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1.  Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial 
To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE program.
Patients and Methods
Patients with previously treated non-small–cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS).
105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for 8-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 (95% confidence interval [CI], 2.04-3.58) and 8.48 months (95% CI, 5.78-10.97), respectively. Eight-week DCR was higher in patients with wt-EGFR than patients with EGFR mutation (P=0.012), and in patients with EGFR gene copy number gain (FISH positive) versus patients FISH negative (P=0.048). In wt-EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS versus 1.84 months in low SSS, P=0.026) but not with 8-week DCR. Increased expression of fibroblast growth factor-1, NF-kB and hypoxia pathways were identified potential drivers of sorafenib resistance.
Sorafenib demonstrates clinical activity in NSCLC, especially with wt-EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials. NCT00411671.
PMCID: PMC3905243  PMID: 24166906
multikinase inhibitor; non–small cell lung cancer; sorafenib; biomarkers; targeted treatment
2.  EGFR Expression and Survival in Patients Given Cetuximab and Chemoradiation for Stage III Non-Small Cell Lung Cancer: A Secondary Analysis of RTOG 0324 
We investigated whether expression of epidermal growth factor receptor (EGFR) was associated with survival and disease control in this secondary analysis of a phase II trial of cetuximab+chemoradiation for stage III non-small cell lung cancer.
Patients received cetuximab weekly before and during radiation (63 Gy/35 fractions/7 weeks) with weekly carboplatin+paclitaxel. We analyzed EGFR expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in pretreatment biopsy specimens and compared findings with overall and progression-free survival (OS, PFS) and time to progression (TTP).
Specimens for IHC and FISH were collected from 51 and 45 of 87 evaluable patients. Pretreatment characteristics did not differ for patients with (n=51) or without (n=36) EGFR IHC data, or with (n=45) or without (n=42) FISH data. However, patients without IHC data had worse OS (HR=1.63, P=0.05), worse PFS (HR=1.88, P=0.008), and worse TTP [HR=1.99, P=0.01] than those with IHC data. EGFR protein expression was not related to pretreatment characteristics or OS; FISH-positive disease was associated with better performance status but not with OS, PFS, or TTP.
Surprisingly, outcomes differed not by EGFR expression but by the availability of samples for analysis, underscoring the importance of obtaining biopsy samples in such trials.
PMCID: PMC4169722  PMID: 25042878
Clinical trials identifier NCT00081302; RTOG 0324; cetuximab; inoperable lung cancer; Erbitux
3.  Phase II Study of Cetuximab in Combination With Chemoradiation in Patients With Stage IIIA/B Non–Small-Cell Lung Cancer: RTOG 0324 
Journal of Clinical Oncology  2011;29(17):2312-2318.
Non–small-cell lung cancer (NSCLC) commonly expresses the epidermal growth factor receptor (EGFR), which is associated with poor clinical outcome. Cetuximab is a chimerized monoclonal antibody that targets the EGFR and, in preclinical models, it demonstrates radiosensitization properties. We report a phase II trial testing the combination of cetuximab with chemoradiotherapy (CRT) in unresectable stage III NSCLC.
Patients and Methods
Eligibility criteria included unresectable stage III NSCLC, Zubrod performance status ≤ 1, weight loss ≤ 5%, forced expiratory volume in 1 second ≥ 1.2 L, and adequate organ function. Patients received an initial dose of cetuximab (400 mg/m2) on day 1 of week 1 and then weekly doses of cetuximab (250 mg/m2) until completion of therapy (weeks 2 through 17). During week 2, patients started CRT (63 Gy in 35 fractions) with weekly carboplatin at area under the [concentration-time] curve (AUC) 2 and six doses of paclitaxel at 45 mg/m2 followed by carboplatin (AUC 6) and two cycles of paclitaxel (200 mg/m2) during weeks 12 through 17. Primary end points included safety and compliance of concurrent cetuximab and CRT.
In all, 93 patients were enrolled and 87 were evaluable. Median follow-up was 21.6 months. Response rate was 62% (n = 54), median survival was 22.7 months, and 24-month overall survival was 49.3%. Adverse events related to treatment included 20% grade 4 hematologic toxicities, 8% grade 3 esophagitis, and 7% grade 3 to 4 pneumonitis. There were five grade 5 events.
