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1.  Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers 
To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer.
Patients and Methods
In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations.
Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles.
AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.
PMCID: PMC2718422  PMID: 18390968
2.  NCCTG N0821 (Alliance): A phase II first-line study of pemetrexed, carboplatin and bevacizumab in elderly patients with advanced nonsquamous non-small cell lung cancer with good performance status 
We hypothesized that the combination of bevacizumab, carboplatin and pemetrexed will be an effective first-line regimen in fit, elderly patients with nonsquamous NSCLC.
Treatment-naïve, stage IIIB/IV nonsquamous NSCLC patients ≥ 70 years old with good performance status (ECOG PS 0-1) and adequate organ function were eligible. Carboplatin AUC 6, pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg were administered on day 1 of each 21-day cycle (up to 6 cycles) followed by maintenance pemetrexed and bevacizumab. The primary endpoint of 6-month progression-free survival rate (PFS6) of at least 70% was assessed using a one-stage binomial design. Quality of life (QOL) questionnaires were administered. Polymorphisms in genes encoding relevant proteins (drug targets, transport and metabolism proteins) were correlated with treatment outcome.
Fifty-seven eligible patients were enrolled. Median age was 74.5 years. Median treatment cycles received was 6. The most common grade 3 or higher non-hematologic adverse events were fatigue (26%) and hypertension (11%). 16% had grade 4 neutropenia and 6.5% had grade 4 thrombocytopenia. Three patients experienced grade 3/4 hemorrhagic events (one pulmonary, two gastrointestinal). Primary endpoint of PFS6 was 60% (95% CI: 45.9–73%). Median PFS was 7.0 months (95% CI: 5.9–10.1), median overall survival was 13.7 months (95% CI: 9.4–16.8). Polymorphic KDR and VEGFA variants correlated with survival and toxicity, respectively. There was no significant change in overall QOL scores over time.
This regimen is feasible and did not decrease the QOL in this study population. However, it did not meet the primary efficacy endpoint.
PMCID: PMC4145612  PMID: 25157767
Non-small cell lung cancer; Elderly; Nonsquamous histology; Bevacizumab; Survival
3.  First-In-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR In Patients With Advanced Cancer 
To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors.
Experimental Design
Part 1 of this open-label phase I study was designed to estimate the maximum tolerated dose (MTD) in patients with non-selected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of Part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation.
Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AEs) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4–5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life, 30–37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies.
These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies.
PMCID: PMC4508327  PMID: 25652454
PF-05212384; PI3K; mTOR; solid tumors; PI3K/TORC1/2; AKT
4.  Evaluation of Lapatinib and Topotecan Combination Therapy: Tissue Culture, Murine Xenograft, and Phase I Clinical Trial Data 
Topotecan resistance can result from drug efflux by P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) as well as survival signals initiated by epidermal growth factor receptor family members. The present studies were done to determine the effect of combining topotecan and the dual epidermal growth factor receptor/HER2 inhibitor lapatinib in tissue culture, a murine xenograft model, and a phase I clinical trial.
Experimental Design
The effects of lapatinib on topotecan accumulation and cytotoxicity in vitro were examined in paired cell lines lacking or expressing Pgp or BCRP. Antiproliferative effects of the combination were assessed in mice bearing HER2+ BT474 breast cancer xenografts. Based on tolerability in this preclinical model, 37 patients with advanced-stage cancers received escalating doses of lapatinib and topotecan in a phase I trial.
Lapatinib increased topotecan accumulation in BCRP- or Pgp-expressing cells in vitro, and the combination showed enhanced efficacy in HER2+ BT474 xenografts. In the phase I study, nausea, vomiting, diarrhea, and fatigue were dose limiting. The maximum tolerated doses were 1,250 mg/d lapatinib by mouth for 21or 28 days with 3.2 mg/m2 topotecan i.v. on days1, 8, and 15 of 28-day cycles. Pharmacokinetic analyses showed that combined drug administration resulted in decreased topotecan clearance consistent with transporter-mediated interactions. Seventeen (46%) patients had disease stabilization.
The lapatinib/topotecan combination is well tolerated and warrants further study.
