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1.  Genomic profiling of multiple sequentially acquired tumor metastatic sites from an “exceptional responder” lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response 
We used next-generation sequencing to identify somatic alterations in multiple metastatic sites from an “exceptional responder” lung adenocarcinoma patient during his 7-yr course of ERBB2-directed therapies. The degree of heterogeneity was unprecedented, with ∼1% similarity between somatic alterations of the lung and lymph nodes. One novel translocation, PLAG1-ACTA2, present in both sites, up-regulated ACTA2 expression. ERBB2, the predominant driver oncogene, was amplified in both sites, more pronounced in the lung, and harbored an L869R mutation in the lymph node. Functional studies showed increased proliferation, migration, metastasis, and resistance to ERBB2-directed therapy because of L869R mutation and increased migration because of ACTA2 overexpression. Within the lung, a nonfunctional CDK12, due to a novel G879V mutation, correlated with down-regulation of DNA damage response genes, causing genomic instability, and sensitivity to chemotherapy. We propose a model whereby a subclone metastasized early from the primary site and evolved independently in lymph nodes.
doi:10.1101/mcs.a001263
PMCID: PMC5111000  PMID: 27900369
neoplasm of the lung
2.  Concurrent Molecular Alterations in Tumors with Germ Line Epidermal Growth Factor Receptor T790M Mutations 
Clinical lung cancer  2013;14(4):452-456.
doi:10.1016/j.cllc.2013.01.005
PMCID: PMC5002228  PMID: 23540867
Concurrent mutations; Familial lung cancer; Germline EGFR mutations; KRAS mutation; Lung cancer prevention
3.  CRKL mediates EML4-ALK signaling and is a potential therapeutic target for ALK-rearranged lung adenocarcinoma 
Oncotarget  2016;7(20):29199-29210.
Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in a small subset of patients with non-small-cell lung cancer (NSCLC). The ALK inhibitors are highly effective in NSCLC patients harboring ALK rearrangements; however, most patients acquire resistance to the therapy following an initial response. Mechanisms of acquired resistance are complex. We used LC-MS/MS-based phosphotyrosine-peptide profiling in the EML4-ALK rearranged H3122 and H2228 cells treated with ALK inhibitors, to identify downstream effectors of ALK. We then used Western blot, siRNA experiments, cell proliferation, viability and migration assays to validate our findings. We identified CRKL as a novel downstream effector of ALK signaling. We demonstrated that CRKL tyrosine phosphorylation was repressed by pharmacological inhibition or small interfering RNA (siRNA) knockdown of ALK in the ALK-rearranged cells. More importantly, CRKL knockdown attenuated their cell proliferation, viability, and migration, but it had no effect on ALK phosphorylation and expression in these cells. Furthermore, CRKL tyrosine phosphorylation was inhibited by dasatinib (an inhibitor of ABL and SRC kinases), which in combination with the ALK inhibitor crizotinib displayed a synergistic inhibitory effect in vitro. In conclusion, our study suggests that CRKL is a key downstream effector of ALK, and combined inhibition of ALK and CRKL may represent an effective strategy for treating ALK-rearranged NSCLC patients.
doi:10.18632/oncotarget.8638
PMCID: PMC5045389  PMID: 27078848
EML4-ALK; NSCLC; CRKL; ALK
4.  Molecular Profiling and Targeted Therapy for Advanced Thoracic Malignancies: A Biomarker-Derived, Multiarm, Multihistology Phase II Basket Trial 
Journal of Clinical Oncology  2015;33(9):1000-1007.
Purpose
We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently.
Patients and Methods
We enrolled patients with advanced non–small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification.
Results
Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years).
Conclusion
This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.
doi:10.1200/JCO.2014.58.2007
PMCID: PMC4356709  PMID: 25667274
6.  Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial 
The Lancet. Oncology  2015;16(2):177-186.
Summary
Background
No standard treatments are available for advanced thymic epithelial tumours after failure of platinum-based chemotherapy. We investigated the activity of sunitinib, an orally administered tyrosine kinase inhibitor.
