivo. Clin Cancer Res; 19(21); 5811–3. ©2013 AACR.
Data from Trial Designs for Personalizing Cancer Care: A Systematic Review and Classification
Authors: Tajik Parvin , Zwinderman Aleiko H. , Mol Ben W. , Bossuyt Patrick M.
Published: April 2023

Abstract
There is an increasing interest in the evaluation of prognostic and predictive biomarkers for personalizing cancer care. The literature on the trial designs for evaluation of these markers is diverse and there is no consensus in the classification or nomenclature. We set this study to review the literature systematically, to identify the proposed trial designs, and to develop a classification scheme. We searched MEDLINE, EMBASE, Cochrane Methodology Register, and MathSciNet up to January 2013 for articles describing these trial designs. In each eligible article, we identified the trial designs presented and extracted the term used for labeling the design, components of patient flow (marker status of eligible participants, intervention, and comparator), study questions, and analysis plan. Our search strategy resulted in 88 eligible articles, wherein 315 labels had been used by authors in presenting trial designs; 134 of these were unique. By analyzing patient flow components, we could classify the 134 unique design labels into four basic patient flow categories, which we labeled with the most frequently used term: single-arm, enrichment, randomize-all, and biomarker-strategy designs. A fifth category consists of combinations of the other four patient flow categories. Our review showed that a considerable number of labels has been proposed for trial designs evaluating prognostic and predictive biomarkers which, based on patient flow elements, can be classified into five basic categories. The classification system proposed here could help clinicians and researchers in designing and interpreting trials evaluating predictive biomarkers, and could reduce confusion in labeling and reporting. Clin Cancer Res; 19(17); 4578–88. ©2013 AACR.
Data from ZEB1 Promotes Invasiveness of Colorectal Carcinoma Cells through the Opposing Regulation of uPA and PAI-1
Authors: Sánchez-Tilló Ester , de Barrios Oriol , Siles Laura , Amendola Pier G. , Darling Douglas S. , Cuatrecasas Miriam , Castells Antoni , Postigo Antonio
Published: April 2023

Abstract
Purpose: Carcinoma cells enhance their invasive capacity through dedifferentiation and dissolution of intercellular adhesions. A key activator of this process is the ZEB1 transcription factor, which is induced in invading cancer cells by canonical Wnt signaling (β-catenin/TCF4). Tumor invasiveness also entails proteolytic remodeling of the peritumoral stroma. This study aimed to investigate the potential regulation by ZEB1 of the plasminogen proteolytic system constituted by the urokinase plasminogen activator (uPA), and its inhibitor, plasminogen activator inhibitor-1 (PAI-1).

Experimental Design: Through multiple experimental approaches, colorectal carcinoma (CRC) cell lines and samples from human primary CRC and ZEB1 (−/−) mice were used to examine ZEB1-mediated regulation of uPA and PAI-1 at the protein, mRNA, and transcriptional level.

Results: ZEB1 regulates uPA and PAI-1 in opposite directions: induces uPA and inhibits PAI-1. In vivo expression of uPA depends on ZEB1 as it is severely reduced in the developing intestine of ZEB1 null (−/−) mice. Optimal induction of uPA by Wnt signaling requires ZEB1 expression. ZEB1 binds to the uPA promoter and activates its transcription through a mechanism implicating the histone acetyltransferase p300. In contrast, inhibition of PAI-1 by ZEB1 does not involve transcriptional repression but rather downregulation of mRNA stability. ZEB1-mediated tumor cell migration and invasion depend on its induction of uPA. ZEB1 coexpresses with uPA in cancer cells at the invasive front of CRCs.

Conclusions: ZEB1 promotes tumor invasiveness not only via induction in cancer cells of a motile dedifferentiated phenotype but also by differential regulation of genes involved in stroma remodeling. Clin Cancer Res; 19(5); 1071–82. ©2013 AACR.
Data from Chemoprevention of Head and Neck Cancer by Simultaneous Blocking of Epidermal Growth Factor Receptor and Cyclooxygenase-2 Signaling Pathways: Preclinical and Clinical Studies
Authors: Shin Dong M. , Zhang Hongzheng , Saba Nabil F. , Chen Amy Y. , Nannapaneni Sreenivas , Amin A.R.M. Ruhul , Müller Susan , Lewis Melinda , Sica Gabriel , Kono Scott , Brandes Johann C. , Grist William J. , Moreno-Williams Rachel , Beitler Jonathan J. , Thomas Sufi M. , Chen Zhengjia , Shin Hyung Ju C. , Grandis Jennifer R. , Khuri Fadlo R. , Chen Zhuo Georgia
Published: April 2023

Abstract
Purpose: We investigated the efficacy and underlying molecular mechanism of a novel chemopreventive strategy combining EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) with cyclooxygenase-2 inhibitor (COX-2I).