The combination of cetuximab with CRT is feasible and shows promising activity. The median and overall survival achieved with this regimen were longer than any previously reported by the Radiation Therapy Oncology Group.
PMCID: PMC3107747  PMID: 21555682
4.  Targeting the Hepatocyte Growth Factor–cMET Axis in Cancer Therapy 
Journal of Clinical Oncology  2012;30(26):3287-3296.
The hepatocyte growth factor (HGF) and its receptor, the transmembrane tyrosine kinase cMET, promote cell proliferation, survival, motility, and invasion as well as morphogenic changes that stimulate tissue repair and regeneration in normal cells but can be co-opted during tumor growth. MET overexpression, with or without gene amplification, has been reported in a variety of human cancers, including breast, lung, and GI malignancies. Furthermore, high levels of HGF and/or cMET correlate with poor prognosis in several tumor types, including breast, ovarian, cervical, gastric, head and neck, and non–small-cell lung cancers. Gene amplification and protein overexpression of cMET drive resistance to epidermal growth factor receptor family inhibitors, both in preclinical models and in patients. It is increasingly apparent that the HGF-cMET axis signaling network is complex, and rational combinatorial therapy is needed for optimal clinical efficacy. Better understanding of HGF-cMET axis signaling and the mechanism of action of HGF-cMET inhibitors, along with the identification of biomarkers of response and resistance, will lead to more effective targeting of this pathway for cancer therapy.
PMCID: PMC3434988  PMID: 22869872
5.  Role of HGF/MET axis in resistance of lung cancer to contemporary management 
Lung cancer is the number one cause of cancer related mortality with over 1 million cancer deaths worldwide. Numerous therapies have been developed for the treatment of lung cancer including radiation, cytotoxic chemotherapy and targeted therapies. Histology, stage of presentation and molecular aberrations are main determinants of prognosis and treatment strategy. Despite the advances that have been made, overall prognosis for lung cancer patients remains dismal. Chemotherapy and/or targeted therapy yield objective response rates of about 35% to 60% in advanced stage non-small cell lung cancer (NSCLC). Even with good initial responses, median overall survival of is limited to about 12 months. This reflects that current therapies are not universally effective and resistance develops quickly. Multiple mechanisms of resistance have been proposed and the MET/HGF axis is a potential key contributor. The proto-oncogene MET (mesenchymal-epithelial transition factor gene) and its ligand hepatocyte growth factor (HGF) interact and activate downstream signaling via the mitogen-activated protein kinase (ERK/MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K/AKT) pathways that regulate gene expression that promotes carcinogenesis. Aberrant MET/HGF signaling promotes emergence of an oncogenic phenotype by promoting cellular proliferation, survival, migration, invasion and angiogenesis. The MET/HGF axis has been implicated in various tumor types including lung cancers and is associated with adverse clinicopathological profile and poor outcomes.
The MET/HGF axis plays a major role in development of radioresistance and chemoresistance to platinums, taxanes, camtothecins and anthracyclines by inhibiting apoptosis via activation of PI3K-AKT pathway. DNA damage from these agents induces MET and/or HGF expression. Another resistance mechanism is inhibition of chemoradiation induced translocation of apoptosis-inducing factor (AIF) thereby preventing apoptosis. Furthermore, this MET/HGF axis interacts with other oncogenic signaling pathways such as the epidermal growth factor receptor (EGFR) pathway and the vascular endothelial growth factor receptor (VEGFR) pathway. This functional cross-talk forms the basis for the role of MET/HGF axis in resistance against anti-EGFR and anti-VEGF targeted therapies. MET and/or HGF overexpression from gene amplification and activation are mechanisms of resistance to cetuximab and EGFR-TKIs. VEGF inhibition promotes hypoxia induced transcriptional activation of MET proto-oncogene that promotes angiogenesis and confers resistance to anti-angiogenic therapy. An extensive understanding of these resistance mechanisms is essential to design combinations with enhanced cytotoxic effects.