Methods
Between May 15, 2012, and Oct 2, 2013, we did an open-label phase 2 trial in patients with histologically confirmed chemotherapy-refractory thymic epithelial tumours. Patients were eligible if they had disease progression after at least one previous regimen of platinum-containing chemotherapy, an Eastern Cooperative Oncology Group performance status of two or lower, measurable disease, and adequate organ function. Patients received 50 mg of sunitinib orally once a day, in 6-week cycles (ie, 4 weeks of treatment followed by 2 weeks without treatment), until tumour progression or unacceptable toxic effects arose. The primary endpoint was investigator-assessed best tumour response at any point, which we analysed separately in thymoma and thymic carcinoma cohorts. Patients who had received at least one cycle of treatment and had their disease reassessed were included in the analyses of response. The trial was registered with ClinicalTrials.gov, number NCT01621568.
Findings
41 patients were enrolled, 25 with thymic carcinoma and 16 with thymoma. One patient with thymic carcinoma was deemed ineligible after enrolment and did not receive protocol treatment. Of patients who received treatment, one individual with thymic carcinoma was not assessable because she died. Median follow-up on trial was 17 months (IQR 14·0–18·4). Of 23 assessable patients with thymic carcinoma, six (26%, 90% CI 12·1–45·3, 95% CI 10·2–48·4) had partial responses, 15 (65%, 95% CI 42·7–83·6) achieved stable disease, and two (9%, 1·1–28·0) had progressive disease. Of 16 patients with thymoma, one (6%, 95% CI 0·2–30·2) had a partial response, 12 (75%, 47·6–92·7) had stable disease, and three (19%, 4·1–45·7) had progressive disease. The most common grade 3 and 4 treatment-related adverse events were lymphocytopenia (eight [20%] of 40 patients), fatigue (eight [20%]), and oral mucositis (eight [20%]). Five (13%) patients had decreases in left-ventricular ejection fraction, of which three (8%) were grade 3 events. Three (8%) patients died during treatment, including one individual who died of cardiac arrest that was possibly treatment-related.
Interpretation
Sunitinib is active in previously treated patients with thymic carcinoma. Further studies are needed to identify potential biomarkers of activity.
Funding
National Cancer Institute (Cancer Therapy Evaluation Program).
doi:10.1016/S1470-2045(14)71181-7
PMCID: PMC4401497  PMID: 25592632
7.  Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update 
Journal of Clinical Oncology  2015;33(30):3488-3515.
Purpose
To provide evidence-based recommendations to update the American Society of Clinical Oncology guideline on systemic therapy for stage IV non–small-cell lung cancer (NSCLC).
Methods
An Update Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of randomized controlled trials from January 2007 to February 2014.
Results
This guideline update reflects changes in evidence since the previous guideline.
Recommendations
There is no cure for patients with stage IV NSCLC. For patients with performance status (PS) 0 to 1 (and appropriate patient cases with PS 2) and without an EGFR-sensitizing mutation or ALK gene rearrangement, combination cytotoxic chemotherapy is recommended, guided by histology, with early concurrent palliative care. Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 (bevacizumab may be added to carboplatin plus paclitaxel if no contraindications); combination or single-agent chemotherapy or palliative care alone for those with PS 2; afatinib, erlotinib, or gefitinib for those with sensitizing EGFR mutations; crizotinib for those with ALK or ROS1 gene rearrangement; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma. Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens, alternative chemotherapy, or a chemotherapy break. In the second-line setting, recommendations include docetaxel, erlotinib, gefitinib, or pemetrexed for patients with nonsquamous cell carcinoma; docetaxel, erlotinib, or gefitinib for those with squamous cell carcinoma; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib. In the third-line setting, for patients who have not received erlotinib or gefitinib, treatment with erlotinib is recommended. There are insufficient data to recommend routine third-line cytotoxic therapy. Decisions regarding systemic therapy should not be made based on age alone. Additional information can be found at http://www.asco.org/guidelines/nsclc and http://www.asco.org/guidelineswiki.
doi:10.1200/JCO.2015.62.1342
PMCID: PMC5019421  PMID: 26324367
8.  A Phase I/II Trial of Belinostat in Combination with Cisplatin, Doxorubicin and Cyclophosphamide in Thymic Epithelial Tumors: A Clinical And Translational Study 
Purpose
This phase I/II study sought to determine the safety and maximum-tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor administered prior to and in combination with cisplatin (P), doxorubicin (A) and cyclophosphamide (C) in thymic epithelial tumors (TET). Anti-tumor activity, pharmacokinetics, and biomarkers of response were also assessed.
