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1.  Evolution of Tumor Invasiveness: The Adaptive Tumor Microenvironment Landscape Model 
Cancer research  2011;71(20):6327-6337.
Interactions between cancer cells and their microenvironment are crucial for promoting tumor growth and invasiveness. In the tumor adaptive landscape model, hypoxic and acidic microenvironmental conditions reduce the fitness of cancer cells and significantly restrict their proliferation. This selects for enhanced motility as cancer cells may evolve an invasive phenotype if the consequent cell movement is rewarded by proliferation. Here, we used an integrative approach combining a mathematical tumor adaptive landscape model with experimental studies to examine the evolutionary dynamics that promote an invasive cancer phenotype. Computer simulation results hypothesized an explicit coupling of motility and proliferation in cancer cells. The mathematical modeling results were also experimentally examined by selecting Panc-1 cells with enhanced motility on a fibroblast-derived 3D matrix for cells that move away from the unfavorable metabolic constraints. After multiple rounds of selection, the cells that adapted through increased motility were characterized for their phenotypic properties compared to stationary cells. Microarray and gene depletion studies demonstrated the role of Rho-GDI2 in regulating both cell movement and proliferation. Together, this work illustrates the partnership between evolutionary mathematical modeling and experimental validation as a potentially useful approach to study the complex dynamics of the tumor microenvironment.
doi:10.1158/0008-5472.CAN-11-0304
PMCID: PMC3197231  PMID: 21859828
Adaptive landscape model; tumor microenvironment; cell motility; 3D matrix; Rho-GDI2
2.  Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold 
ACS Medicinal Chemistry Letters  2013;4(5):491-496.
Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp2 hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>103) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.
doi:10.1021/ml300410d
PMCID: PMC4027141  PMID: 24900696
Fibroblast activation protein (FAP); dipeptidyl peptidase IV (DPPIV); prolyl oligopeptidase (PREP); seprase
3.  Identification and characterization of the promoter of fibroblast activation protein 
Fibroblast activation protein (FAP) is a type II integral membrane glycoprotein belonging to the serine protease family. It is selectively expressed by tumor stromal fibroblasts and transiently in the fibroblasts of healing wounds. FAP has been shown to modulate growth, differentiation, adhesion, and metastasis of tumor cells. Despite the importance of FAP in cancer, the mechanisms that govern its expression have not been defined. In this study, we determined the transcription start site of the FAP gene and identified a 2-kb segment with promoter activity in cells expressing FAP. Truncation of this fragment revealed that the core promoter activity resided in a 245-bp fragment surrounding the transcription start site. Electrophoretic mobility shift assay showed that EGR1 binds to the FAP promoter. Mutation of the EGR1 site within this fragment significantly decreased the promoter activity of FAP and eliminated EGR1 binding. Down-regulation of EGR1 resulted in a significant reduction in endogenous FAP mRNA expression. These findings identify the basal transcriptional requirements of FAP gene expression and show EGR1 is an important regulator of FAP expression.
PMCID: PMC2880831  PMID: 20515787
Fibroblast activation protein; Promoter
4.  An Activatable Near Infrared Fluorescent Probe for In Vivo Imaging of Fibroblast Activation Protein-alpha 
Bioconjugate chemistry  2012;23(8):1704-1711.
Fibroblast activation protein-alpha (FAPα) is a cell surface glycoprotein which is selectively expressed by tumor-associated fibroblasts in malignant tumors but rarely on normal tissues. FAPα has also been reported to promote tumor growth and invasion and therefore has been of increasing interest as a promising target for designing tumor-targeted drugs and imaging agents. Although medicinal study on FAPα inhibitors has led to the discovery of many FAPα-targeting inhibitors including a drug candidate in a phase II clinical trial, the development of imaging probes to monitor the expression and activity of FAPα in vivo has largely lagged behind. Herein we report an activatable near infrared (NIR) fluorescent probe (ANPFAP) for in vivo optical imaging of FAPα. The ANPFAP consists of a NIR dye (Cy5.5) and a quencher dye (QSY21) which are linked together by a short peptide sequence (KGPGPNQC) specific for FAPα cleavage. Because of the efficient fluorescence resonance energy transfer (FRET) between Cy5.5 and QSY21 in ANPFAP, high contrast on the NIR fluorescence signal can be achieved after the cleavage of the peptide sequence by FAPα both in vitro and in vivo. In vitro assay on ANPFAP indicated the specificity of the probe to FAPα. The in vivo optical imaging using ANPFAP showed fast tumor uptake as well as high tumor to background contrast on U87MG tumor models with FAPα expression, while much lower signal and tumor contrast were observed in the C6 tumor without FAPα expression, demonstrating the in vivo targeting specificity of the ANPFAP. Ex vivo imaging also demonstrated ANPFAP had high tumor uptake at 4 h post injection. Collectively, these results indicated that ANPFAP could serve as a useful NIR optical probe for early detection of FAPα expressing tumors.