Experimental Design: We examined the inhibition of tumor cell growth by combined EGFR-TKI (erlotinib) and COX-2I (celecoxib) treatment using head and neck cancer cell lines and a preventive xenograft model. We studied the antiangiogenic activity of these agents and examined the affected signaling pathways by immunoblotting analysis in tumor cell lysates and immunohistochemistry (IHC) and enzyme immunoassay (EIA) analyses on the mouse xenograft tissues and blood, respectively. Biomarkers in these signaling pathways were studied by IHC, EIA, and an antibody array analysis in samples collected from participants in a phase I chemoprevention trial of erlotinib and celecoxib.

Results: The combined treatment inhibited head and neck cancer cell growth significantly more potently than either single agent alone in cell line and xenograft models, and resulted in greater inhibition of cell-cycle progression at G1 phase than either single drug. The combined treatment modulated the EGFR and mTOR signaling pathways. A phase I chemoprevention trial of combined erlotinib and celecoxib revealed an overall pathologic response rate of 71% at time of data analysis. Analysis of tissue samples from participants consistently showed downregulation of EGFR, pERK, and pS6 levels after treatment, which correlated with clinical response.

Conclusion: Treatment with erlotinib combined with celecoxib offers an effective chemopreventive approach through inhibition of EGFR and mTOR pathways, which may serve as potential biomarkers to monitor the intervention of this combination in the clinic. Clin Cancer Res; 19(5); 1244–56. ©2013 AACR.
Data from Characterization of CD45−/CD31+/CD105+ Circulating Cells in the Peripheral Blood of Patients with Gynecologic Malignancies
Authors: Yu Hyun-Kyung , Lee Ho-Jeong , Choi Ha-Na , Ahn Jin-Hyung , Choi Ji-Young , Song Haeng-Seok , Lee Ki-Heon , Yoon Yeup , Yi Lee S. H. , Kim Jang-Seong , Kim Sun Jin , Kim Tae Jin
Published: April 2023

Abstract
Purpose: Circulating endothelial cells (CEC) have been widely used as a prognostic biomarker and regarded as a promising strategy for monitoring the response to treatment in several cancers. However, the presence and biologic roles of CECs have remained controversial for decades because technical standards for the identification and quantification of CECs have not been established. Here, we hypothesized that CECs detected by flow cytometry might be monocytes rather than endothelial cells.

Experimental Design: The frequency of representative CEC subsets (i.e., CD45−/CD31+, CD45−/CD31+/CD146+, CD45−/CD31+/CD105+) was analyzed in the peripheral blood of patients with gynecologic cancer (n = 56) and healthy volunteers (n = 44). CD45−/CD31+ cells, which are components of CECs, were isolated and the expression of various markers (CD146, CD105, vWF, and CD144 for endothelial cells; CD68 and CD14 for monocytes) was examined by immunocytochemistry.

Results: CD45−/CD31+/CD105+ cells were significantly increased in the peripheral blood of patients with cancer, whereas evaluation of CD45−/CD31+/CD146+ cells was not possible both in patients with cancer and healthy controls due to the limited resolution of the flow cytometry. Immunocytochemistry analyses showed that these CD45−/CD31+/CD105+ cells did not express vWF and CD146 but rather CD144. Furthermore, CD45−/CD31+/CD105+ cells uniformly expressed the monocyte-specific markers CD14 and CD68. These results suggest that CD45−/CD31+/CD105+ cells carry the characteristics of monocytes rather than endothelial cells.

Conclusions: Our data indicate that CD45−/CD31+/CD105+ circulating cells, which are significantly increased in the peripheral blood of patients with gynecologic cancer, are monocytes rather than endothelial cells. Further investigation is required to determine the biologic significance of their presence and function in relation with angiogenesis. Clin Cancer Res; 19(19); 5340–50. ©2013 AACR.