Lung cancer treatment is challenging. Current therapies have limited efficacy due to primary and acquired resistance. The MET/HGF axis plays a key role in development of this resistance. Combining MET/HGF inhibitors with chemotherapy, radiotherapy and targeted therapy holds promise for improving outcomes.
PMCID: PMC4367559  PMID: 25806180
Mesenchymal-epithelial transition factor gene (MET); hepatocyte growth factor (HGF); lung cancer; resistance; epidermal growth factor receptor (EGFR)
6.  The BATTLE Trial: Personalizing Therapy for Lung Cancer 
Cancer discovery  2011;1(1):44-53.
Lung cancer is the leading cancer cause of mortality worldwide; large-scale trials have failed to improve clinical outcomes of patients with chemorefractory non-small-cell lung cancer (NSCLC).
Following an initial equal randomization period, BATTLE adaptively randomized patients with chemorefractory NSCLC to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib based on molecular biomarkers of NSCLC pathogenesis in fresh core needle biopsy specimens. The primary end point was disease control rate (DCR) at 8 weeks.
Of 255 patients randomly assigned to erlotinib (59 patients), vandetanib (54), erlotinib plus bexarotene (37), and sorafenib (105), 244 were eligible for the DCR analysis. Pneumothorax after lung biopsy occurred in 11.5% and treatment-related toxicities grade 3–4 in 6.5% of patients. Overall results were a 46% 8-week DCR, 1.9-month median progression-free survival, 9-month median overall survival, and 35% 1-year survival. Individual markers predicting a significantly superior DCR for a treatment included: epidermal growth factor receptor (EGFR) mutation (P=0.04) for erlotinib; cyclin D1 positivity (P=0.01) or EGFR amplification (P=0.006) for erlotinib plus bexarotene; vascular endothelial growth factor receptor 2 positivity (P=0.05) for vandetanib; and absence of EGFR mutation (P=0.01) or of EGFR high polysomy (P=0.05) for sorafenib. A better 8-week DCR occurred with sorafenib versus all other regimens (64% versus 33%; P<0.001) among EGFR wild-type patients and versus all other regimens (61% versus 32%; P=0.11) among mutant-KRAS patients. The prespecified biomarker groups were less predictive than the individual biomarkers analyzed in this study.
The first completed biopsy-mandated study in pretreated NSCLC, BATTLE confirmed our pre-specified hypotheses regarding biomarker and targeted treatment interactions, establishing a new paradigm for personalizing therapy for patients with NSCLC. ( numbers, NCT00409968, NCT00411671, NCT00411632, NCT00410059, NCT00410189.)
PMCID: PMC4211116  PMID: 22586319
7.  Mesothelin expression and survival outcomes in triple receptor negative breast cancer 
Clinical breast cancer  2013;13(5):10.1016/j.clbc.2013.05.001.
Mesothelin is an ideal tumor-associated marker for the development of targeted therapy due to its limited expression in normal tissues. The aim of this study was to evaluate mesothelin expression in triple-negative breast cancer (TNBC) and its correlation with survival outcomes.
Mesothelin expression was completed using immunohistochemistry, and quantified by H-score. An H-score >10 was considered positive. Patient's characteristics were compared by mesothelin expression. Kaplan-Meier product limit method was used to estimate survival outcomes. Cox proportional hazards models was used to adjust for patient and tumor characteristics.
Median age was 52 years. Of the 109 TNBC, 37 (34%) were positive for mesothelin expression. There were no differences on patient/tumor characteristics by mesothelin expression with the exception of high frequency of lymphovascular space invasion in mesothelin-negative tumors (P=0.03). At a median follow up of 75.8 months 20 (18.3%) patients had experienced a recurrence and 22 (20.2%) had died. Five-year progression-free survival was 87% and 92% in patients with mesothelin-positive and mesothelin-negative tumors (P=0.43). Five-year overall survival was 85% and 91% in patients with mesothelin-positive and mesothelin-negative tumors (P=0.57), respectively. Mesothelin expression was not an independent predictor of survival outcomes.
Mesothelin expression was identified in 34% of TNBC. Mesothelin expression did not correlate with survival outcomes in TNBC.
PMCID: PMC3839051  PMID: 23810431
Meosthelin expression; triple-negative breast cancer; prognosis
8.  Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials 
Oncotarget  2014;5(19):8937-8946.
