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1.  Targeting metastatic upper gastrointestinal adenocarcinomas 
Upper gastrointestinal (GI) tumors, including adenocarcinoma of the esophagus, stomach, pancreas, and biliary tree, have traditionally been difficult to treat with cytotoxic chemotherapeutic agents. There has been little drug development success in treating these cancers over the last 20 years, perhaps a reflection of a combination of the aggressive biology of these tumors, the void in effective and specific drug development for these varied tumors, and the lack of properly designed, biologically-based clinical trials. Recently, so called “targeted agents” have risen to the forefront in the care of cancer patients and have made strong impacts in many areas of oncology, particularly gastrointestinal stromal tumors (GIST), colon, breast, and lung cancers. Unfortunately, slow progress has been made using such agents in upper GI tumors. However, more recently, trials in some tumor types have demonstrated gains in progression free survival and overall survival. In this review, we discuss the drugs and pathways that have been most successful in the treatment of upper GI tumors and present the relevant data supporting their use for each tumor site. Additionally, we will explore a few novel pathways that may prove effective in the treatment of upper GI malignancies in the near future.
doi:10.5306/wjco.v2.i3.135
PMCID: PMC3100479  PMID: 21611088
Targeted therapy; Epidermal growth factor inhibition; Angiogenesis; Antiangiogenic agents; Mammalian target of rapamycin; Her2/neu; Tyrosine kinase inhibition; Pancreatic cancer; Gastric cancer; Biliary cancer; Hepatocellular cancer
2.  Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G1 Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2 
Journal of Clinical Oncology  2010;28(5):780-787.
Purpose
To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2.
Patients and Methods
Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed.
Results
Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients.
Conclusion
Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.
doi:10.1200/JCO.2009.23.7537
PMCID: PMC2834394  PMID: 20048182
3.  First-in-Human Phase I Trial of Two Schedules of OSI-930, a Novel Multikinase Inhibitor, Incorporating Translational Proof-of-Mechanism Studies 
Purpose
OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors.
Experimental Design
OSI-930 was administered once or twice a day using a modified accelerated titration design. Pharmacokinetics and plasma soluble VEGFR2 (sVEGFR2) studies were undertaken. Dynamic contrast-enhanced MRI (DCE-MRI) and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) MTD expansion cohorts were conducted.
Results
Fifty-eight patients received OSI-930 in 2 schedules; once a day schedule: 12 patients at doses up to 1,600 mg without reaching MTD; twice a day schedule: 46 patients at 400 mg (n = 7), 500 mg (n = 31), and 600 mg (n =8). Dose-limiting toxicities were observed at 600 mg twice a day (n =3): G3 rash (n =2) and G4 γ-glutamyltransferase, establishing the MTD at 500 mg twice a day. Common G1–2 toxicities included fatigue, diarrhea, nausea, and rash. Antitumor responses were seen in 2 patients with advanced ovarian cancer [Response Evaluation Criteria in Solid Tumors (RECIST) partial response (PR) (n = 1); GCIG CA125 response (n = 1)]. Eleven of 19 heavily pretreated imatinib-resistant patients with gastrointestinal stromal tumors achieved RECIST stable disease (median duration: 126 days), with FDG-PET scans showing PRs in 4 of 9 patients. OSI-930 exposure increased with dose; substantial decreases in sVEGFR levels were observed with OSI-930 twice a day doses ≥400 mg, while DCE-MRI responses were shown in 4 of 6 patients.
Conclusions
OSI-930 is safe and well tolerated, with pharmacokinetic–pharmacodynamic data supporting proof-of-mechanism with clinically relevant antitumor activity.
doi:10.1158/1078-0432.CCR-12-2258
PMCID: PMC3880798  PMID: 23403628
4.  Clinical Applications of Metabolomics in Oncology: A Review 
Metabolomics, an omic science in systems biology, is the global quantitative assessment of endogenous metabolites within a biological system. Either individually or grouped as a metabolomic profile, detection of metabolites is carried out in cells, tissues, or biofluids by either nuclear magnetic resonance spectroscopy or mass spectrometry. There is potential for the metabolome to have a multitude of uses in oncology, including the early detection and diagnosis of cancer and as both a predictive and pharmacodynamic marker of drug effect. Despite this, there is lack of knowledge in the oncology community regarding metabolomics and confusion about its methodologic processes, technical challenges, and clinical applications. Metabolomics, when used as a translational research tool, can provide a link between the laboratory and clinic, particularly because metabolic and molecular imaging technologies, such as positron emission tomography and magnetic resonance spectroscopic imaging, enable the discrimination of metabolic markers noninvasively in vivo. Here, we review the current and potential applications of metabolomics, focusing on its use as a biomarker for cancer diagnosis, prognosis, and therapeutic evaluation.
doi:10.1158/1078-0432.CCR-08-1059
PMCID: PMC2676437  PMID: 19147747
5.  Looking to the Future: Biomarkers in the Management of Pancreatic Adenocarcinoma 
The incidence and mortality of pancreas cancer converge. There has been little advancement in the treatment of pancreas cancer since the acceptance of gemcitabine as the standard therapy. Unfortunately, the efficacy of gemcitabine is dismal. While there is much discussion for the development of biomarkers to help direct therapy in this area, there is little action to move them into clinical practice. Herein, we review potential pancreatic cancer biomarkers and discuss the limitations in their implementation.
doi:10.3390/ijms12095895
PMCID: PMC3189759  PMID: 22016635
pancreatic adenocarcinoma; hENT1; hCNT3; SPARC; cDK; biomarker; clinical trials; gemcitabine; oxaliplatin
6.  Human Equilibrative Nucleoside Transporter 1 (hENT1) in Pancreatic Adenocarcinoma: Towards Individualized Treatment Decisions  
Cancers  2010;2(4):2044-2054.
Pancreatic cancer is one of the most lethal cancers, where curative surgical resections are rare and less than 5% of patients experience long-term survival. Despite numerous clinical trials, improvements in the systemic treatment of this disease have been limited. Gemcitabine, a nucleoside analogue, is still considered the standard of care chemotherapy for most patients in the advanced disease setting. To exert its cytotoxic effects, gemcitabine must enter cells via nucleoside transporters, most notably human equilibrative nucleoside transporter 1 (hENT1). Increasingly strong evidence suggests hENT1 is a prognostic biomarker in gemcitabine-treated pancreatic cancer, and may well be a predictive biomarker of gemcitabine efficacy. In this review, we synthesize the literature surrounding hENT1 in pancreatic cancer, identify the key outstanding questions, and suggest strategies to prospectively evaluate the clinical utility of hENT1 in future clinical studies.
doi:10.3390/cancers2042044
PMCID: PMC3840445  PMID: 24281217
nucleoside transporters; hENT1; pancreatic adenocarcinoma; predictive tool; individualized medicine

Results 1-6 (6)