doi:10.1021/bc300278r
PMCID: PMC3419799  PMID: 22812530
FAPα; NIRF; glioma; activatable probe; optical imaging
5.  Symptomatic cardiac toxicity is predicted by dosimetric and patient factors rather than changes in 18F-FDG PET determination of myocardial activity after chemoradiotherapy for esophageal cancer 
Radiotherapy and Oncology  2012;104(1):72-77.
Purpose
To determine factors associated with symptomatic cardiac toxicity in patients with esophageal cancer treated with chemoradiotherapy.
Material and Methods
We retrospectively evaluated 102 patients treated with chemoradiotherapy for locally advanced esophageal cancer. Our primary endpoint was symptomatic cardiac toxicity. Radiation dosimetry, patient demographic factors, and myocardial changes seen on 18F-FDG PET were correlated with subsequent cardiac toxicity. Cardiac toxicity measured by RTOG and CTCAE v3.0 criteria was identified by chart review.
Results
During the follow up period, 12 patients were identified with treatment related cardiac toxicity, 6 of which were symptomatic. The mean heart V20 (79.7% vs. 67.2%, p=0.05), V30 (75.8% vs. 61.9%, p=0.04), and V40 (69.2% vs. 53.8%, p=0.03) were significantly higher in patients with symptomatic cardiac toxicity than those without. We found the threshold for symptomatic cardiac toxicity to be a V20, V30 and V40 above 70%, 65% and 60%, respectively. There was no correlation between change myocardial SUV on PET and cardiac toxicity, however, a greater proportion of women suffered symptomatic cardiac toxicity compared to men (p=0.005).
Conclusions
A correlation did not exist between percent change in myocardial SUV and cardiac toxicity. Patients with symptomatic cardiac toxicity received significantly greater mean V20, 30 and 40 values to the heart compared to asymptomatic patients. These data need validation in a larger independent data set.
doi:10.1016/j.radonc.2012.04.016
PMCID: PMC3389132  PMID: 22682539
Chemoradiotherapy; Esophageal cancer; Cardiac Toxicity
6.  Phase II and Coagulation Cascade Biomarker Study of Bevacizumab with or without Docetaxel in Patients with Previously Treated Metastatic Pancreatic Adenocarcinoma 
Purpose
Treatment options are limited for advanced pancreatic cancer progressive after gemcitabine therapy. The vascular endothelial growth factor (VEGF) pathway is biologically important in pancreatic cancer, and docetaxel has modest anti-tumor activity. We evaluated the role of the anti-VEGF antibody bevacizumab as second-line treatment for patients with metastatic pancreatic cancer.
Design
Patients with metastatic adenocarcinoma of the pancreas who had progressive disease on a gemcitabine-containing regimen were randomized to receive bevacizumab alone or bevacizumab in combination with docetaxel.
Results
Thirty-two patients were enrolled; 16 to bevacizumab alone (Arm A) and 16 to bevacizumab plus docetaxel (Arm B). Toxicities were greater in Arm B with the most common grade 3/4 nonhematologic toxicities including fatigue, diarrhea, dehydration and anorexia. No confirmed objective responses were observed. At 4 months, 2/16 patients in Arm A and 3/16 in Arm B were free from progression. The study was stopped according to the early stopping rule for futility. Median PFS and OS were 43 days and 165 days in Arm A and 48 days and 125 days in Arm B. Elevated D-dimer levels and thrombin-antithrombin complexes were associated with decreased survival and increased toxicity.
Conclusion
Bevacizumab with or without docetaxel does not have antitumor activity in gemcitabine-refractory metastatic pancreatic cancer. Baseline and on-treatment D-dimer and thrombin-antithrombin complex levels are associated with increased toxicity and decreased survival.
doi:10.1097/COC.0b013e3181d2734a
PMCID: PMC3030655  PMID: 20458210
7.  FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells 
BMC Cancer  2011;11:245.
Background
Alterations towards a permissive stromal microenvironment provide important cues for tumor growth, invasion, and metastasis. In this study, Fibroblast activation protein (FAP), a serine protease selectively produced by tumor-associated fibroblasts in over 90% of epithelial tumors, was used as a platform for studying tumor-stromal interactions.
We tested the hypothesis that FAP enzymatic activity locally modifies stromal ECM (extracellular matrix) components thus facilitating the formation of a permissive microenvironment promoting tumor invasion in human pancreatic cancer.
