bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases
Authors: Tabernero Josep , Elez Maria Elena , Herranz Maria , Rico Isabel , Prudkin Ludmila , Andreu Jordi , Mateos Jose , Carreras Maria Josep , Han May , Gifford James , Credi Marc , Yin Wei , Agarwal Shefali , Komarnitsky Philip , Baselga Jose 
Published: March 2014

Abstract
Purpose: This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases.
Patients and Methods: Patients with p-Met (phosphorylated c-Met)–positive tumors enrolled in three dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed.
Results: No dose-limiting toxicities occurred in the 19 patients enrolled (n = 6, 2 mg/kg; n = 7, 10 mg/kg; n = 6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n = 15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (−53%), p-ERK (−43%), p-Akt (−2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4–10 days). Best overall response was stable disease in 28% of patients, including 1 patient with pancreatic cancer with stable disease &gt;1 year.
Conclusions: Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase II dose of 20 mg/kg once per 14-day cycle. Clin Cancer Res; 20(10); 2793–804. ©2014 AACR.
PI3K Pathway Activation in High-Grade Ductal CarcinomaIn Situ—Implications for Progression to Invasive Breast Carcinoma
Authors: Sakr Rita A. , Weigelt Britta , Chandarlapaty Sarat , Andrade Victor P. , Guerini-Rocco Elena , Giri Dilip , Ng Charlotte K.Y. , Cowell Catherine F. , Rosen Neal , Reis-Filho Jorge S. , King Tari A. 
Published: March 2014

AbstractPurpose: To assess the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in pure high-grade ductal carcinoma in situ (DCIS) and DCIS associated with invasive breast cancer (IBC), and to determine whether DCIS and adjacent IBCs harbor distinct PI3K pathway aberrations.Experimental Design: Eighty-nine cases of pure high-grade DCIS and 119 cases of high-grade DCIS associated with IBC were characterized according to estrogen receptor (ER) and HER2 status, subjected to immunohistochemical analysis of PTEN, INPP4B, phosphorylated (p)AKT and pS6 expression, and to microdissection followed by Sequenom genotyping of PIK3CA and AKT1 hotspot mutations.Results: Alterations affecting the PI3K pathway were found in a subset of pure DCIS and DCIS adjacent to IBC. A subtype-matched comparison of pure DCIS and DCIS adjacent to IBC revealed that PIK3CA hotspot mutations and pAKT expression were significantly more prevalent in ER-positive/HER2-negative DCIS adjacent to IBC (P values, 0.005 and 0.043, respectively), and that in ER-negative/HER2-positive cases INPP4B loss of expression was more frequently observed in pure DCIS (a P value of 0.013). No differences in the parameters analyzed were observed in a pairwise comparison of the in situ and invasive components of cases of DCIS and adjacent IBC. Analysis of the PIK3CA-mutant allelic frequencies in DCIS and synchronous IBC revealed cases in which PIK3CA mutations were either restricted to the DCIS or to the invasive components.Conclusion: Molecular aberrations affecting the PI3K pathway may play a role in the progression from high-grade DCIS to IBC in a subset of cases (e.g., a subgroup of ER-positive/HER2-negative lesions). Clin Cancer Res; 20(9); 2326–37. ©2014 AACR.
FOXM1 Promotes the Warburg Effect and Pancreatic Cancer Progression via Transactivation of LDHA Expression
Authors: Cui Jiujie , Shi Min , Xie Dacheng , Wei Daoyan , Jia Zhiliang , Zheng Shaojiang , Gao Yong , Huang Suyun , Xie Keping 
Published: March 2014

