Glen J Weiss

Cancer Treatment Centers of America, Schaumburg, Illinois, United States

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Publications (126)771.96 Total impact

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    ABSTRACT: Purpose: Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of VX15/2503 in advanced solid tumor patients. Experimental design: Weekly IV doses were administered on a 28-day cycle. Safety, immunogenicity, PK, efficacy, T-cell membrane-associated SEMA4D (cSEMA4D) expression and saturation, soluble SEMA4D (sSEMA4D) serum levels, and serum biomarker levels were evaluated. Results: Forty-two patients were enrolled into 7 sequential cohorts and an expansion cohort (20 mg/kg). VX15/2503 was well tolerated. Treatment-related adverse events were primarily Grade 1 or 2 and included nausea (14.3%) and fatigue (11.9%); arthralgia, decreased appetite, infusion-related reaction, and pyrexia were each 7.3%. One pancreatic cancer patient (15 mg/kg) experienced a Grade 3 dose-limiting toxicity; elevated γ-glutamyl transferase. Complete cSEMA4D saturation was generally observed at serum antibody concentrations ≥ 0.3 µg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusion number. Neutralizing anti-VX15/2503 antibodies led to treatment discontinuation for one patient. VX15/2503 Cmax and AUC generally increased with dose and dose number. One patient (20 mg/kg) experienced a partial response; 19 patients (45.2%) exhibited SD for ≥8 weeks and eight (19%) had SD for ≥16 weeks. Subjects with elevated B /T lymphocytes exhibited longer progression-free survival. Conclusions: VX15/2503 was well tolerated and produced expected PD effects. The correlation between immune cell levels at baseline and PFS is consistent with an immune-mediated mechanism of action. Future investigations will be in combination with immunomodulatory agents.
    Clinical Cancer Research 10/2015; DOI:10.1158/1078-0432.CCR-15-0431 · 8.72 Impact Factor
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    Glen J Weiss · Vivek Khemka ·