Methods
We generated a tetracycline-inducible FAP overexpressing fibroblastic cell line to synthesize an in vivo-like 3-dimensional (3D) matrix system which was utilized as a stromal landscape for studying matrix-induced cancer cell behaviors. A FAP-dependent topographical and compositional alteration of the ECM was characterized by measuring the relative orientation angles of fibronectin fibers and by Western blot analyses. The role of FAP in the matrix-induced permissive tumor behavior was assessed in Panc-1 cells in assorted matrices by time-lapse acquisition assays. Also, FAP+ matrix-induced regulatory molecules in cancer cells were determined by Western blot analyses.
Results
We observed that FAP remodels the ECM through modulating protein levels, as well as through increasing levels of fibronectin and collagen fiber organization. FAP-dependent architectural/compositional alterations of the ECM promote tumor invasion along characteristic parallel fiber orientations, as demonstrated by enhanced directionality and velocity of pancreatic cancer cells on FAP+ matrices. This phenotype can be reversed by inhibition of FAP enzymatic activity during matrix production resulting in the disorganization of the ECM and impeded tumor invasion. We also report that the FAP+ matrix-induced tumor invasion phenotype is β1-integrin/FAK mediated.
Conclusion
Cancer cell invasiveness can be affected by alterations in the tumor microenvironment. Disruption of FAP activity and β1-integrins may abrogate the invasive capabilities of pancreatic and other tumors by disrupting the FAP-directed organization of stromal ECM and blocking β1-integrin dependent cell-matrix interactions. This provides a novel preclinical rationale for therapeutics aimed at interfering with the architectural organization of tumor-associated ECM. Better understanding of the stromal influences that fuel progressive tumorigenic behaviors may allow the effective future use of targeted therapeutics aimed at disrupting specific tumor-stromal interactions.
doi:10.1186/1471-2407-11-245
PMCID: PMC3141768  PMID: 21668992
8.  Correlation of molecular response as measured by 18-FDG PET with outcome after chemo-radiation in patients with esophageal carcinoma 
Purpose
Determine if 18-FDG PET-CT scans predict pathologic complete response, disease-free and overall survival in patients with esophageal carcinoma undergoing definitive or pre-operative chemoradiation.
Material & Methods
Patients with esophageal carcinoma presenting for definitive or pre-operative treatment undergoing pre- and post-treatment 18-FDG PET-CT scans were retrospectively reviewed. Histology, T-stage, nodal status, radiation dose, days from end of radiation to PET scan and surgery were the variables investigated to determine a relationship to baseline SUV of the primary tumor at the time of diagnosis. We also attempted to determine if a relationship existed between % decrease SUV and pathologic complete response, overall and disease-free survival.
Results
Eighty-one patients, 14 female and 67 male, underwent 18-FDG PET-CT scanning prior to treatment and 63 had post-treatment scans. T-stage and tumor location predicted in univariate but not multivariate analysis for initial SUV. Sixty-six percent of patients with a post-chemoradiation SUV <2.5 had tumor seen in the surgical specimen and 64% of patients had positive lymph nodes at surgery not imaged on the post-chemoradiation PET scan. A trend existed for post-treatment SUV and days from radiation to surgery to predict for pathologic complete response, p=0.09 and p=0.08, respectively. Post-treatment SUV predicted for disease-free survival in the definitive chemoradiation group, p=0.01.
Conclusion
A correlation existed between depth of tumor invasion and baseline SUV level. Post-treatment SUV predicted for disease-free survival in the definite chemoradiation group. Caution should be exercised in utilizing post-treatment PET scans to determine the necessity of surgical resection.
doi:10.1016/j.ijrobp.2007.03.053
PMCID: PMC2933372  PMID: 17532577
Molecular imaging; esophageal cancer; chemoradiation
9.  Photodynamic Molecular Beacon Triggered by Fibroblast Activation Protein on Cancer-associated Fibroblasts for Diagnosis and Treatment of Epithelial Cancers 
Journal of medicinal chemistry  2009;52(2):358-368.