Abstract
Purpose: The transcription factor Forkhead box protein M1 (FOXM1) plays critical roles in cancer development and progression. However, the regulatory role and underlying mechanisms of FOXM1 in cancer metabolism are unknown. In this study, we characterized the regulation of aerobic glycolysis by FOXM1 and its impact on pancreatic cancer metabolism.
Experimental Design: The effect of altered expression of FOXM1 on expression of glycolytic enzymes and tumor development and progression was examined using animal models of pancreatic cancer. Also, the underlying mechanisms of altered pancreatic cancer glycolysis were analyzed using in vitro molecular biology. The clinical relevance of aberrant metabolism caused by dysregulated FOXM1 signaling was determined using pancreatic tumor and normal pancreatic tissue specimens.
Results: We found that FOXM1 did not markedly change the expression of most glycolytic enzymes except for phosphoglycerate kinase 1 (PGK-1) and lactate dehydrogenase A (LDHA). FOXM1 and LDHA were overexpressed concomitantly in pancreatic tumors and cancer cell lines. Increased expression of FOXM1 upregulated the expression of LDHA at both the mRNA and protein level and elevated LDH activity, lactate production, and glucose utilization, whereas reduced expression of FOXM1 did the opposite. Further studies demonstrated that FOXM1 bound directly to the LDHA promoter region and regulated the expression of the LDHA gene at the transcriptional level. Also, elevated FOXM1–LDHA signaling increased the pancreatic cancer cell growth and metastasis.
Conclusions: Dysregulated expression and activation of FOXM1 play important roles in aerobic glycolysis and tumorigenesis in patients with pancreatic cancer via transcriptional regulation of LDHA expression. Clin Cancer Res; 20(10); 2595–606. ©2014 AACR.
Biologic Effects of Platelet-Derived Growth Factor Receptor α Blockade in Uterine Cancer
Authors: Roh Ju-Won , Huang Jie , Hu Wei , Yang XiaoYun , Jennings Nicholas B. , Sehgal Vasudha , Sohn Bo Hwa , Han Hee Dong , Lee Sun Joo , Thanapprapasr Duangmani , Bottsford-Miller Justin , Zand Behrouz , Dalton Heather J. , Previs Rebecca A. , Davis Ashley N. , Matsuo Koji , Lee Ju-Seog , Ram Prahlad , Coleman Robert L. , Sood Anil K. 
Published: March 2014

Abstract
Purpose: Platelet-derived growth factor receptor α (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer.
Experimental Design: Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biologic effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer.
Results: PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and mitogen-activated protein kinase (MAPK). Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in the PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis.
Conclusions: These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer. Clin Cancer Res; 20(10); 2740–50. ©2014 AACR.
Profound Prevention of Experimental Brain Metastases of Breast Cancer by Temozolomide in an MGMT-Dependent Manner
Authors: Palmieri Diane , Duchnowska Renata , Woditschka Stephan , Hua Emily , Qian Yongzhen , Biernat Wojciech , Sosińska-Mielcarek Katarzyna , Gril Brunilde , Stark Andreas M. , Hewitt Stephen M. , Liewehr David J. , Steinberg Seth M. , Jassem Jacek , Steeg Patricia S. 
Published: March 2014

AbstractPurpose: Brain metastases of breast cancer cause neurocognitive damage and are incurable. We evaluated a role for temozolomide in the prevention of brain metastases of breast cancer in experimental brain metastasis models.Experimental Design: Temozolomide was administered in mice following earlier injection of brain-tropic HER2–positive JIMT-1-BR3 and triple-negative 231-BR-EGFP sublines, the latter with and without expression of O6-methylguanine-DNA methyltransferase (MGMT). In addition, the percentage of MGMT-positive tumor cells in 62 patient-matched sets of breast cancer primary tumors and resected brain metastases was determined immunohistochemically.Results: Temozolomide, when dosed at 50, 25, 10, or 5 mg/kg, 5 days per week, beginning 3 days after inoculation, completely prevented the formation of experimental brain metastases from MGMT-negative 231-BR-EGFP cells. At a 1 mg/kg dose, temozolomide prevented 68% of large brain metastases, and was ineffective at a dose of 0.5 mg/kg. When the 50 mg/kg dose was administered beginning on days 18 or 24, temozolomide efficacy was reduced or absent. Temozolomide was ineffective at preventing brain metastases in MGMT-transduced 231-BR-EGFP and MGMT-expressing JIMT-1-BR3 sublines. In 62 patient-matched sets of primary breast tumors and resected brain metastases, 43.5% of the specimens had concordant low MGMT expression, whereas in another 14.5% of sets high MGMT staining in the primary tumor corresponded with low staining in the brain metastasis.Conclusions: Temozolomide profoundly prevented the outgrowth of experimental brain metastases of breast cancer in an MGMT-dependent manner. These data provide compelling rationale for investigating the preventive efficacy of temozolomide in a clinical setting. Clin Cancer Res; 20(10); 2727–39. ©2014 AACR.
Effect of Aromatase Inhibition on Functional Gene Modules in Estrogen Receptor–Positive Breast Cancer and Their Relationship with Antiproliferative Response
Authors: Gao Qiong , Patani Neill , Dunbier Anita K. , Ghazoui Zara , Zvelebil Marketa , Martin Lesley-Ann , Dowsett Mitch 
Published: March 2014