PMCID: PMC2725396  PMID: 19047120
5.  Non–Small Cell Lung Cancer: Epidemiology, Risk Factors, Treatment, and Survivorship 
Lung cancer is the leading cause of cancer-related mortality not only in the United States but also around the world. In North America, lung cancer has become more predominant among former than current smokers. Yet in some countries, such as China, which has experienced a dramatic increase in the cigarette smoking rate during the past 2 decades, a peak in lung cancer incidence is still expected. Approximately two-thirds of adult Chinese men are smokers, representing one-third of all smokers worldwide. Non–small cell lung cancer accounts for 85% of all lung cancer cases in the United States. After the initial diagnosis, accurate staging of non–small cell lung cancer using computed tomography or positron emission tomography is crucial for determining appropriate therapy. When feasible, surgical resection remains the single most consistent and successful option for cure. However, close to 70% of patients with lung cancer present with locally advanced or metastatic disease at the time of diagnosis. Chemotherapy is beneficial for patients with metastatic disease, and the administration of concurrent chemotherapy and radiation is indicated for stage III lung cancer. The introduction of angiogenesis, epidermal growth factor receptor inhibitors, and other new anticancer agents is changing the present and future of this disease and will certainly increase the number of lung cancer survivors. We identified studies for this review by searching the MEDLINE and PubMed databases for English-language articles published from January 1, 1980, through January 31, 2008. Key terms used for this search included non–small cell lung cancer, adenocarcinoma, squamous cell carcinoma, bronchioalveolar cell carcinoma, large cell carcinoma, lung cancer epidemiology, genetics, survivorship, surgery, radiation therapy, chemotherapy, targeted therapy, bevacizumab, erlotinib, and epidermal growth factor receptor.
PMCID: PMC2718421  PMID: 18452692
6.  A Randomized Phase II Study of Gemcitabine and Carboplatin With or Without Cediranib as First-Line Therapy in Advanced Non-Small Cell Lung Cancer: North Central Cancer Treatment Group Study N0528 
To assess the safety and efficacy of gemcitabine (G) and carboplatin (C) with (arm A) or without (arm B) daily oral cediranib as first-line therapy for advanced non-small cell lung cancer (NSCLC).
A lead-in phase to determine the tolerability of G 1000 mg/m2 on days 1 and 8, and C on day 1 at AUC 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 (B) randomized phase II study. The primary endpoint was confirmed overall response rate (ORR), with 6-month progression-free survival (PFS6) rate in arm A as secondary endpoint. Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome.
Based on the safety assessment, 30mg daily cediranib was used in the phase II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3+ non-hematologic adverse events, 71% vs 45%, p=0.01. The ORR was 19% (A) vs. 20% (B) (p=1.0). PFS6 in A was 48% (95% CI: 35%-62%), thus meeting the protocol specified threshold of at least 40%. The median OS was 12.0 vs. 9.9 months (p=0.10). FGFR1 rs7012413, FGFR2 rs2912791, and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased OS (HR 2.78-5.01, p=0.0002-0.0095).
The trial did not meet its primary endpoint of ORR but met its secondary endpoint of PFS6. Combination with cediranib 30 mg daily resulted in increased toxicity. Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival.
PMCID: PMC4193613  PMID: 23232491
7.  Phase I dose escalation study of the PKCι inhibitor aurothiomalate for advanced non-small cell lung cancer, ovarian cancer and pancreatic cancer 
Anti-cancer drugs  2013;24(10):1079-1083.
Protein kinase C iota (PKCι) is overexpressed in non-small cell lung (NSCLC), ovarian and pancreatic cancers where it plays a critical role in oncogenesis. The gold compound aurothiomalate (ATM) has been shown to inhibit PKCι signaling and exhibits potent anti-tumor activity in preclinical models. We sought to determine the maximum tolerated dose (MTD) of ATM.
We conducted a phase I dose escalation trial of ATM in patients with NSCLC, ovarian or pancreatic cancer. Patients received ATM IM weekly for three cycles (cycle duration 4 weeks) at 25 mg, 50 mg or 75 mg in a 3+3 design. The dose was not escalated for individual patients. Blood samples were analyzed for elemental gold levels. Patients were evaluated every four weeks for toxicity and every eight weeks for response.