Patients and methods
Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48-hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used.
Results
26 patients were enrolled (thymoma: 12; thymic carcinoma: 14). Dose-limiting toxicities at 2000 mg/m2 belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. 24 patients were treated at the MTD of 1000 mg/m2 with chemotherapy (P 50 mg/m2 on day 2; A 25 mg/m2 on days 2, 3; C 500 mg/m2 on day 3). Objective response rates in thymoma and thymic carcinoma were 64% [95% confidence interval: 30.8%–89.1%] and 21% (4.7%–50.8%) respectively. Modulation of pharmacodynamic markers of HDAC-inhibition and declines in regulatory T cell (Tregs) and exhausted CD8+ T cell populations were observed. Decline in Tregs was associated with response (p=0.0041) and progression-free survival (p=0.021). Declines in TIM-3+ CD8+T cells were larger in responders than non-responders (p=0.049).
Conclusion
This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on regulatory T cells and TIM3+ CD8+ T cells warrant further study.
doi:10.1158/1078-0432.CCR-14-0968
PMCID: PMC4216756  PMID: 25189481
thymic epithelial tumors; thymoma; thymic carcinoma; histone deacetylase inhibitor
9.  Biomarkers in Early-Stage Non-Small Cell Lung Cancer: Current Concepts and Future Directions 
Advances in molecular biology and bioinformatics have resulted in the identification of a number of potential biomarkers that could be relevant in the management of patients with non-small cell lung cancer (NSCLC). Although there is an increasing amount of literature related to these biomarkers, major issues need to be resolved including validity and reproducibility of results. Additionally, in order to interpret the existing literature accurately a clear distinction must be made between the prognostic and predictive value of biomarkers. The practical applicability of biomarker discovery for patients with lung cancer includes the identification of patients with early-stage NSCLC who are most likely to benefit from adjuvant therapy. Information gleaned from biomarkers has the potential to help in evaluating the role of targeted therapies including immunotherapy in the neoadjuvant and adjuvant setting. The role of gene signatures and the use of newer platforms such as RNA, methylation and protein signatures is being explored in patients with early stage NSCLC. This review focuses on the applications of biomarker discovery in patients with early stage NSCLC
doi:10.1097/JTO.0000000000000302
PMCID: PMC4254270  PMID: 25185530
10.  Alterations of immune cell subsets in relapsed, thymoma-associated minimal change disease: A case report 
Oncology Letters  2015;10(2):1155-1158.
The most frequently described glomerulopathy in patients with thymoma is minimal change disease (MCD). The present study reports the case of a 63-year-old female with recurrent thymoma and poorly-controlled paraneoplastic MCD, who was enrolled on a phase I/II clinical trial (no. NCT01100944) and treated with the histone deacetylase inhibitor, belinostat, in combination with cisplatin, doxorubicin and cyclophosphamide. Treatment resulted in a complete radiological response, a dramatic reduction in proteinuria and changes in immune cell subset composition, consisting of a reduction in the number of T helper (Th)1, Th2, Th17 and regulatory T cells. Changes in T-cell polarization were also observed with an increase in the Th1/Th2 ratio. To the best of our knowledge, the current study is the first to provide a detailed description of changes in immune cell subset composition in thymoma-associated MCD. Early administration of effective antitumor therapy should be considered in these cases, particularly when proteinuria is poorly controlled despite the use of steroids and other immunosuppressive therapies.
doi:10.3892/ol.2015.3325
PMCID: PMC4509017  PMID: 26622643
thymoma; proteinuria; nephrotic syndrome; minimal change disease; T-cells
11.  High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis 
Oncotarget  2015;6(13):11694-11703.