Abstract
Purpose: To investigate potential associations between gene modules representing key biologic processes and response to aromatase inhibitors (AI) in estrogen receptor–positive (ER+) breast cancer.
Patients and Methods: Paired gene expression and Ki67 protein expression were available from 69 postmenopausal women with ER+ early breast cancer, at baseline and 2 weeks post-anastrozole treatment, in the presurgical setting. Functional gene modules (n = 26) were retrieved from published studies and their module scores were computed before and after elimination of proliferation-associated genes (PAG). Ki67 and module scores were assessed at baseline and 2 weeks post-anastrozole. Unsupervised clustering was used to assess associations between modules and Ki67.
Results: Proliferation-based modules were highly correlated with Ki67 expression both pretreatment and on-treatment. At baseline with and without PAGs, Ki67 expression was significantly inversely correlated with ERG, ESR1.2, SET, and PIK3CA modules. Modules measuring estrogen signaling strongly predicted antiproliferative response to therapy with and without PAGs. Baseline expression of insulin-like growth factor-1 (IGF-I) module predicted a poor change in Ki67-implicating genes within the module as involved in de novo resistance to AIs. High expression of Immune.2.STAT1 module pretreatment predicted poor antiproliferative response to therapy. A significant association between estrogen-regulated genes modules (ESR1, ESR1-2, SET, and ERG) was evident post AI.
Conclusions: Multiple processes and pathways are affected by AI treatment in ER+ breast cancer. Modules closely associated with ESR1 expression were predictive of good antiproliferative response to AIs, but modules representing immune activity and IGF-I/MAPK were predictive of poor Ki67 response, supporting their therapeutic targeting in combination with AIs. Clin Cancer Res; 20(9); 2485–94. ©2014 AACR.
Circulating Tumor Cells in Patients with Testicular Germ Cell Tumors
Authors: Nastały Paulina , Ruf Christian , Becker Pascal , Bednarz-Knoll Natalia , Stoupiec Małgorzata , Kavsur Refik , Isbarn Hendrik , Matthies Cord , Wagner Walter , Höppner Dirk , Fisch Margit , Bokemeyer Carsten , Ahyai Sascha , Honecker Friedemann , Riethdorf Sabine , Pantel Klaus 
Published: March 2014

Abstract
Purpose: Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell–specific markers, and results were correlated with disease stage, histology, and serum tumor markers.
Experimental Design: CTCs were enriched from peripheral blood (n = 143 patients) and testicular vein blood (TVB, n = 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell–specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system.
Results: In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P &lt; 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P &lt; 0.001), with higher percentage of yolk sac (P &lt; 0.001) and teratoma (P = 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of α-fetoprotein (AFP; P = 0.025), β-human chorionic gonadotropin (βHCG; P = 0.002), and lactate dehydrogenase (LDH; P = 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood.
Conclusions: The inclusion of germ cell tumor–specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery. Clin Cancer Res; 20(14); 3830–41. ©2014 AACR.
CD133+ Tumor Initiating Cells in a Syngenic Murine Model of Pancreatic Cancer Respond to Minnelide
Authors: Banerjee Sulagna , Nomura Alice , Sangwan Veena , Chugh Rohit , Dudeja Vikas , Vickers Selwyn M. , Saluja Ashok 
Published: March 2014

Abstract
Purpose: Pancreatic adenocarcinoma is the fourth leading cause for cancer-related mortality with a survival rate of less than 5%. Late diagnosis and lack of effective chemotherapeutic regimen contribute to these grim survival statistics. Relapse of any tumor is largely attributed to the presence of tumor-initiating cells (TIC) or cancer stem cells (CSC). These cells are considered as hurdles to cancer therapy as no known chemotherapeutic compound is reported to target them. Thus, there is an urgent need to develop a TIC-targeted therapy for pancreatic cancer.
Experimental Design: We isolated CD133+ cells from a spontaneous pancreatic ductal adenocarcinoma mouse model and studied both surface expression, molecular markers of pancreatic TICs. We also studied tumor initiation properties by implanting low numbers of CD133+ cells in immune competent mice. Effect of Minnelide, a drug currently under phase I clinical trial, was studied on the tumors derived from the CD133+ cells.
Results: Our study showed for the first time that CD133+ population demonstrated all the molecular markers for pancreatic TIC. These cells initiated tumors in immunocompetent mouse models and showed increased expression of prosurvival and proinvasive proteins compared to the CD133− non-TIC population. Our study further showed that Minnelide was very efficient in downregulating both CD133− and CD133+ population in the tumors, resulting in a 60% decrease in tumor volume compared with the untreated ones.
Conclusion: As Minnelide is currently under phase I clinical trial, its evaluation in reducing tumor burden by decreasing TIC as well as non-TIC population suggests its potential as an effective therapy. Clin Cancer Res; 20(9); 2388–99. ©2014 AACR.
Adoptive Transfer of MART-1 T-Cell Receptor Transgenic Lymphocytes and Dendritic Cell Vaccination in Patients with Metastatic Melanoma
Authors: Chodon Thinle , Comin-Anduix Begoña , Chmielowski Bartosz , Koya Richard C. , Wu Zhongqi , Auerbach Martin , Ng Charles , Avramis Earl , Seja Elizabeth , Villanueva Arturo , McCannel Tara A. , Ishiyama Akira , Czernin Johannes , Radu Caius G. , Wang Xiaoyan , Gjertson David W. , Cochran Alistair J. , Cornetta Kenneth , Wong Deborah J.L. , Kaplan-Lefko Paula , Hamid Omid , Samlowski Wolfram , Cohen Peter A. , Daniels Gregory A. , Mukherji Bijay , Yang Lili , Zack Jerome A. , Kohn Donald B. , Heath James R. , Glaspy John A. , Witte Owen N. , Baltimore David , Economou James S. , Ribas Antoni 
Published: March 2014