Fifteen patients were enrolled in this study. Six patients were treated at 25 mg, 7 patients at 50 mg, and 2 at 75 mg. There was 1 dose limiting toxicity at 25 mg (hypokalemia), one at 50 mg (urinary tract infection), and none at 75 mg. There were 3 grade 3 hematologic toxicities. The recommended MTD of ATM is 50 mg. Patients received treatment for a median of 2 cycles (range 1-3). There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold consistent with linear pharmacokinetics.
In summary, this phase I study was successful in identifying ATM 50 mg IM weekly as the MTD. Future clinical investigations targeting PKCι are currently in progress.
PMCID: PMC3937851  PMID: 23962904
protein kinase C iota; aurothiomalate; non-small cell lung cancer; ovarian cancer; pancreatic cancer
9.  Systematic evaluation of genetic variants in three biological pathways on patient survival in low stage non-small cell lung cancer 
Studies from selected candidate genes suggest that single nucleotide polymorphisms (SNP) involved in glutathione metabolism, DNA repair, or inflammatory responses may affect overall survival (OS) in stages I-II or low stage non-small cell lung cancer (LS-NSCLC); however, results are inconclusive. In this study, we took a systematic pathway-based approach to simultaneously evaluate the impact of genetic variation from these three pathways on OS following LS-NSCLC diagnosis.
DNA from 647 patients with LS-NSCLC was genotyped for 480 SNPs (tagSNPs) tagging 57 genes from the three candidate pathways. Associations of tagSNPs with OS were assessed at the individual SNP and whole gene levels, adjusting for age, tumor stage, surgery type, and adjuvant therapy. The genotype combinations of the SNPs associated with OS was also estimated.
Among the 412 tagSNPs that were successfully genotyped and passed multi-step quality assessments, 28 showed association with OS (p<0.05). Two of the 28 were estimated to have less than a 20% chance of being false positives (rs3768490 in GSTM4 gene: p=1.32×10-4, q=0.06; rs1729786 in ABCC4 gene: p=9.25×10-4, q=0.20). Gene-based analysis suggested that, in addition to GSTM4 and ABCC4, variation in two other genes, PTGS2 and GSTA2, was also associated with OS.
We describe further evidence that variations in genes involved in the glutathione and inflammatory response pathways are associated with OS in patients with LS-NSCLC. Further studies are warranted to verify our findings and elucidate their functional mechanisms and clinical utility leading to improved survival for lung cancer patients.
PMCID: PMC3158278  PMID: 21792076
glutathione metabolism; DNA repair; inflammation response; genetic polymorphisms; non-small-cell lung cancer; survival analysis
10.  Development of a Multidisciplinary, Multicampus Subspecialty Practice in Endocrine Cancers 
Journal of Oncology Practice  2012;8(3 Suppl):e1s-e5s.
The development of subspecialty tumor groups for uncommon malignancies represents an effective approach to building experience, increasing patient volumes and referrals, and fostering development of increased therapeutic options and clinical trials for patients afflicted with otherwise historically neglected cancers.
Relative to more abundant neoplasms, endocrine cancers have been historically neglected, yet their incidence is increasing. We therefore sought to build interest in endocrine cancers, improve physician experience, and develop innovative approaches to treating patients with these neoplasms.
Between 2005 and 2010, we developed a multidisciplinary Endocrine Malignancies Disease Oriented Group involving all three Mayo Clinic campuses (Rochester, MN; Jacksonville, FL; and Scottsdale, AZ). In response to higher demand at the Rochester campus, we sought to develop a Subspecialty Tumor Group and an Endocrine Malignancies Tumor Clinic within the Division of Medical Oncology.
The intended groups were successfully formed. We experienced difficulty in integration of the Mayo Scottsdale campus resulting from local uncertainty as to whether patient volumes would be sufficient to sustain the effort at that campus and difficulty in developing enthusiasm among clinicians otherwise engaged in a busy clinical practice. But these obstacles were ultimately overcome. In addition, with respect to the newly formed medical oncology subspecialty endocrine malignancies group, appointment volumes quadrupled within the first year and increased seven times within two years. The number of active therapeutic endocrine malignancies clinical trials also increased from one in 2005 to five in 2009, with all three Mayo campuses participating.