Mesothelin is a cell surface glycoprotein which is highly expressed in several epithelial cancers and may have a role in cell adhesion and metastases. In this study, we used prospectively obtained clinical and pathological data to characterize mesothelin expression in advanced lung adenocarcinoma. Tissue was obtained from patients who underwent molecular profiling of potentially actionable genes on a trial of molecular profiling and targeted therapies in advanced thoracic malignancies. We immunohistochemically evaluated the intensity, and the percentage of cells expressing mesothelin in 93 advanced lung adenocarcinomas. The evaluation was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. 53% of advanced lung adenocarcinomas expressed mesothelin to some degree; high mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with inferior survival (median 18.2 months vs. 32.9 months; P = 0.014). High mesothelin expression was strongly associated with mutant KRAS (P < 0.0001) and wild-type EGFR (P = 0.002). Our results provide strong rationale to explore anti-mesothelin targeted therapies in advanced lung adenocarcinoma especially in the KRAS-mutant subgroup.
PMCID: PMC4484487  PMID: 26028668
mesothelin; non-small cell lung cancer; KRAS; EGFR
12.  HSP-90 Inhibitor Ganetespib is Synergistic with Doxorubicin in Small Cell Lung Cancer 
Oncogene  2013;33(40):4867-4876.
SCLC at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment. Anthracyclines, such as doxorubicin, have definite activity in this disease, and ganetespib has shown promising activity in preclinical models, but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that ganetespib (IC50: 31nM) was much more potent than 17-AAG, a geldanamycin derivative (IC50: 16 μM). Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and Caspase 3-dependent cell death. MTS assay revealed that ganetespib synergized with both doxorubicin and etoposide, two topoisomerase II inhibitors commonly used in SCLC chemotherapy. Expression of RIP1, a protein that may function as a pro-survival scaffold protein or a pro-death kinase in TNFR1-activated cells, was induced by doxorubicin and downregulated by ganetespib. Depletion of RIP1 by either RIP1 siRNA or ganetespib sensitized doxorubicin-induced cell death, suggesting that RIP1 may promote survival in doxorubicin-treated cells and that ganetespib may synergize with doxorubicin in part through downregulation of RIP1. In comparison to ganetespib or doxorubicin alone, the ganetespib + doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immuocompromised mice. We conclude that genetespib and doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that ganetespib and doxorubicin combination therapy may be an effective strategy for SCLC treatment, which warrants clinical testing.
doi:10.1038/onc.2013.439
PMCID: PMC4002667  PMID: 24166505
Doxorubicin; Ganetespib; HSP90 inhibitor; RIP1; SCLC
13.  CYB5A and autophagy-mediated cell death in pancreatic cancer 
Autophagy  2014;10(4):697-698.
The highly invasive and chemoresistant phenotype of pancreatic cancer highlights the urgency to identify prognostic biomarkers and novel therapeutic targets. Recently, we observed a significant correlation between shorter survival and loss of the cytoband 18q22.3. Here we investigated genes encoded by this cytoband, and demonstrated the prognostic value of CYB5A in resected and metastatic patients. Furthermore, our in vitro and in vivo studies clarified CYB5A inhibitory activity of oncogenic phenotypes through autophagy induction. This raises the possibility that inhibition of CYB5A-deregulated downstream pathways, such as those involving TRAF6, may favor autophagy-mediated cancer cell death in selected subgroups of patients.
doi:10.4161/auto.27803
PMCID: PMC4091157  PMID: 24448000
pancreatic cancer; 18q22.3 cytoband; prognosis; CYB5A; TRAF6
14.  Systemic Therapy, Clinical Outcomes, and Overall Survival in Locally Advanced or Metastatic Pulmonary Carcinoid 
Background
Data to guide the management of advanced pulmonary carcinoid (APC) come from retrospective reports and subgroup analyses of trials that included mainly extrapulmonary carcinoid tumors. We report the largest series to date of 49 patients with locally advanced or metastatic pulmonary carcinoid.
Methods
The Johns Hopkins Pathology Database was reviewed for APC patients treated between January 1992 and December 2012. Data on time to recurrence, progression-free survival, and overall survival were estimated by using the Kaplan–Meier method.
Results
Forty-nine patients were treated for APC in the specified time period. Median time to recurrence after surgical resection was 2.5 years (atypical carcinoid [AC] versus typical carcinoid [TC], 2.5 versus 6.3 years; p = 0.063). Median survival with advanced disease was 7.1 years and significantly longer for TC compared with AC (10.2 versus 4 years; p = 0.009). Among the diverse systemic therapies used, responses occurred in four of 17 patients (23.5%) who received platinum/ etoposide with a median progression-free survival of 7 months.