    OncoTargets and Therapy 10/2015; 8:2643. DOI:10.2147/OTT.S96038 · 2.31 Impact Factor
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    ABSTRACT: Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924), and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced non-hematological malignancies Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on Days 1-5 (schedule A, n=12), or Days 1, 3, and 5 (schedules B, n=17, and C, n=19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg prior to each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0 Results: Schedule A MTD was 50 mg/m2; based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m2, respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via immunohistochemical detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. Conclusions: Pevonedistat was generally well tolerated on a Day 1, 3, 5 schedule every 3 weeks with an MTD between 50 and 67 mg/m2. DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated pevonedistat tumor NAE inhibition. Clinical trials are ongoing.
    Clinical Cancer Research 10/2015; DOI:10.1158/1078-0432.CCR-15-1338 · 8.72 Impact Factor
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    ABSTRACT: Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in clinical trials. Here we report safety and clinical activity of avelumab in patients (pts) with previously treated, recurrent or refractory ovarian cancer (NCT01772004). Materials and Methods: Pts received avelumab at 10mg/kg as a 1-h infusion Q2W until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumours were assessed every 6 wks (RECIST 1.1). Unconfirmed best overall response (BOR) and progression-free survival (PFS) were evaluated and analyses of overall survival are ongoing. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Tumour PD-L1 expression at baseline was assessed by immunohistochemistry. Results: Seventy-five women with recurrent or refractory stage III-IV ovarian cancer were treated with avelumab. As of 13 Feb 2015, median duration of treatment was 12 wks (range, 2–54), and 8 pts remained on treatment. Median age was 62y (range 38–84), ECOG performance status was 0 [41.3%] or 1 [58.7%], and pts had received a median of 5 lines of prior treatment (range, 2-≥5). Treatment-related treatment-emergent adverse events (TEAEs) of any grade occurred in 52 pts (69.3%); the most common (>10%) were fatigue (12 [16.0%]), chills (9 [12.0%]), nausea (8 [10.7%]), and diarrhoea (8 [10.7%]). There were 6 pts (8.0%) reporting treatment-related grade 3/4 TEAEs (none occurred in more than 1 pt) and no treatment-related grade 5 TEAEs. Objective responses were observed in 8 (10.7%) pts (95%CI: 4.7, 19.9). All were partial responses and 5 (62.5%) were ongoing at data cutoff. Tumour shrinkage by ≥30% in target lesions was observed in 3 additional pts (4.0%); however, these pts did not meet RECIST criteria for response. Stable disease was observed in 33 pts (44.0%). Median PFS was 11.4 wks (95%CI: 6.3, 12.0) and the PFS rate at 24 wks was 17.2% (95%CI: 8.1, 29.2). Tumours were PD-L1+ in 74.6% of evaluable pts (n=67; 1% tumour expression cutoff). The ORR in PD-L1+ pts (n=50) was 12.0% and 5.9% in PD-L1− pts (n=17). OS data are immature at this time. Conclusions: Avelumab showed an acceptable safety profile and encouraging clinical activity in this largest-to-date cohort of pts with heavily pretreated, advanced ovarian cancer treated with anti-PD-(L)1 therapy. Analysis of PD-L1 expression shows a trend towards better response in PD-L1+ tumours. Additional clinical studies with avelumab as monotherapy and in combination with other agents in this pt population are planned. *Proposed INN.
    ECC 2015, Vienna, Austria; 09/2015
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    ABSTRACT: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R). Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor. A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment. Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. (Funded by Plexxikon; number, NCT01004861.).
    New England Journal of Medicine 07/2015; 373(5):428-37. DOI:10.1056/NEJMoa1411366 · 55.87 Impact Factor
  • Kristen R Dearing · Glen J Weiss ·
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    ABSTRACT: Next-generation sequencing (NGS) is being applied in oncology care to identify specific molecular aberrations of patient's tumors. The use of NGS now allows for sequencing entire human genomes within a reasonable cost and practical time frames for treatment decision making. Further delineation of epigenetics, transcriptomics, metagenomics and NGS at the level of circulating tumor DNA reveal ever increasing complexity to understand these interactions and the roles they play in cancer. With the improvement in understanding the study of proteomics, it has become clear that NGS has room for innovation to someday include sequencing of proteins. Early embarkation of NGS incorporated into clinical trials has begun. Here, we review the feasibility and practicality of translating NGS from clinical trials to clinical practice.
    Personalized Medicine 07/2015; 12(2):1-8. DOI:10.2217/pme.14.54 · 1.34 Impact Factor
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    ABSTRACT: Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab (proposed INN) (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. Here we present results from a cohort of patients (pts) with recurrent or refractory ovarian cancer in an ongoing phase Ib study (NCT01772004). Methods: Pts with ECOG PS 0-1 received avelumab at 10 mg/kg Q2W. Best overall response (BOR) and progression-free survival (PFS) were assessed according to RECIST 1.1. Adverse events (AEs) were evaluated by CTCAE v4.0. A prespecified analysis of 23 pts with follow-up of ≥ 2 months showed confirmed and unconfirmed partial responses (PRs), leading to cohort expansion to 75 pts. Results: Seventy-five pts were enrolled from November 2013 to November 2014 (median age 62 [range 38-84]; ECOG PS 0 [41%] or 1 [59%]; median of four prior lines of therapy). As of January 2015, median duration of treatment with avelumab was 10 weeks (range 2-54 weeks), and 27 pts remained on treatment. Efficacy data from the 23 pts followed-up for ≥ 2 months (range 2–8 months) demonstrated 4 pts (17.4%, [95% CI, 5.0%, 38.8%]) achieved an unconfirmed BOR of PR,11 (47.8%) had stable disease, and 2 pts had >30% tumor shrinkage after progression was reported. Median PFS was 11.9 weeks (95% CI, 5.9, not reached), and the PFS rate at 24 weeks was 33.3% (95% CI, 11.5, 57.2). Drug-related treatment-emergent AEs (TEAEs; all grades) were reported in 18 pts (78.3%), and 2 pts (8.7%) experienced grade ≥ 3 drug-related TEAEs (increased lipase [1] and elevated creatine kinase and autoimmune myositis that led to discontinuation [1]). No drug-related serious TEAEs occurred. The most commonly reported drug-related TEAEs (> 10%) were fatigue, nausea, and diarrhea. Conclusions: These data represent the largest reported dataset of pts with recurrent ovarian cancer treated with anti-PD-L1 therapy. Avelumab demonstrated an acceptable safety profile and is clinically active in this heavily pretreated ovarian cancer pt population. Clinical trial information: NCT01772004
    2015 ASCO annual Meeting; Chicago; 06/2015, Chicago, IL; 06/2015
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    Glen J Weiss ·