The development of subspecialty tumor groups for uncommon malignancies represents an effective approach to building experience, increasing patient volumes and referrals, and fostering development of increased therapeutic options and clinical trials for patients afflicted with otherwise historically neglected cancers.
PMCID: PMC3348595  PMID: 22942830
11.  Tumor Response and Progression-Free Survival as Potential Surrogate Endpoints for Overall Survival in Extensive-Stage Small Cell Lung Cancer (ES-SCLC): Findings Based on North Central Cancer Treatment Group (NCCTG) Trials 
Cancer  2010;117(6):1262-1271.
We investigated the putative surrogate endpoints (PSEs) of best response (BR), complete response (CR), confirmed response (CoR), and progression-free survival (PFS) for associations with Overall Survival (OS), and as possible surrogate endpoints for OS.
Individual patient (pt) data from 870 untreated ES-SCLC pts participating in 6 single-arm (274 pts) and 3 randomized trials (596 pts) were pooled. Patient-level associations between PSEs and OS were assessed by Cox models using landmark analyses. Trial-level surrogacy of PSEs assessed by the association of treatment effects on OS and individual PSEs. Trial-level surrogacy measures included: R2 from weighted least squares regression model (WLS R2), Spearman's correlation coefficient, and R2 from bivariate survival model (Copula R2).
Median OS and PFS were 9.6 (95% CI: 9.1-10.0) and 5.5 (95% CI: 5.2-5.9) months, respectively; BR, CR, and CoR rates were 44%, 22%, and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (HR=0.42 (95% CI: 0.35-0.51); concordance index=0.63; p<0.01), with 6-month PFS being the strongest (HR=0.41 (95% CI: 0.35-0.49); concordance index=0.66; p<0.01). At the trial-level, PFS showed the highest level of surrogacy for OS (WLS R2=0.79; Copula R2=0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (WLS R2≤0.48).
PFS was strongly associated with OS at both the patient and trial-level. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase III trials.
PMCID: PMC3025267  PMID: 20960500
extensive-stage small cell lung cancer; surrogate endpoints; pooled analysis; progression-free survival; tumor response
12.  Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study 
The lancet oncology  2010;11(10):962-972.
Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib.
This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with, number NCT00625846.
39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35–68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=−0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders.
Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient’s response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done.
National Cancer Institute, supported in part by NCI CA15083 and CM62205.
PMCID: PMC3107731  PMID: 20851682
13.  Phase II Trial of Pemetrexed Plus Bevacizumab for Second-Line Therapy of Patients With Advanced Non–Small-Cell Lung Cancer: NCCTG and SWOG Study N0426 
Journal of Clinical Oncology  2009;28(4):614-619.
To evaluate the efficacy and toxicity of pemetrexed combined with bevacizumab as second-line therapy for patients with advanced non–small-cell lung cancer (NSCLC) and to correlate allelic variants in pemetrexed-metabolizing genes with clinical outcome.
Patients and Methods
Patients with previously treated NSCLC received pemetrexed (500 mg/m2 intravenous) combined with bevacizumab (15 mg/kg intravenous) every 3 weeks. The primary end point, evaluated using a one-stage Fleming design for detecting a true success rate of at least 70%, was the proportion of patients who were progression free and on treatment at 3 months. Polymorphisms in genes responsible for pemetrexed transport (reduced folate carrier [SLC19A1]) and metabolism (folylpolyglutamate synthase [FPGS] and gamma-glutamyl hydrolase [GGH]) evaluated in germline DNA (blood) were correlated with treatment outcome.
Forty-eight evaluable patients (14 females and 34 males) received a median of four cycles (range, one to 20 cycles). The most common grade 3 or 4 nonhematologic adverse events (AEs) were fatigue (13%), dyspnea (10%), and thrombosis (10%). Grade 3 or 4 hematologic AEs were neutropenia (19%) and lymphopenia (13%). Twenty-four (57%; 95% CI, 41% to 72%) of the first 42 patients met the success criteria. Median overall survival (OS) and progression-free survival (PFS) times were 8.6 and 4.0 months, respectively. The exon 6 (2522)C→T polymorphism in SLC19A1 correlated with 3-month progression-free status (P = .01) and with PFS (P = .05). The IVS1(1307)C→T polymorphism in GGH correlated with OS (P = .04).
