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1.  Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models 
Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models.
A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ.
CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC50 values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC50 values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP).
CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-014-0111-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4304157  PMID: 25612802
Carfilzomib; Proteasome inhibitor; Lung cancer; Cisplatin
2.  A pilot clinical study of resveratrol in postmenopausal women with high body mass index: effects on systemic sex steroid hormones 
Breast cancer risk is partially determined by several hormone-related factors. Preclinical and clinical studies suggested that resveratrol may modulate these hormonal factors.
We conducted a pilot study in postmenopausal women with high body mass index (BMI ≥ 25 kg/m2) to determine the clinical effect of resveratrol on systemic sex steroid hormones. Forty subjects initiated the resveratrol intervention (1 gm daily for 12 weeks) with six withdrawn early due to adverse events (AEs). Thirty-four subjects completed the intervention.
Resveratrol intervention did not result in significant changes in serum concentrations of estradiol, estrone, and testosterone but led to an average of 10% increase in the concentrations of sex steroid hormone binding globulin (SHBG). Resveratrol intervention resulted in an average of 73% increase in urinary 2-hydroxyestrone (2-OHE1) levels leading to a favorable change in urinary 2-OHE1/16α-OHE1 ratio. One participant had asymptomatic Grade 4 elevation of liver enzymes at the end of study intervention. Two subjects had Grade 3 skin rashes. The remaining adverse events were Grade 1 or 2 events. The most common adverse events were diarrhea and increased total cholesterol, reported in 30% and 27.5% of the subjects, respectively.
We conclude that among overweight and obese postmenopausal women, daily 1 gm dose of resveratrol has favorable effects on estrogen metabolism and SHBG. Further placebo-controlled studies are needed to confirm our findings on these hormone-related breast cancer risk factors and the attribution of the adverse effects observed in the study population.
Trial registration NCT01370889.
PMCID: PMC4243716  PMID: 25115686
Resveratrol; Sex steroid hormones; High adiposity; Post-menopausal women
3.  Using logistic regression to improve the prognostic value of microarray gene expression data sets: application to early-stage squamous cell carcinoma of the lung and triple negative breast carcinoma 
BMC Medical Genomics  2014;7:33.
Numerous microarray-based prognostic gene expression signatures of primary neoplasms have been published but often with little concurrence between studies, thus limiting their clinical utility. We describe a methodology using logistic regression, which circumvents limitations of conventional Kaplan Meier analysis. We applied this approach to a thrice-analyzed and published squamous cell carcinoma (SQCC) of the lung data set, with the objective of identifying gene expressions predictive of early death versus long survival in early-stage disease. A similar analysis was applied to a data set of triple negative breast carcinoma cases, which present similar clinical challenges.
Important to our approach is the selection of homogenous patient groups for comparison. In the lung study, we selected two groups (including only stages I and II), equal in size, of earliest deaths and longest survivors. Genes varying at least four-fold were tested by logistic regression for accuracy of prediction (area under a ROC plot). The gene list was refined by applying two sliding-window analyses and by validations using a leave–one-out approach and model building with validation subsets. In the breast study, a similar logistic regression analysis was used after selecting appropriate cases for comparison.
A total of 8594 variable genes were tested for accuracy in predicting earliest deaths versus longest survivors in SQCC. After applying the two sliding window and the leave-one-out analyses, 24 prognostic genes were identified; most of them were B-cell related. When the same data set of stage I and II cases was analyzed using a conventional Kaplan Meier (KM) approach, we identified fewer immune-related genes among the most statistically significant hits; when stage III cases were included, most of the prognostic genes were missed. Interestingly, logistic regression analysis of the breast cancer data set identified many immune-related genes predictive of clinical outcome.
Stratification of cases based on clinical data, careful selection of two groups for comparison, and the application of logistic regression analysis substantially improved predictive accuracy in comparison to conventional KM approaches. B cell-related genes dominated the list of prognostic genes in early stage SQCC of the lung and triple negative breast cancer.
PMCID: PMC4110620  PMID: 24916928
4.  Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2013;31(7):895-902.