    Journal of Clinical Oncology 05/2015; 33(19). DOI:10.1200/JCO.2015.61.7464 · 18.43 Impact Factor
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    ABSTRACT: It is widely acknowledged that there is value in examining cancers for genomic aberrations via next-generation sequencing (NGS). How commercially available NGS platforms compare with each other, and the clinical utility of the reported actionable results, are not well known. During the course of the current study, the Foundation One (F1) test generated data on a combination of somatic mutations, insertion and deletion polymorphisms, chromosomal abnormalities, and deoxyribonucleic acid (DNA) copy number changes at ~250× coverage, while the Paradigm Cancer Diagnostic (PCDx) test generated the same type of data at >5,000× coverage, plus provided messenger RNA (mRNA) expression levels. We sought to compare and evaluate paired formalin-fixed paraffin-embedded tumor tissue using these two platforms. Samples from patients with advanced solid tumors were submitted to both the F1 and PCDx vendors for NGS analysis. Turnaround time (TAT) was calculated. Biomarkers were considered clinically actionable if they had a published association with treatment response in humans and were assigned to the following categories: commercially available drug (CA), clinical trial drug (CT), or neither option (hereafter referred to as "None"). The demographics of the 21 unique patient tumor samples included ten men and eleven women, with a median age of 56 years. Due to insufficient archival tissue from the same collection period, in one case, we used samples from different collections. PCDx reported first results faster than F1 in 20 cases. When received at both vendors on the same day, PCDx reported first results for 14 of 15 cases, with a median TAT of 9 days earlier than F1 (P<0.0001). Categorization of CA compared to CT and none significantly favored PCDx (P=0.012). In the current analysis, commercially available NGS platforms provided clinically relevant actionable targets (CA or CT) in 47%-67% of diverse cancer types. In the samples analyzed, PCDx significantly outperformed F1 in TAT, and had statistically significant higher clinically relevant actionable targets categorized as CA.
    OncoTargets and Therapy 04/2015; 8(15 Supplement):959-67. DOI:10.2147/OTT.S81995 · 2.31 Impact Factor