The study did not meet its primary end point. However, the median PFS time of 4 months is promising. Pharmacogenetic studies in larger cohorts are needed to definitively identify polymorphisms that predict for survival and toxicity of pemetrexed.
PMCID: PMC2815996  PMID: 19841321
14.  FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth 
The Journal of Clinical Investigation  2010;120(5):1524-1534.
Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes. One characteristic of FA is an extremely high incidence of cancer, indicating the importance of the FA pathway in tumor suppression. However, the role of this pathway in the development and progression of human cancers in individuals who do not have FA has not been clearly determined. Here, we report that elevated expression of what we believe to be a novel splice variant of FA complementation group L (FANCL), which we identified and named FAVL, can impair the FA pathway in non-FA human tumor cells and act as a tumor promoting factor. FAVL expression was elevated in half of the human carcinoma cell lines and carcinoma tissue samples tested. Expression of FAVL resulted in decreased FANCL expression by sequestering FANCL to the cytoplasm and enhancing its degradation. Importantly, this impairment of the FA pathway by FAVL elevation provided human cancer cells with a growth advantage, caused chromosomal instability in vitro, and promoted tumor development in a xenograft mouse model. These data indicate that FAVL impairment of the FA pathway likely contributes to the development of non-FA human cancers and therefore add a challenging layer of complexity to the pathogenesis of human cancer. We further believe that these data will prove useful for developing additional tools for fighting human cancer.
PMCID: PMC2860942  PMID: 20407210
15.  Effect of Disrupting Seven-in-Absentia Homolog 2 Function on Lung Cancer Cell Growth 
Hyperactivated epidermal growth factor receptor (EGFR) and/or RAS signaling drives cellular transformation and tumorigenesis in human lung cancers, but agents that block activated EGFR and RAS signaling have not yet been demonstrated to substantially extend patients’ lives. The human homolog of Drosophila seven-in-absentia—SIAH-1 and SIAH-2—are ubiquitin E3 ligases and conserved downstream components of the RAS pathway that are required for mammalian RAS signal transduction. We examined whether inhibiting SIAH-2 function blocks lung cancer growth.
The antiproliferative and antitumorigenic effects of lentiviral expression of anti-SIAH-2 molecules (ie, a dominant-negative protease-deficient mutant of SIAH-2 [SIAH-2PD] and short hairpin RNA [shRNA]–mediated gene knockdown against SIAH-2) were assayed in normal human lung epithelial BEAS-2B cells and in human lung cancer BZR, A549, H727, and UMC11 cells by measuring cell proliferation rates, by assessing MAPK and other activated downstream components of the RAS pathway by immunoblotting, assessing apoptosis by terminal deoxynucleotidyltransferase–mediated UTP end-labeling (TUNEL) assay, quantifying anchorage-independent cell growth in soft agar, and assessing A549 cell–derived tumor growth in athymic nude mice (groups of 10 mice, with two injections of 1 × 106 cells each at the dorsal left and right scapular areas). All statistical tests were two-sided.
SIAH-2 deficiency in human lung cancer cell lines reduced MAPK signaling and statistically significantly inhibited cell proliferation compared with those in SIAH-proficient cells (P < .001) and increased apoptosis (TUNEL-positive A549 cells 3 days after lentivirus infection: SIAH-2PD vs control, 30.1% vs 0.0%, difference = 30.1%, 95% confidence interval [CI] = 23.1% to 37.0%, P < .001; SIAH-2-shRNA#6 vs control shRNA, 27.9% vs 0.0%, difference = 27.9%, 95% CI = 23.1% to 32.6%, P < .001). SIAH-2 deficiency also reduced anchorage-independent growth of A549 cells in soft agar (mean number of colonies: SIAH-2PD vs control, 124.7 vs 57.3, difference = 67.3, 95% CI = 49.4 to 85.3, P < .001; shRNA-SIAH-2#6 vs shRNA control: 27.0 vs 119.7, difference = 92.7, 95% CI = 69.8 to 115.5, P < .001), and blocked the growth of A549 cell–derived tumors in nude mice (mean tumor volume on day 36 after A549 cell injection: SIAH-2PD infected vs uninfected, 191.0 vs 558.5 mm3, difference = 367.5 mm3, 95% CI = 237.6 to 497.4 mm3, P < .001; SIAH-2PD infected vs control infected, 191.0 vs 418.3 mm3, difference = 227.5 mm3, 95% CI = 87.4 to 367.1 mm3, P = .003; mean resected tumor weight: SIAH-2PD infected vs uninfected, 0.12 vs 0.48 g, difference = 0.36 g, 95% CI = 0.23 to 0.50 g, P < .001; SIAH-2PD infected vs control infected, 0.12 vs 0.29 g, difference = 0.17 g, 95% CI = 0.04 to 0.31 g, P = .016).