Brain metastasis (BM) is a leading cause of death from non–small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety.
Patients and Methods
Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility.
Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations.
Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.
PMCID: PMC3577951  PMID: 23341526
5.  Phase II Study of AZD2171 in Patients with Malignant Pleural Mesothelioma: SWOG S0509 
Malignant pleural mesothelioma (MPM) tumors express VEGF and VEGF receptors. MPM patients have high circulating levels of VEGF, suggesting that tumor angiogenesis is a relevant therapeutic target for MPM. We conducted a phase 2 trial of the VEGFR1/2 TKI AZD2171 in patients with MPM after platinum-based systemic chemotherapy.
Patients and Methods
Patients (pts) with MPM previously treated with a platinum-containing chemotherapy regimen, good performance status, measureable disease and no significant bleeding diathesis or thrombotic history were eligible for enrollment. Pts were treated with AZD2171 45 mg/day on days 1-28 of each 28 day dosing cycle. Tumor measurements were made by RECIST criteria, with a subset analysis of modified RECIST. A two-stage design with a stopping rule based on number of patients with complete or partial response was utilized.
Fifty-four patients were enrolled on study between 11/05 and 4/08. For 47 evaluable patients, 4 patients (9%) had objective responses, including two patients who had 91% and 56% responses in bulky pleural tumor; 16 patients (34%) had stable disease, 20 pts (43%) had disease progression; 2 pts (4%) had symptomatic deterioration and 1 pt (2%) had early death. Four were not assessable for response and assumed to be non-responders. The most common AZD2171-attributable toxicities were fatigue (64%), diarrhea (64%) and hypertension (70%); the majority of patients required a dose reduction. Median overall survival was 9.5 months, 1-year survival was 36% and median progression-free survival was 2.6 months.
The anti-angiogenic AZD2171 has modest single agent activity in MPM. However, several patient tumors were exquisitely sensitive to AZD2171. The starting dose was not well tolerated in this setting. Tumor response by Modified RECIST available for a small subset of patients correlated well with tumor response by RECIST. This study provides a rationale for further testing of AZD2171 with chemotherapy in MPM.
PMCID: PMC3477852  PMID: 21964533
Phase 2; angiogenesis inhibitor; pleural mesothelioma
6.  Molecular Analysis of Non-Small Cell Lung Cancer (NSCLC) Identifies Subsets with Different Sensitivity to Insulin like Growth Factor I Receptor (IGF-IR) Inhibition 
Identify molecular determinants of sensitivity of NSCLC to anti-insulin like growth factor receptor (IGF-IR) therapy.
Experimental Design
216 tumor samples were investigated. 165 consisted of retrospective analyses of banked tissue and an additional 51 were from patients enrolled in a phase 2 study of figitumumab (F), a monoclonal antibody against the IGF-IR, in stage IIIb/IV NSCLC. Biomarkers assessed included IGF-IR, EGFR, IGF-2, IGF-2R, IRS-1, IRS-2, vimentin and E-cadherin. Sub-cellular localization of IRS-1 and phosphorylation levels of MAPK and Akt1 were also analyzed.
IGF-IR was differentially expressed across histological subtypes (P=0.04), with highest levels observed in squamous cell tumors. Elevated IGF-IR expression was also observed in a small number of squamous cell tumors responding to chemotherapy combined with F (p=0.008). Since no other biomarker/response interaction was observed using classical histological sub-typing, a molecular approach was undertaken to segment NSCLC into mechanism-based subpopulations. Principal component analysis and unsupervised Bayesian clustering identified 3 NSCLC subsets that resembled the steps of the epithelial-to-mesenchymal transition: E-cadherin high/IRS-1 low (Epithelial-like), E-cadherin intermediate/IRS-1 high (Transitional) and E-cadherin low/IRS-1 low (Mesenchymal-like). Several markers of the IGF-IR pathway were over-expressed in the Transitional subset. Furthermore, a higher response rate to the combination of chemotherapy and F was observed in Transitional tumors (71%) compared to those in the Mesenchymal-like subset (32%, p=0.03). Only one Epithelial-like tumor was identified in the phase 2 study, suggesting that advanced NSCLC has undergone significant de-differentiation at diagnosis.