  • EORTC-NCI-AACR Symposium 2014; 11/2014

  • Cancer Research 10/2014; 74(19 Supplement):911-911. DOI:10.1158/1538-7445.AM2014-911 · 9.33 Impact Factor
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    ABSTRACT: Background: Orally administered SNX-5422, a novel, selective prodrug of the Heat shock protein 90 (Hsp90) inhibitor SNX-2112, was investigated in two sequential phase I studies to determine the safety, maximum tolerated doses (MTDs) and pharmacokinetic profile of SNX-5422. Methods: Using a dose-escalation design, 3-6 adults with advanced solid tumours received SNX-5422 every-other-day (QOD) or once-daily (QD) 3weeks on/1week off or QD continuously, with disease assessments every 8 weeks. Single-dose and steady-state pharmacokinetic parameters of SNX-2112 were determined. Results: In total, 56 patients were enrolled: QOD 3 weeks on/1 week off, n=36; QD 3weeks on/1 week off, n=17; QD continuous, n=3. Doses ranged from 4 to 133mg/m(2) QOD and 50 to 89 mg/m(2) QD. The MTDs were defined as 100mg/m(2) QOD and 67 mg/m(2) QD, respectively, with diarrhoea being dose-limiting on both 3 weeks on/1 week off schedules. Overall, treatment-related adverse events were mainly low grade, including diarrhoea (64%), nausea (39%), fatigue (28%), and vomiting (28%). Reversible grade 1-3 nyctalopia (night blindness) was reported by four patients (dose: 50-89mg/m(2) QD; 100mg/m(2) QOD). Exposure was generally linear, though greater than dose-proportional. Of 32 evaluable patients on QOD dosing, there was one durable complete response (prostate cancer), one confirmed (HER2+breast cancer) and one unconfirmed partial response (adrenal gland cancer). Three patients (QOD schedule) had stable disease for ⩾ 6 months. Conclusions: The dose and schedule recommended for further study with SNX-5422 is 100mg/m(2) QOD 3 weeks on/1 week off based on improved tolerability and preliminary evidence of clinical activity.
    European journal of cancer (Oxford, England: 1990) 09/2014; 50(17). DOI:10.1016/j.ejca.2014.07.017 · 5.42 Impact Factor
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    ABSTRACT: Background: Ficlatuzumab, a humanised hepatocyte growth factor (HGF) IgG1κ inhibitory monoclonal antibody, was evaluated for recommended phase II dose (RP2D), safety, pharmacokinetics (PKs), antidrug antibody (ADA), pharmacodynamics (PDs) and antitumour activity as monotherapy or combined with erlotinib. Methods: Patients with solid tumours received ficlatuzumab 2, 5, 10 or 20 mg kg–1 intravenously every 2 weeks (q2w). Additional patients were treated at the RP2D erlotinib. Results: Forty-one patients enrolled at doses ⩽20 mg kg–1. Common adverse events (AEs) included peripheral oedema, fatigue and nausea. Three patients experienced grade ⩾3 treatment-related hyperkalaemia/hypokalaemia, diarrhoea or fatigue. Best overall response (44%) was stable disease (SD); median duration was 5.5 months (0.4–18.7 months). One patient has been on therapy with SD for >4 years. Pharmacokinetics of ficlatuzumab showed low clearance (0.17–0.26 ml h–1 kg–1), a half-life of 6.8–9.4 days and dose-proportional exposure. Ficlatuzumab/erlotinib had no impact on the PK of either agent. No ADAs were detected. Ficlatuzumab increased serum HGF levels. Conclusions: Recommended phase II dose is 20 mg kg–1 q2w for ficlatuzumab monotherapy or with erlotinib. Preliminary antitumour activity and manageable AEs were observed. Pharmacokinetics were dose-proportional and consistent with other IgG therapeutics. Ficlatuzumab was not immunogenic, and serum HGF was a potential PD marker.
    British Journal of Cancer 06/2014; 111(2). DOI:10.1038/bjc.2014.290 · 4.84 Impact Factor
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    ABSTRACT: Purpose: To present a radiogenomic computed tomographic (CT) characterization of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) (ALK+). Materials and methods: In this HIPAA-compliant institutional review board-approved retrospective study, CT studies, ALK status, and clinical-pathologic data in 172 patients with NSCLC from three institutions were analyzed. A screen of 24 CT image traits was performed in a training set of 59 patients, followed by random forest variable selection incorporating 24 CT traits plus six clinical-pathologic covariates to identify a radiogenomic predictor of ALK+ status. This predictor was then validated in an independent cohort (n = 113). Test-for-accuracy and subset analyses were performed. A similar analysis was performed to identify a biomarker associated with shorter progression-free survival (PFS) after therapy with the ALK inhibitor crizotinib. Results: ALK+ status was associated with central tumor location, absence of pleural tail, and large pleural effusion. An ALK+ radiogenomic CT status biomarker consisting of these three imaging traits with patient age of younger than 60 years showed strong discriminatory power for ALK+ status, with a sensitivity of 83.3% (15 of 18), a specificity of 77.9% (74 of 95), and an accuracy of 78.8% (89 of 113) in independent testing. The discriminatory power was particularly strong in patients with operable disease (stage IIIA or lower), with a sensitivity of 100.0% (five of five), a specificity of 88.1% (37 of 42), and an accuracy of 89.4% (42 of 47). Tumors with a disorganized vessel pattern had a shorter PFS with crizotinib therapy than tumors without this trait (11.4 vs 20.2 months, P = .041). Conclusion: ALK+ NSCLC has distinct characteristics at CT imaging that, when combined with clinical covariates, discriminate ALK+ from non-ALK tumors and can potentially identify patients with a shorter durable response to crizotinib.
    Radiology 06/2014; 272(2):140789. DOI:10.1148/radiol.14140789 · 6.87 Impact Factor
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    Kristen R Dearing · Ashish Sangal · Glen J Weiss ·