KRAS mutation is common in human cancer. We assessed the clinical factors, including type of KRAS mutation and treatment, of patients with advanced cancer and tumor KRAS mutations and their association with treatment outcomes.
Patients referred to the Phase I Clinic for treatment who underwent testing for KRAS mutations were analyzed.
Of 1,781 patients, 365 (21%) had a KRAS mutation. The G12D mutation was the most common mutation (29%). PIK3CA mutations were found in 24% and 10% of patients with and without KRAS mutations (p<0.0001). Of 223 patients with a KRAS mutation who were evaluable for response, 56 were treated with a MEK inhibitor-containing therapy and 167 with other therapies. The clinical benefit (partial response and stable disease lasting ≥ 6 months) rates were 23% and 9%, respectively, for the MEK inhibitor versus other therapies (p=0.005). The median progression-free survival (PFS) was 3.3 and 2.2 months, respectively (p=0.09). The respective median overall survival was 8.4 and 7.0 months (p=0.38). Of 66 patients with a KRAS mutation and additional alterations, higher rates of clinical benefit (p=0.04), PFS (p=0.045), and overall survival (p=0.02) were noted in patients treated with MEK inhibitor-containing therapy (n=9) compared to those treated with targeted therapy matched to the additional alterations (n=24) or other therapy (n=33).
MEK inhibitors in patients with KRAS-mutated advanced cancer were associated with higher clinical benefit rates compared to other therapies. Therapeutic strategies that include MEK inhibitors or novel agents combined with other targeted therapies or chemotherapy need further investigation.
PMCID: PMC4253408  PMID: 25313136
Personalized medicine; Phase I; Clinical trials; Targeted therapy; Molecular alterations
9.  A Phase I/II Study Combining Erlotinib and Dasatinib for Non-Small Cell Lung Cancer 
The Oncologist  2014;19(10):1040-1041.
EGFR and Src are frequently activated in non-small cell lung cancer (NSCLC). In preclinical models, combining EGFR and Src inhibition has additive synergistic effects. We conducted a phase I/II trial of the combination of Src inhibitor dasatinib with EGFR inhibitor erlotinib to determine the maximum tolerated dose (MTD), pharmacokinetic drug interactions, biomarkers, and efficacy in NSCLC.
The phase I 3+3 dose-escalation study enrolled patients with solid tumors to determine the MTD. The phase II trial enrolled patients with advanced NSCLC who had undergone no previous treatments to determine progression-free survival (PFS) and response. Pharmacokinetic and tissue biomarker analyses were performed.
MTD was 150 mg of erlotinib and 70 mg of dasatinib daily based on 12 patients treated in the phase I portion. No responses were observed in phase I. The 35 NSCLC patients treated in phase II had an overall disease control rate of 59% at 6 weeks. Five patients (15%) had partial responses; all had activating EGFR mutations. Median PFS was 3.3 months. Epithelial-mesenchymal transition markers did not correlate with outcomes.
The combination of erlotinib and dasatinib is safe and feasible in NSCLC. The results of this study do not support use of this combination in molecularly unselected NSCLC.
PMCID: PMC4201000  PMID: 25170013
10.  Feasibility of Image-Guided Transthoracic Core Needle Biopsy in the BATTLE Lung Trial 
As therapy for non-small cell lung cancer (NSCLC) patients becomes more personalized, additional tissue in the form of core needle biopsies (CNBs) for biomarker analysis is increasingly required for determining appropriate treatment and for enrollment into clinical trials. We report our experience with small-caliber percutaneous transthoracic (PT) CNBs for the evaluation of multiple molecular biomarkers in BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination), a personalized, targeted therapy NSCLC clinical trial.
The medical records of patients who underwent PTCNB for consideration of enrollment in BATTLE, were reviewed for diagnostic yield of 11 predetermined molecular markers, and procedural complications. Univariate and multivariate analyses of factors related to patient and lesion characteristics were performed to determine possible influences on diagnostic yield.