Conclusion
Although systemic chemotherapy has moderate activity for APC, novel approaches are required. TC and AC, although both classified as pulmonary carcinoid, are clearly different clinical and molecular entities and require separate treatment paradigms in the advanced/metastatic setting.
doi:10.1097/JTO.0000000000000065
PMCID: PMC4322909  PMID: 24518093
Pulmonary carcinoid; Metastatic carcinoid; Chemotherapy pulmonary carcinoid; Chemotherapy bronchial carcinoid; Therapy carcinoid; Atypical carcinoid; Typical carcinoid
15.  Role of CYB5A in Pancreatic Cancer Prognosis and Autophagy Modulation 
Background
Loss of 18q22.3 is a prognostic marker in pancreatic ductal adenocarcinoma (PDAC). This study investigated genes encoded by this cytoband.
Methods
We studied mRNA/protein expression in radically resected (n = 130) and metastatic patients (n = 50). The role of CYB5A was tested in 11 PDAC cell lines and five primary cultures through retrovirus-mediated upregulation and small interfering RNA using wound-healing, invasion, annexin-V, electron microscopy, and autophagic assays, as well as autophagy genes and kinases arrays. CYB5A+ orthotopic models (n = 6 mice/group) were monitored by Firefly and Gaussia-luciferase bioluminescence, magnetic resonance imaging, and high-frequency ultrasound. Data were analyzed by t test, Fisher exact-test, log-rank test and Cox proportional hazards models. All statistical tests were two-sided.
Results
Both resected and metastatic patients with low mRNA or protein expression of CYB5A had statistically significantly shorter survival (eg, median = 16.7 months, 95% confidence interval [CI] = 13.5 to 19.9; vs median = 24.8 months, 95% CI = 12.8 to 36.9; P = .02, two-sided log-rank test; n = 82 radically resected PDACs), and multivariable analyses confirmed prognostic relevance. Moreover, we characterized a novel function to CYB5A, autophagy induction, concomitant with reduced proliferation and migration/invasion of PDAC cells. Network analysis of proautophagic pathways suggested CYB5A interaction with TRAF6, which was confirmed by TRAF6 downregulation after CYB5A reconstitution (−69% in SU.86.86-CYB5A+; P = .005, two-sided t test). CYB5A silencing had opposite effects, restoring TRAF6 expression and wound healing. In vivo studies showed that CYB5A induced autophagy while inhibiting tumor growth/metastasis and increasing survival (median = 57 days, 95% CI = 52 to 61; vs median = 44 days, 95% CI = 21 to 57; P = .03, two-sided log-rank test).
Conclusions
These results define CYB5A as a novel prognostic factor for PDAC that exerts its tumor-suppressor function through autophagy induction and TRAF6 modulation.
doi:10.1093/jnci/djt346
PMCID: PMC3906994  PMID: 24301457
16.  Trends and Characteristics of Young Non-Small Cell Lung Cancer Patients in the United States 
Frontiers in Oncology  2015;5:113.
Background
Although the median age at diagnosis of non-small cell lung cancer (NSCLC) is 70 years, a subset of patients with NSCLC present at a younger age (<40 years). Little is known about the time-trends in incidence of NSCLC in the young, their characteristics and outcomes.
Methods
The surveillance, epidemiology, and end results database was used to extract NSCLC cases from 1978 to 2010. Yearly incidence rates in various age groups, race, site of disease, histology, treatment patterns, and outcomes were assessed. We modeled Kaplan–Meyer survival curves stratified by age of presentation.
Results
Young patients represented 0.6% of incident NSCLC from 1978 to 2010. The incidence of young NSCLC declined significantly during this time-period. Young NSCLCs had a higher proportion of women (51%), Asians or Pacific Islanders (14%), adenocarcinoma histology (59%) and were more likely to present with distant metastases (68%). The young had better all cause and lung cancer-specific survival than the older patients (median survival for localized, regional, and distant disease: not reached, 28, 9 vs. 46, 17, 5 months; p < 0.001 for all groups). Male sex, non-adenocarcinoma histology, and main bronchial primary were independent negative prognostic factors among the young. In contrast to the overall population, black race was a poor prognostic factor among the young.