Fibroblast activation protein (FAP) is a cell-surface serine protease highly expressed on cancer-associated fibroblasts of human epithelial carcinomas but not on normal fibroblasts, normal tissues, and cancer cells. We report herein a novel FAP-triggered photodynamic molecular beacon (FAP-PPB) comprising of a fluorescent photosensitizer and a black hole quencher 3 linked by a peptide sequence (TSGPNQEQK) specific to FAP. FAP-PPB was effectively cleaved by both human FAP and murine FAP. Using the HEK293 transfected cells (HEK-mFAP, FAP+; HEK-Vector, FAP−), systematic in vitro and in vivo experiments validated the FAP-specific activation of FAP-PPB in cancer cells and mouse xenografts, respectively. FAP-PPB was cleaved by FAP, allowing fluorescence restoration in FAP-expressing cells, while leaving non-expressing FAP cells undetectable. Moreover, FAP-PPB showed FAP-specific photocytotoxicity toward HEK-mFAP cells whereas it was non-cytotoxic toward HEK-Vector cells. This study suggests that the FAP-PPB is a potentially useful tool for epithelial cancer detection and treatment.
doi:10.1021/jm801052f
PMCID: PMC2773291  PMID: 19093877
Fibroblast Activation Protein (FAP); Cancer-associated Fibroblast (CAF); Molecular Beacon; In Vivo Imaging; Photodynamic Therapy (PDT)
10.  A Phase I Study of the Safety and Pharmacokinetics of Trabectedin in Combination With Pegylated Liposomal Doxorubicin in Patients With Advanced Malignancies 
SUMMARY
Background
To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and Methods
Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-hour PLD (30 mg/m2) infusion was followed immediately by 1 of 6 trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 hours, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable txicity. Plasma samples were obtained to assess PK profiles.
Results
The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxicities were neutropenia (31%) and elevated transaminases (31%). Six patients responded (1 CR, 5 partial responses), with an overall response rate of 16.7%, and 14 had stable disease >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared to trabectedin and PLD each given as a single agent.
Conclusion
Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types, and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
doi:10.1093/annonc/mdn363
PMCID: PMC2598415  PMID: 18497430
trabectedin; ET-743; pegylated liposomal doxorubicin (PLD); sarcomas; ovarian cancer
11.  Long-Term Results of Concomitant Boost Radiation plus Concurrent Cisplatin for Advanced Head and Neck Carcinomas: a Phase II Trial of the Radiation Therapy Oncology Group (RTOG 99-14) 
Purpose
The feasibility of combining concomitant boost accelerated radiation regimen (AFX-C) with cisplatin was previously demonstrated in this phase II trial. This manuscript reports the long-term toxicity, relapse patterns, and survival in patients with advanced head and neck carcinoma (HNC).
Patients and Methods
Between April and November 2000, 84 patients with stage III–IV HNC were enrolled, and 76 patients were analyzable. Radiation consisted of 72 Gy over 6 weeks. Cisplatin dose was 100 mg/m2 on days 1 and 22. Tumor and clinical status were assessed and acute-late toxicities were graded.
Results
The median follow-up for surviving patients is 4.3 years. The 2- and 4-year local-regional failure rates are 33% and 36%, respectively, and the 2- and 4-year survival rates are 70% and 54%, respectively. The worst overall late grade 3 or 4 toxicity rate was 42%. The prevalence rates of a gastrostomy at any time during follow-up, at 12 months, and at 48 months were 83%, 41%, and 17%, respectively. Five of 36 patients (14%) alive and without disease at last follow-up were gastrostomy tube dependent..
Conclusion
These data of long-term follow-up of patients treated with AFX-C with cisplatin show encouraging results with regard to locoregional disease control and survival, with few recurrences after 2 years. The late toxicity rates are relatively high. However, while prolonged dysphagia was noted in our preliminary report, its prevalence does decrease over time. A phase III trial comparing AFX-C plus cisplatin against standard radiation plus cisplatin has completed accrual.
doi:10.1016/j.ijrobp.2008.04.006
PMCID: PMC2582390  PMID: 18640496
Radiation; chemoradiation; accelerated radiotherapy; late toxicity
12.  Influence of Diabetes on the Interpretation of PET Scans in Patients With Esophageal Cancer 
Purpose:
Patients with diabetes mellitus (DM) can have altered sugar transport into cells, potentially affecting the results of 18-FDG PET scans. The specific aim of this study was to determine the effect of DM on pre- and post-treatment standard uptake value (SUV) scores in patients undergoing chemoradiotherapy for esophageal cancer.
Methods:
Patients with locally advanced esophageal carcinoma undergoing preoperative or definitive chemoradiotherapy underwent pre- and posttreatment 18-FDG PET scans. Maximum SUV score was measured from the tumor before chemoradiotherapy and 3 to 4 weeks after chemoradiotherapy (preoperatively). Patients were identified as having DM by medical record review. Random serum glucose measurements were obtained prior to 18-FDG PET scans. The Wilcoxon signed-rank test was used to test for differences in SUV scores between patients with and without DM, and a generalized linear model with backward selection was applied to search for significant predictors of initial and posttreatment SUV scores.