SIAH-2 may be a viable target for novel anti-RAS and anticancer agents aimed at inhibiting EGFR and/or RAS-mediated tumorigenesis.
PMCID: PMC2720765  PMID: 19001609
16.  Ranibizumab Combined With Low-Dose Sorafenib for Exudative Age-Related Macular Degeneration 
Angiogenesis is a common factor in the pathogenesis of cancer and in exudative age-related macular degeneration (AMD). Therefore, angiogenesis inhibition has been developed as a therapeutic strategy. We report 2 cases of recurrent exudative AMD in which oral sorafenib, a tyrosine kinase inhibitor approved for cancer, was added to intravitreal ranibizumab, an antibody to vascular endothelial growth factor. These 2 patients were followed up by determination of visual acuity, fluorescein angiography, fundoscopy, and optical coherence tomography. The visual acuity of 1 patient improved from 20/70 to 20/60 while he was receiving sorafenib therapy; that of the other did not. Marked improvement was noted in both patients on optical coherence tomography. Additionally, both patients appeared to receive some benefit when low-dose oral sorafenib was used as monotherapy after its initial addition to ranibizumab therapy. Randomized trials of adding sorafenib to standard therapy for patients with neovascular AMD should be considered.
PMCID: PMC2763274  PMID: 18241635
17.  Salivary gland-type lung carcinomas: an EGFR immunohistochemical, molecular genetic, and mutational analysis study 
Salivary gland-type lung carcinomas are uncommon neoplasms of the lung, the two most common being adenoid cystic carcinoma and mucoepidermoid carcinoma. Although they usually have an indolent behavior, adenoid cystic carcinomas can be more aggressive, with 5-year survival as low as 55%. Unfortunately, these tumors do not respond well to chemotherapy. In contrast to the most common subtypes of lung carcinomas, epidermal growth factor receptor studies have not been carried out in this group of tumors. Herein we report a series of 24 cases (12 adenoid cystic and 12 mucoepidermoid carcinomas) tested for epidermal growth factor receptor protein expression, epidermal growth factor receptor gene copy gains, and epidermal growth factor receptor gene mutational status, through immunohistochemistry, fluorescence in situ hybridization, and sequencing of the exons 18-21, respectively. Overall, 91 and 92% of the adenoid cystic carcinomas and mucoepidermoid carcinomas expressed epidermal growth factor receptor protein. Chromosome 7 polysomy occurred in 25% of the cases (four adenoid cystic carcinomas and two mucoepidermoid carcinomas). No epidermal growth factor receptor gene amplification was detected and no mutation was found in exons 18-21 of the epidermal growth factor receptor gene. Immunoexpression of epidermal growth factor receptor in salivary gland-type lung carcinomas is not related to epidermal growth factor receptor gene copy number or mutational status.
PMCID: PMC2752817  PMID: 18587327
salivary gland-type lung carcinoma; adenoid cystic carcinoma; mucoepidermoid carcinoma; epidermal growth factor receptor; immunohistochemistry; FISH
18.  Do patients with schizophrenia receive state-of-the-art lung cancer therapy? A brief report 
Psycho-oncology  2008;17(7):721-725.
Patients with schizophrenia sometimes receive substandard medical care. This study explored such disparities among lung cancer patients with underlying schizophrenia.