Conclusion
The incidence of NSCLC in the young decreased from 1978 to 2010. The clinical characteristics of NSCLC in the young, including demographic distribution, treatment, and outcomes are different from those observed in the older patients.
doi:10.3389/fonc.2015.00113
PMCID: PMC4443720  PMID: 26075181
non-small cell lung cancer; SEER; young; population-based studies; disparities
17.  Novel Treatments for Thymoma and Thymic Carcinoma 
Frontiers in Oncology  2015;5:267.
doi:10.3389/fonc.2015.00267
PMCID: PMC4663242  PMID: 26649279
thymic epithelial tumors; autoimmune paraneoplastic disorders; genomic changes; anti-cytokine antibodies; biological therapies
18.  The janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo 
Purpose
The prognosis of small cell lung cancer (SCLC) is poor, and there has been very little progress in the medical treatment of SCLC in the past two decades. We investigated the potential of janus kinases (JAKs) inhibitor AZD1480 for treatment of SCLC in vitro and in vivo.
Experimental Design
JAK1 or JAK2 were inhibited by AZD1480 or siRNAs, and the effect of inhibition of JAK gene family on SCLC cell viability was evaluated. The effect of AZD1480 on cell cycle distribution and apoptosis induction were studied. Antitumor effects of AZD1480 in tumor xenografts were assessed.
Results
AZD1480 significantly inhibited growth of 6 out of 13 SCLC cells with IC50s ranging from 0.73 to 3.08 μM. Knocking-down of JAK2 and JAK1 inhibited proliferation of Jak2-positive/Jak1-negative H82 cells and Jak1-positive/Jak2-negative GLC4 cells, respectively. Treatment of SCLC cells with AZD1480 for 24 hours resulted in increase of 4N DNA content and Histone 3 serine 10 phosphorylation, indicative of G2/M phase arrest. Moreover, SCLCs underwent apoptosis after AZD1480 treatment as exemplified by the downregulation of MCL1, the accumulation of cleaved-Caspase 3, cleaved PARP and increase of annexin-V positive cells. Finally, xenograft experiments showed that AZD1480 attenuated the growth of H82 and GLC4 tumors in mice, and we observed stronger apoptosis as well as decreased CD31 positive endothelial cells in H82 and GLC4 xenografts upon AZD1480 treatment.
Conclusions
Janus kinases inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation.
doi:10.1158/1078-0432.CCR-13-1110
PMCID: PMC3872034  PMID: 24158701
Small cell lung carcinoma; Janus kinases; Therapy
19.  Mutations of epigenetic regulatory genes are common in thymic carcinomas 
Scientific Reports  2014;4:7336.
Genetic alterations and etiology of thymic epithelial tumors (TETs) are largely unknown, hampering the development of effective targeted therapies for patients with TETs. Here TETs of advanced-stage patients enrolled in a clinical trial of molecularly-guided targeted therapies were employed for targeted sequencing of 197 cancer-associated genes. Comparative sequence analysis of 78 TET/blood paired samples obtained from 47 thymic carcinoma (TC) and 31 thymoma patients revealed a total of 86 somatic non-synonymous sequence variations across 39 different genes in 33 (42%) TETs. TCs (62%; 29/47) showed higher incidence of somatic non-synonymous mutations than thymomas (13%; 4/31; p < 0.0001). TP53 was the most frequently mutated gene in TETs (n = 13; 17%), especially in TCs (26%), and was associated with a poorer overall survival (p < 0.0001). Genes in histone modification [BAP1 (n = 6; 13%), SETD2 (n = 5; 11%), ASXL1 (n = 2; 4%)], chromatin remodeling [SMARCA4 (n = 2; 4%)], and DNA methylation [DNMT3A (n = 3; 7%), TET2 (n = 2; 4%), WT1 (n = 2; 4%)] pathways were recurrently mutated in TCs, but not in thymomas. Our results suggest a potential disruption of epigenetic homeostasis in TCs, and a substantial difference in genetic makeup between TCs and thymomas. Further investigation is warranted into the roles of epigenetic dysregulation in TC development and its potential for targeted therapy.