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    ABSTRACT: The purpose of this article is to review the role of maintenance therapy in the treatment of advanced non-small cell lung cancer (NSCLC). A brief overview about induction chemotherapy and its primary function in NSCLC is provided to address the basis of maintenance therapies foundation. The development of how maintenance therapy is utilized in this population is discussed and current guidelines for maintenance therapy are reviewed. Benefits and potential pitfalls of maintenance therapy are addressed, allowing a comprehensive review of the achieved clinical benefit that maintenance therapy may or may not have on NSCLC patient population. A review of current literature was conducted and a table is provided comparing the results of various maintenance therapy clinical trials. The table includes geographical location of each study, the number of patients enrolled, progression free survival and overall survival statistics, post-treatment regimens and if molecular testing was conducted. The role of molecular testing in relation to therapeutic treatment options for advanced NSCLC patients is discussed. A treatment algorithm clearly depicts first line and second line treatment for management of NSCLC and includes molecular testing, maintenance therapy and the role clinical trials have in treatment of NSCLC. This treatment algorithm has been specifically tailored and developed to assist clinicians in the management of advanced NSCLC.
    05/2014; 5(2):103-113. DOI:10.5306/wjco.v5.i2.103
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    ABSTRACT: This Phase 1, open-label, uncontrolled, ascending-dose study explored the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacology of the TLR8 agonist VTX-2337 in subjects with advanced solid tumors or lymphoma. VTX-2337 doses (0.1-3.9 mg/m2) were administered subcutaneously on Days 1, 8, and 15 of each 28-day cycle. Safety/tolerability assessments included adverse events (AEs); physical, ophthalmologic, and laboratory evaluations; and electrocardiograms. Dose-limiting toxicities (DLTs) were evaluated during the first cycle. Pharmacokinetics were evaluated after the first dose. Plasma samples were quantitatively assessed for chemokines, cytokines, and other inflammatory mediators. Anti tumor activity was assessed. Thirty-three subjects were enrolled in 8 cohorts and received an average of 2 treatment cycles (range: 1-8 cycles). Most AEs were grade 1-2; the most common drug-related AEs were injection site reactions, chills, pyrexia, and influenza-like illness. One DLT was reported: grade 3 hypotension (3.9 mg/m2). The MTD was considered the highest dose administered. Peak drug plasma levels and total systemic exposure were generally dose proportional. At doses greater than or equal to 0.4 mg/m2, increases above baseline levels were observed for plasma levels of G-CSF, MCP-1, MIP-1β, and TNFα. Eight subjects (24.2%) had a best response of stable disease (median duration: 54.5 days). VTX-2337 is clinically well tolerated and biologically active with a predictable pharmacokinetic profile. Suitable doses for testing in combination studies were identified. Phase II placebo-controlled studies of VTX-2337 in combination with doxorubicin in ovarian cancer, and in combination with platinum chemotherapy, 5FU, and cetuximab in head and neck cancer have been initiated.
    Clinical Cancer Research 05/2014; 20(14). DOI:10.1158/1078-0432.CCR-14-0392 · 8.72 Impact Factor
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    ABSTRACT: The five-year survival rate in advanced non-small cell lung cancer (NSCLC) remains below ten percent. The invasive and metastatic nature of NSCLC tumor cells contributes to the high mortality rate, and as such the mechanisms that govern NSCLC metastasis is an active area of investigation. Two surface receptors that influence NSCLC invasion and metastasis are the hepatocyte growth factor receptor (HGFR/MET) and fibroblast growth factor-inducible 14 (FN14). MET protein is over-expressed in NSCLC tumors and associated with poor clinical outcome and metastasis. FN14 protein is also elevated in NSCLC tumors and positively correlates with tumor cell migration and invasion. In this report, we show that MET and FN14 protein expressions are significantly correlated in human primary NSCLC tumors, and the protein levels of MET and FN14 are elevated in metastatic lesions relative to patient-matched primary tumors. In vitro, HGF/MET activation significantly enhances FN14 mRNA and protein expression. Importantly, depletion of FN14 is sufficient to inhibit MET-driven NSCLC tumor cell migration and invasion in vitro. This work suggests that MET and FN14 protein expressions are associated with the invasive and metastatic potential of NSCLC. Receptor-targeted therapeutics for both MET and FN14 are in clinical development, the use of which may mitigate the metastatic potential of NSCLC.
    Clinical and Experimental Metastasis 04/2014; 31(6). DOI:10.1007/s10585-014-9653-6 · 3.49 Impact Factor
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    ABSTRACT: To conduct a phase I study determining the safety, pharmacokinetics and preliminary efficacy of EP-100, a novel anticancer drug consisting of natural luteinizing-hormone-releasing hormone (LHRH) ligand linked to a cationic membrane-disrupting peptide. Patients with advanced, solid tumors, positive for LHRH receptor by immunohistochemistry (IHC), received EP-100 weekly or twice weekly for 3 of 4 weeks in a 28 day cycle. A modified Fibonacci 3 + 3 dose-escalation schema was used. Initial cohorts received EP-100 once weekly (cohorts 1-7, 0.6-7.8 mg/m(2), n = 21). Later cohorts received doses twice weekly (cohorts 7-11, 7.8-40 mg/m(2), n = 16). LHRH-receptor expression was confirmed by IHC in 52 of 89 consented patients; 37 patients received at least 1 dose. Cohorts receiving doses of 5.2 mg/m(2) and above achieved therapeutic levels from in vitro studies Clearance was rapid (mean half-life 7.1 ± 3.8 to 15.9 ± 3.6 min). The maximum-tolerated dose was not reached at the highest dose evaluated (40 mg/m(2) twice weekly). Grade 2 increase in alanine aminotransferase/serum aspartate aminotransferase in one patient resolved, did not recur upon re-treatment, and was not observed in other patients. The only drug-related adverse event was transient infusion-related dermatologic reactions (10 patients). No complete or partial tumor responses were observed; seven patients had stable disease of 16 weeks. EP-100 was well tolerated in patients with advanced, LHRH-receptor-expressing solid tumors. The recommended phase 2 dose is 40 mg/m(2) twice weekly for 3 of 4 weeks per cycle.
    Cancer Chemotherapy and Pharmacology 03/2014; 73(5). DOI:10.1007/s00280-014-2424-x · 2.77 Impact Factor