Results:
Sixty-three patients underwent 18-FDG PET scans during the course of treatment for esophageal malignancies between 6/02 and 8/05. Fifty-four patients received chemotherapy. The median radiation dose was 46.8 Gy. Eighteen patients had DM, six were insulin-dependent DM (IDDM). There was no difference in initial SUV scores between DM and non-DM patients (P > .05). There was also no difference in initial SUV scores between IDDM and non-IDDM groups. Patients with tumors at the gastroesophageal junction had lower initial SUV scores compared to patients with tumors in the lower or mid-esophagus (P = .05). T stage was associated with initial SUV score (T2 lower than T3, P = .014). Older age (P = .03), diabetes (P = .007), higher T stage (P = .002), and presence of nodes (P = .05) were each positively associated with posttreatment SUV scores. Blood glucose levels prior to 18-FDG PET scan, endoscopic tumor length, and tumor location were not predictive of posttreatment SUV scores. Patients with DM had significantly lower posttreatment SUV scores compared to patients without DM (P = .04). Pathologic complete response or percent SUV decrease did not differ between patients with or without DM.
Conclusion:
Regardless of glucose levels, DM and IDDM do not influence pretreatment SUV scores in patients with localized esophageal cancer. However, DM may influence posttreatment SUV scores and thus complicate interpretation of treatment response. Further confirmatory study in a larger cohort of DM patients to evaluate the relationship of posttreatment SUV score to pathologic response is warranted.
PMCID: PMC2739639  PMID: 19742140
13.  Review of docetaxel in the treatment of gastric cancer 
Gastric cancer is a global health problem accounting for 800,000 cancer related deaths annually. Often diagnosed at an advanced stage, the treatment of gastric cancer with chemotherapy is directed towards palliating cancer related symptoms with only modest improvements in survival. In addition, no regimen has emerged as a globally accepted standard. New therapeutic options are desperately needed for the treatment of gastric cancer. Docetaxel given in combination has recently emerged as a new option for patients with advanced gastric cancer. This review focuses on the treatment of advanced gastric cancer utilizing docetaxel-based therapy and the novel additions of biotherapy to the existing cytotoxic platforms. In addition, the current investigations of docetaxel for the treatment of potentially curable gastric cancer will be discussed.
PMCID: PMC2621422  PMID: 19209281
docetaxel; gastric cancer; chemotherapy; biotherapy
14.  Thromboembolism in Gastrointestinal Cancers 
The link between thromboembolism and cancer has been recognized for over 100 years. Venous thromboembolism (VTE) is associated with considerable morbidity in patients with cancer, with emerging research also indicating a detrimental effect on survival. Investigations aimed at improving outcomes for patients with cancer have focused on the role of low molecular weight heparin in primary and secondary prevention of VTE and in improving patient survival. Important fundamental questions remain unanswered, however, and a significant line of research needs to be dedicated to investigating VTE in GI cancers. The effect of VTE on survival needs to be clarified, as does the role of anticoagulation in this patient population. Opportunities for additional research include investigating methods to identify patients at risk of developing VTE and developing new strategies and therapeutic interventions to reduce the morbidity and mortality associated with VTE. This review focuses on the current understanding of VTE related to gastrointestinal cancers and directions of interest in research specific to GI cancers and VTE.
PMCID: PMC2632566  PMID: 19259275
15.  Selective Fluorescence Probes for Dipeptidyl Peptidase Activity - Fibroblast Activation Protein and Dipeptidyl Peptidase IV 
Bioconjugate chemistry  2007;18(4):1246-1250.
Development of suitable tools to assess enzyme activity directly from their complex cellular environment has a dramatic impact on understanding the functional roles of proteins as well as on the discovery of new drugs. In this study, a novel fluorescence-based chemosensor strategy for the direct readout of dipeptidase activities within intact living cells is described. Selective activity-based probes were designed to sense two important type II transmembrane serine proteases, Fibroblast activation protein (FAP) and Dipeptidyl peptidase IV (DPP-IV). These serine proteases have been implicated in diverse cellular activities, including blood coagulation, digestion, immune responses, wound healing, tumor growth, tumor invasion and metastasis. We here validated that Ac-GPGP-2SBPO and GPGP-2SBPO probes are excellent reporters of both proteolytic activities. Furthermore, the novel probes can differentiate between FAP and DPP-IV proteolytic activities in cellular assay. Potentially, this assay platform is immediately useful for novel drug discovery.
doi:10.1021/bc0603586
PMCID: PMC2562575  PMID: 17489551
Fibroblast activation protein; dipeptidyl peptidase IV; dipeptidyl peptidase; fluorogenic substrate; fluorescence

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