NSCLC comprises molecular subsets with differential sensitivity to IGF-IR inhibition.
PMCID: PMC2952544  PMID: 20670944
IGF-IR; Figitumumab; NSCLC
7.  Resveratrol Modulates Drug and Carcinogen Metabolizing Enzymes in a Healthy Volunteer Study 
Resveratrol has been shown to exhibit cancer preventive activities in preclinical studies. We conducted a clinical study to determine the effect of pharmacological doses of resveratrol on drug and carcinogen metabolizing enzymes. Forty-two healthy volunteers underwent baseline assessment of cytochrome P450 (CYP) and Phase II detoxification enzymes. CYP 1A2, 2D6, 2C9, and 3A4 enzyme activities were measured by the metabolism of caffeine, dextromethorphan, losartan, and buspirone, respectively. Blood lymphocyte glutathione S-transferase (GST) activity and GST-π level and serum total and direct bilirubin, a surrogate for UDP-glucuronosyl transferase (UGT) 1A1 activity, were measured to assess Phase II enzymes. After the baseline evaluation, study participants took 1 gm of resveratrol once daily for 4 wks. Enzyme assessment was repeated upon intervention completion. Resveratrol intervention was found to inhibit the phenotypic indices of CYP3A4, 2D6, and 2C9, and to induce the phenotypic index of 1A2. Overall, GST and UGT1A1 activities were minimally affected by the intervention, although an induction of GST-π level and UGT1A1 activity was observed in individuals with low baseline enzyme level/activity. We conclude that resveratrol can modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which resveratrol inhibits carcinogenesis. However, pharmacological doses of resveratrol could potentially lead to increased adverse drug reactions or altered drug efficacy due to inhibition or induction of certain CYPs. Further clinical development of resveratrol for cancer prevention should consider evaluation of lower doses of resveratrol to minimize adverse metabolic drug interactions.
PMCID: PMC2933312  PMID: 20716633
resveratrol; Cytochrome P450 enzymes; cancer prevention; phase II enzymes
8.  Safety, Pharmacokinetics, and Pharmacodynamics of the Insulin-Like Growth Factor Type 1 Receptor Inhibitor Figitumumab (CP-751,871) in Combination with Paclitaxel and Carboplatin 
This phase 1 study was conducted to determine the recommended phase 2 dose of the selective insulin-like growth factor type 1 receptor (IGF-IR) inhibitor figitumumab (F, CP-751,871) given in combination with paclitaxel and carboplatin in patients with advanced solid tumors.
Patients received paclitaxel 200 mg/m2, carboplatin (area under the curve of 6), and F (0.05–20 mg/kg) q3 weeks for up to six cycles. Patients with objective response or stable disease were eligible to receive additional cycles of single agent F until disease progression. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints were investigated.
Forty-two patients, including 35 with stages IIIB and IV non-small cell lung cancer (NSCLC), were enrolled in eight dose escalation cohorts. A maximum tolerated dose was not identified. Severe adverse events possibly related to F included fatigue, diarrhea, hyperglycemia, gamma glutamyl transpeptidase elevation, and thrombocytopenia (one case each). F plasma exposure parameters increased with dose. Fifteen objective responses (RECIST) were reported, including two complete responses in NSCLC and ovarian carcinoma. Notably, levels of bioactive IGF-1 seemed to influence response to treatment with objective responses in patients with a high baseline-free IGF-1 to IGF binding protein-3 ratio seen only in the 10 and 20 mg/kg dosing cohorts.
F was well tolerated in combination with paclitaxel and carboplatin. Based on its favorable safety, pharmacokinetic, and pharmacodynamic properties, the maximal feasible dose of 20 mg/kg has been selected for further investigation.
PMCID: PMC2941876  PMID: 19745765
IGF-1R; Figitumumab; CP-751,871; NSCLC

Results 1-8 (8)