Abstract
Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy.
Experimental Design: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation.
Results: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1–specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1–specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells.
Conclusion: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. Clin Cancer Res; 20(9); 2457–65. ©2014 AACR.
Integrated Next-Generation Sequencing and Avatar Mouse Models for Personalized Cancer Treatment
Authors: Garralda Elena , Paz Keren , López-Casas Pedro P. , Jones Siân , Katz Amanda , Kann Lisa M. , López-Rios Fernando , Sarno Francesca , Al-Shahrour Fátima , Vasquez David , Bruckheimer Elizabeth , Angiuoli Samuel V. , Calles Antonio , Diaz Luis A. , Velculescu Victor E. , Valencia Alfonso , Sidransky David , Hidalgo Manuel 
Published: March 2014

Abstract
Background: Current technology permits an unbiased massive analysis of somatic genetic alterations from tumor DNA as well as the generation of individualized mouse xenografts (Avatar models). This work aimed to evaluate our experience integrating these two strategies to personalize the treatment of patients with cancer.
Methods: We performed whole-exome sequencing analysis of 25 patients with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. Avatar models were used as an in vivo platform to test proposed treatment strategies.
Results: Successful exome sequencing analyses have been obtained for 23 patients. Tumor-specific mutations and copy-number variations were identified. All samples profiled contained relevant genomic alterations. Tumor was implanted to create an Avatar model from 14 patients and 10 succeeded. Occasionally, actionable alterations such as mutations in NF1, PI3KA, and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and, accordingly, treatment of the patients with these drugs was not effective. To date, 13 patients have received a personalized treatment and 6 achieved durable partial remissions. Prior testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in some patients with no actionable mutations.
Conclusion: The use of full genomic analysis for cancer care is encouraging but presents important challenges that will need to be solved for broad clinical application. Avatar models are a promising investigational platform for therapeutic decision making. While limitations still exist, this strategy should be further tested. Clin Cancer Res; 20(9); 2476–84. ©2014 AACR.
Seeing the Forest for the Trees: Kidney Oncogenomes in Relation to Therapeutic Outcomes
Authors: Chism David D. , Rathmell W. Kimryn 
Published: March 2014

Abstract
Renal cell carcinoma is a heterogeneous disease, and tissue investigations provide clues that may predict treatment response. Oncogenomic analysis of five outliers, who achieved a sustained response with rapalogs, implicates alterations of the TSC1 and mTOR genes and reveals insights into the conserved evolution of tumors. Clin Cancer Res; 20(7); 1721–3. ©2014 AACR.
SETting OP449 into the PP2A-Activating Drug Family
Authors: Neviani Paolo , Perrotti Danilo 
Published: March 2014

Abstract
The protein phosphatase 2A (PP2A) tumor suppressor is inactivated in different leukemias through the activity of its endogenous inhibitors (e.g., SET), which are aberrantly regulated by oncogenic tyrosine kinases. Like other effective and nontoxic PP2A-activating drugs (PAD), OP449 inhibits SET and impairs leukemogenesis. This further supports the immediate use of PADs in patients with leukemia. Clin Cancer Res; 20(8); 2026–8. ©2014 AACR.
Emerging Immunologic Biomarkers: Setting the (TNM-Immune) Stage
Authors: Taube Janis M. 
Published: March 2014

Abstract
The cooperation of tumor-infiltrating lymphocytes and tertiary lymphoid tissue in early-stage colorectal carcinoma further corroborates the strong immune influences on tumor progression and patient outcome. Immune factors in the tumor microenvironment may warrant inclusion in pathology reports and staging systems for prognostication and prediction of therapeutic response. Clin Cancer Res; 20(8); 2023–5. ©2014 AACR.