  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):A120-A120. DOI:10.1158/1535-7163.TARG-13-A120 · 5.68 Impact Factor
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    ABSTRACT: Unlabelled: Insensitivity to standard clinical interventions, including chemotherapy, radiotherapy, and tyrosine kinase inhibitor (TKI) treatment, remains a substantial hindrance towards improving the prognosis of patients with non-small cell lung cancer (NSCLC). The molecular mechanism of therapeutic resistance remains poorly understood. The TNF-like weak inducer of apoptosis (TWEAK)-FGF-inducible 14 (TNFRSF12A/Fn14) signaling axis is known to promote cancer cell survival via NF-κB activation and the upregulation of prosurvival Bcl-2 family members. Here, a role was determined for TWEAK-Fn14 prosurvival signaling in NSCLC through the upregulation of myeloid cell leukemia sequence 1 (MCL1/Mcl-1). Mcl-1 expression significantly correlated with Fn14 expression, advanced NSCLC tumor stage, and poor patient prognosis in human primary NSCLC tumors. TWEAK stimulation of NSCLC cells induced NF-κB-dependent Mcl-1 protein expression and conferred Mcl-1-dependent chemo- and radioresistance. Depletion of Mcl-1 via siRNA or pharmacologic inhibition of Mcl-1, using EU-5148, sensitized TWEAK-treated NSCLC cells to cisplatin- or radiation-mediated inhibition of cell survival. Moreover, EU-5148 inhibited cell survival across a panel of NSCLC cell lines. In contrast, inhibition of Bcl-2/Bcl-xL function had minimal effect on suppressing TWEAK-induced cell survival. Collectively, these results position TWEAK-Fn14 signaling through Mcl-1 as a significant mechanism for NSCLC tumor cell survival and open new therapeutic avenues to abrogate the high mortality rate seen in NSCLC. Implications: The TWEAK-Fn14 signaling axis enhances lung cancer cell survival and therapeutic resistance through Mcl-1, positioning both TWEAK-Fn14 and Mcl-1 as therapeutic opportunities in lung cancer.
    Molecular Cancer Research 01/2014; 12(4). DOI:10.1158/1541-7786.MCR-13-0458 · 4.38 Impact Factor

Publication Stats

2k Citations
771.96 Total Impact Points


  • 2013-2015
    • Cancer Treatment Centers of America
      Schaumburg, Illinois, United States
  • 2008-2015
    • Translational Genomics Research Institute
      • • Division of Computational Biology
      • • Division of Neurogenomics
      Phoenix, Arizona, United States
  • 2014
    • Cancer Treatment Centre
      Anaheim, California, United States
  • 2008-2013
    • Scottsdale Healthcare Research Institute
      Arizona City, Arizona, United States
  • 2012
    • Aegera Therapeutics
      Montréal, Quebec, Canada
  • 2006
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States