One hundred and seventy PTCNBs were performed using 20-gauge biopsy needles in 151 NSCLC patients screened for the trial. 82.9% of the biopsy specimens were found to have adequate tumor tissue for analysis of the required biomarkers. On multivariate analysis, metastatic lesions were 5.4 times more likely to yield diagnostic tissue as compared to primary tumors (p = 0.0079). Pneumothorax and chest tube insertion rates were 15.3% and 9.4%, respectively.
Image-guided 20-gauge PTCNB is safe and provides adequate tissue for analysis of multiple biomarkers in the majority of patients being considered for enrollment into a personalized, targeted therapy NSCLC clinical trial. Metastatic lesions are more likely to yield diagnostic tissue as compared to primary tumors.
PMCID: PMC3879952  PMID: 23442309
research biopsy; biomarker analysis; percutaneous transthoracic biopsy
11.  Frequency of MET and PIK3CA copy number elevation and correlation with outcome in early stage breast cancer 
Cancer  2012;119(1):7-15.
To determine the frequency and association with relapse-free survival (RFS) of MET and PIK3CA copy number elevations in early stage breast cancer.
Tumor DNA was extracted from 971 formalin-fixed paraffin-embedded early breast cancers for molecular inversion probes arrays. Data was segmented using the SNP-FASST2 segmentation algorithm. Copy number gains were called when copy number of each segment was greater than 2.3 or 1.7 respectively. RFS was estimated by Kaplan-Meier. Cox proportional hazards models were fit to determine independent associations of copy number with RFS.
82 (8.44%) and 134 (13.8%) of tumors had MET or PIK3CA copy number elevation respectively, and 25.6% with MET copy number elevation had PIK3CA copy number elevation. Patients with either MET or PI3KCA high copy number tended to have poorer prognostic features (larger tumor size, higher grade, and hormone receptor negativity), Both, MET and PIK3CA high copy number were more likely to occur in triple negative disease (P=0.019 and <0.001, respectively). At a median follow-up of 7.4 years, there were 252 recurrences. Five-year RFS were 63.5%, and 83.1% for MET high copy number and MET normal/low copy number respectively, (P=0.06); and 73.1%, and 82.3% for PIK3CA high copy number and PIK3CA normal/low copy number respectively, (P=0.15). High copy number for either gene was not an independent predictor of RFS.
High copy number of MET or PIK3CA was associated with poorer prognostic features and triple negative disease. Co-amplification was frequent. Patients with high MET copy number tumors tended to have a worst RFS.
PMCID: PMC3461089  PMID: 22736407
MET; PIK3CA; gene copy number; breast cancer; prognosis
12.  An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance 
EMT has been associated with metastatic spread and EGFR inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using NSCLC cell lines and patients treated in the BATTLE study.
We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from NSCLC patients. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) study, and potential therapeutic targets associated with EMT were identified.
Compared with epithelial cells, mesenchymal cells demonstrated significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend towards greater sensitivity to the Axl inhibitor SGI-7079, while the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In NSCLC patients, the EMT signature predicted 8-week disease control in patients receiving erlotinib, but not other therapies.
We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype
PMCID: PMC3567921  PMID: 23091115
lung cancer; EMT; EGFR inhibition; PI3K inhibition; Axl
13.  cMET and phospho-cMET protein levels in breast cancers and survival outcomes 
To evaluate cMET and phospho-cMET (p-cMET) levels in breast cancer subtypes and its impact on survival outcomes.
Experimental Design
We measured protein levels of cMET and p-cMET in 257 breast cancers using reverse phase protein array. Regression tree method and Martingale residual plots were applied to find best cutoff point for high and low levels. Kaplan-Meier survival curves were used to estimate relapse-free (RFS) and overall (OS) survival. Cox proportional hazards models were fit to determine associations of cMET/p-cMET with outcomes after adjustment for other characteristics.