This retrospective study focused on patients with pre-existing schizophrenia (or in some instances schizoaffective disorder) and a lung cancer diagnosis made between 1980 and 2004. ‘Disparity’ was defined as a patient’s having been prescribed less aggressive therapy for a potentially curable cancer based on state-of-the-art treatment standards for the time and for the cancer stage. Qualitative methods were used to assess healthcare providers’ decision-making.
29 patients were included. The median age was 59 years; 38% were men. Twenty-three had non-small cell lung cancer and 6 small cell lung cancer; 17 had potentially curable cancers. Five of 17 had a ‘disparity’ in cancer care: (1) no cancer therapy was prescribed because of chronic obstructive pulmonary disease; (2) no cancer therapy was prescribed because of infection; (3) no chemotherapy was prescribed because the patient declined it; radiation was provided; (4) no chemotherapy was prescribed because of the patient’s schizophrenia symptoms; radiation was administered; and (5) no surgery was performed because of disorientation from a lobotomy; radiation was prescribed. Comments from healthcare providers suggest reflection and ethical adjudication in decision-making.
Schizophrenia was never the sole reason for no cancer treatment in patients with potentially curable lung cancer. This study provides the impetus for others to begin to assess the effect of schizophrenia on lung cancer management in other healthcare settings.
PMCID: PMC2715919  PMID: 18050362
lung cancer; schizophrenia; disparities
19.  53BP1 Cooperates with p53 and Functions as a Haploinsufficient Tumor Suppressor in Mice 
Molecular and Cellular Biology  2005;25(22):10079-10086.
p53 binding protein 1 (53BP1) is a putative DNA damage sensor that accumulates at sites of double-strand breaks (DSBs) in a manner dependent on histone H2AX. Here we show that the loss of one or both copies of 53BP1 greatly accelerates lymphomagenesis in a p53-null background, suggesting that 53BP1 and p53 cooperate in tumor suppression. A subset of 53BP1−/− p53−/− lymphomas, like those in H2AX−/− p53−/− mice, were diploid and harbored clonal translocations involving antigen receptor loci, indicating misrepair of DSBs during V(D)J recombination as one cause of oncogenic transformation. Loss of a single 53BP1 allele compromised genomic stability and DSB repair, which could explain the susceptibility of 53BP1+/− mice to tumorigenesis. In addition to structural aberrations, there were high rates of chromosomal missegregation and accumulation of aneuploid cells in 53BP1−/− p53+/+ and 53BP1−/− p53−/− tumors as well as in primary 53BP1−/− splenocytes. We conclude that 53BP1 functions as a dosage-dependent caretaker that promotes genomic stability by a mechanism that preserves chromosome structure and number.
PMCID: PMC1280262  PMID: 16260621
20.  Concurrent MCL1 and JUN amplification in pseudomyxoma peritonei: a comprehensive genetic profiling and survival analysis 
Journal of Human Genetics  2013;59(3):124-128.
Pseudomyxoma peritonei (PMP) is a rare abdominal malignancy. We hypothesized that next-generation exomic sequencing would identify recurrent mutations that may have prognostic or therapeutic implications. Ten patients were selected on the basis of availability of tissue and adequate follow-up. They were treated at our institution between September 2002 and August 2004. Using next-generation exomic sequencing, we tested for mutations in 236 cancer-related genes in formalin-fixed paraffin-embedded slides. MCL1 amplification was additionally tested with immunohistochemical staining. Detectable mutations were found in 8 patients (80%). Seven patients harbored a KRAS mutation, most commonly involving codon 12. Four GNAS mutations (R201H/R201C substitutions) were also detected. MCL1 and JUN were concurrently amplified in three patients. One patient with MCL1 and JUN amplification had concurrent amplification of MYC and NFKBIA. ZNF703 was amplified in one patient. Patients with MCL1 amplification were also found to express MCL1 with immunohistochemistry, but MCL1 expression was also detected in some patients without amplification. To our knowledge, we are the first to report MCL1 and JUN coamplification in PMP. Expression of MCL1 may not be completely dependent on amplification. The prognostic and therapeutic implications of these recurrent mutational events are the subject of ongoing investigation.
PMCID: PMC3973125  PMID: 24369359
colorectal cancer; JUN; MCL1; next-generation sequencing; pseudomyxoma peritonei

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