Median age was 51years. There were 140 (54.5%) hormone receptor (HR)-positive, 53 (20.6%) HER2-positive and 64 (24.9%) triple-negative tumors. Using selected cutoffs, 181 (70.4%) and 123 (47.9%) cancers had high levels of cMET and p-cMET, respectively. There were no significant differences in mean expression of cMET (P<0.128) and p-cMET (P<0.088) by breast cancer subtype. Dichotomized cMET and p-cMET level was a significant prognostic factor for RFS (HR:2.44,95%CI:1.34-4.44,P=0.003 and HR:1.64,95%CI:1.04-2.60,P=0.033) and OS (HR:3.18,95%CI:1.43-7.11,P=0.003 and HR:1.92,95% CI:1.08-3.44,P=0.025). Within breast cancer subtypes, high cMET levels were associated with worse RFS (P=0.014) and OS (P=0.006) in HR-positive tumors, and high p-cMET levels were associated with worse RFS (P=0.019) and OS (P=0.014) in HER2-positive breast cancers. In multivariable analysis patients with high cMET had a significantly higher risk of recurrence (HR:2.06; 95%CI:1.08-3.94,P=0.028) and death (HR:2.81; 95%CI:1.19-6.64,P=0.019). High p-cMET level was associated with higher risk of recurrence (HR:1.79,95%CI 1.08-2.95.77,P=0.020).
High levels of cMET and p-cMET were seen in all breast cancer subtypes and correlated with poor prognosis.
PMCID: PMC3821167  PMID: 22374333
cMET; phospho-cMET; breast cancer prognosis; breast cancer subtype
14.  Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome 
Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non–small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting.
We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan–Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided.
Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor–dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers.
Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.
PMCID: PMC3274509  PMID: 22247021
15.  Sunitinib in combination with paclitaxel plus carboplatin in patients with advanced solid tumors: phase I study results 
To evaluate the maximum tolerated dose (MTD), safety, and antitumor activity of sunitinib combined with paclitaxel and carboplatin.
Successive cohorts of patients with advanced solid tumors received oral sunitinib (25, 37.5, or 50 mg) for 2 consecutive weeks of a 3-week cycle (Schedule 2/1) or as a continuous daily dose for 3-week cycles (CDD schedule) in combination with paclitaxel (175–200 mg/m2) plus carboplatin (AUC 6 mg•min/mL) on day 1 of each of 4 cycles. Dose-limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the MTD. Efficacy parameters were analyzed in patients with measurable disease.
Forty-three patients were enrolled (n = 25 Schedule 2/1; n = 18 CDD schedule). Across all doses, 6 DLTs were observed (grade 4 papilledema, grade 5 GI hemorrhage, grade 3 neutropenic infection, grade 4 thrombocytopenia [n = 3]). The MTD for Schedule 2/1 was sunitinib 25 mg plus paclitaxel 175 mg/m2 and carboplatin AUC 6 mg•min/mL. The MTD was not determined for the CDD schedule. Treatment-related AEs included neutropenia (77%), thrombocytopenia (56%), and fatigue (47%). Of 38 evaluable patients, 4 (11%) had partial responses and 12 (32%) had stable disease. PK data indicated an increase in maximum and total plasma exposures to sunitinib and its active metabolite when given with paclitaxel and carboplatin compared with sunitinib monotherapy.
Myelosuppression resulting in prolonged dose delays and frequent interruptions was observed, suggesting that this treatment combination is not feasible in the general cancer population.
PMCID: PMC3400085  PMID: 21140147
Sunitinib; Phase I; Solid tumor; NSCLC; Antiangiogenesis; Chemotherapy
16.  Phase II Study of Dasatinib in Patients With Advanced Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2010;28(30):4609-4615.
Src family kinases (SFKs) promote cancer progression and are commonly expressed in non–small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib.
Patients and Methods
Patients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression.
Thirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy.
Dasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC.
PMCID: PMC2974341  PMID: 20855820
17.  Phase I Study of Celecoxib with Concurrent Irinotecan, Cisplatin, and Radiation Therapy for Patients with Unresectable Locally Advanced Non-Small Cell Lung Cancer 
Purpose: Preclinical findings suggest that adding targeted therapies to combination radiation-chemotherapy can enhance treatment efficacy; however, this approach may enhance normal tissue toxicity. We investigated the maximum tolerated dose, dose-limiting toxicities, and response rate when the selective cyclooxygenase-2 inhibitor celecoxib is added to concurrent irinotecan, cisplatin, and radiation therapy for patients with inoperable stage II–III non-small cell lung cancer (NSCLC). Methods and Materials: Eighteen patients were analyzed in a phase I clinical dose-escalation trial. Celecoxib was given daily beginning 5 days before radiation followed by maintenance doses for 12 weeks. Toxicity was graded with the Common Terminology Criteria for Adverse Events V3.0 and response with the World Health Organization system. Primary endpoints were maximum tolerated dose of celecoxib and treatment toxicity; secondary endpoints were response and survival rates. Results: The maximum tolerated dose of celecoxib was not reached, in part owing to discontinuation of the drug supply. At doses of 200 or 400 mg/day, no patients experienced any dose-limiting toxicity (acute grade ≥4 esophagitis or pneumonitis, neutropenic fever or thrombocytopenia requiring transfusion, or acute grade ≥3 diarrhea). Grade 3 toxicities were leukopenia (five patients), fatigue (3), pneumonitis (2), dyspnea (1), pain (1), and esophageal stricture (1). Interestingly, pulmonary fibrosis (a late toxicity) was no more severe in the higher-dose (400-mg) group and may have been less common than in the lower-dose group. The clinical response rate was 100% (8 complete, 10 partial). Two-year rates were: overall survival 65%; local-regional control 69%; distant metastasis-free survival 71%; and disease-free survival 64%. Conclusion: Although preliminary, our results suggest that adding celecoxib to concurrent chemoradiation for inoperable NSCLC is safe and can improve outcome without increasing normal tissue toxicity.
PMCID: PMC3355954  PMID: 22649768
celebrex; CPT-11; cyclooxygenase-2 inhibitor; concurrent chemoradiotherapy; stage II or III non-small cell lung cancer
18.  Endobronchial Metastases in Breast Carcinoma 
Western Journal of Medicine  1978;129(3):177-180.
In a consecutive series of 1,628 patients with breast carcinoma, six cases of endobronchial metastases were diagnosed for an incidence of 0.4 percent. The median latent interval from the diagnosis of the primary carcinoma until the time of diagnosis of endobronchial metastases was 21 months. Endobronchial metastases can be the initial manifestation of recurrent cancer and can present with no abnormalities shown on x-ray films of the chest. Because of similar symptomatology, the diagnosis of endobronchial metastases may be confused with a central bronchogenic carcinoma but the histological appearance could differentiate the two entities. Local treatment with radiation therapy is usually inadequate and patients should also be treated with some form of systemic treatment such as chemotherapy. The median survival after the diagnosis of endobronchial metastases was 13 months.
PMCID: PMC1238308  PMID: 706354
19.  Combined Effects of Phytohemagglutinin and Staphylococcal Enterotoxin B on Deoxyribonucleic Acid Synthesis During Blast Transformation in Human Lymphocytes 
Infection and Immunity  1974;9(2):384-390.
Three mitogenic agents, phytohemagglutinin (PHA), staphylococcal enterotoxin B (SEB), and concanavalin A (Con A) were tested for their effects on deoxyribonucleic acid (DNA) synthesis in the normal human lymphocyte. When optimal concentrations of PHA and SEB were combined, tritiated thymidine incorporation in lymphocytes derived from several donors was enhanced significantly. In the presence of graded concentrations of one of these mitogens added to fixed optimal concentrations of the other, this enhancement was shown to be additive. By contrast, when PHA or SEB were combined with Con A, the resulting thymidine incorporation was slightly lower than for either mitogen alone. An inhibition of further thymidine incorporation when puromycin was added to lymphocytes incubated with PHA and SEB suggested that the additive effect of these mitogens was due to increased enzyme synthesis. To define potential differences in mechanisms of action underlying the additive effect of SEB and PHA, the relative contribution of the de novo and salvage pathways for pyrimidine biosynthesis was tested with cytidine, a specific salvage pathway inhibitor. Cytidine (10−3 M) inhibited synthesis through the salvage pathway, but did not significantly alter induction of carbamyl phosphate synthetase II, the rate-limiting enzyme for the de novo pathway. An inhibition of DNA synthesis by millimolar cytidine concentrations in lymphocytes incubated with PHA or SEB, singly or in combination, suggested that pyrimidines for the observed enhancement of DNA synthesis were derived largely via the salvage pathway.
PMCID: PMC414813  PMID: 4361297

Results 1-19 (19)