doi:10.1038/srep07336
PMCID: PMC4258655  PMID: 25482724
20.  Classification of current anticancer immunotherapies 
Galluzzi, Lorenzo | Vacchelli, Erika | Pedro, José-Manuel Bravo-San | Buqué, Aitziber | Senovilla, Laura | Baracco, Elisa Elena | Bloy, Norma | Castoldi, Francesca | Abastado, Jean-Pierre | Agostinis, Patrizia | Apte, Ron N. | Aranda, Fernando | Ayyoub, Maha | Beckhove, Philipp | Blay, Jean-Yves | Bracci, Laura | Caignard, Anne | Castelli, Chiara | Cavallo, Federica | Celis, Estaban | Cerundolo, Vincenzo | Clayton, Aled | Colombo, Mario P. | Coussens, Lisa | Dhodapkar, Madhav V. | Eggermont, Alexander M. | Fearon, Douglas T. | Fridman, Wolf H. | Fučíková, Jitka | Gabrilovich, Dmitry I. | Galon, Jérôme | Garg, Abhishek | Ghiringhelli, François | Giaccone, Giuseppe | Gilboa, Eli | Gnjatic, Sacha | Hoos, Axel | Hosmalin, Anne | Jäger, Dirk | Kalinski, Pawel | Kärre, Klas | Kepp, Oliver | Kiessling, Rolf | Kirkwood, John M. | Klein, Eva | Knuth, Alexander | Lewis, Claire E. | Liblau, Roland | Lotze, Michael T. | Lugli, Enrico | Mach, Jean-Pierre | Mattei, Fabrizio | Mavilio, Domenico | Melero, Ignacio | Melief, Cornelis J. | Mittendorf, Elizabeth A. | Moretta, Lorenzo | Odunsi, Adekunke | Okada, Hideho | Palucka, Anna Karolina | Peter, Marcus E. | Pienta, Kenneth J. | Porgador, Angel | Prendergast, George C. | Rabinovich, Gabriel A. | Restifo, Nicholas P. | Rizvi, Naiyer | Sautès-Fridman, Catherine | Schreiber, Hans | Seliger, Barbara | Shiku, Hiroshi | Silva-Santos, Bruno | Smyth, Mark J. | Speiser, Daniel E. | Spisek, Radek | Srivastava, Pramod K. | Talmadge, James E. | Tartour, Eric | Van Der Burg, Sjoerd H. | Van Den Eynde, Benoît J. | Vile, Richard | Wagner, Hermann | Weber, Jeffrey S. | Whiteside, Theresa L. | Wolchok, Jedd D. | Zitvogel, Laurence | Zou, Weiping | Kroemer, Guido
Oncotarget  2014;5(24):12472-12508.
During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
PMCID: PMC4350348  PMID: 25537519
adoptive cell transfer; checkpoint blockers; dendritic cell-based interventions; DNA-based vaccines; immunostimulatory cytokines; peptide-based vaccines; oncolytic viruses; Toll-like receptor agonists
21.  Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs 
IMPORTANCE
Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials.
OBJECTIVES
To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival.
DESIGN, SETTING, AND PARTICIPANTS
From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival.
INTERVENTIONS
Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies.
MAIN OUTCOMES AND MEASURES
Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival.
RESULTS
From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score–adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006).
CONCLUSIONS AND RELEVANCE
Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.
doi:10.1001/jama.2014.3741
PMCID: PMC4163053  PMID: 24846037
22.  Capillary isoelectric-focusing immunoassays to study dynamic oncoprotein phosphorylation and drug response to targeted therapies in non-small cell lung cancer 
Molecular cancer therapeutics  2013;12(11):10.1158/1535-7163.MCT-13-0074.
Developing proteomic biomarkers is valuable for evaluating therapeutic effects of drugs and generating better treatment strategies. However, conventional protein analysis is often challenging due to inadequate sample size of clinical specimens, lack of assay reproducibility, accuracy and sensitivity. A novel capillary isoelectricfocusing (IEF) immunoassay system (NanoPro) was used to study the dynamic phosphorylation status of signaling molecules in non-small cell lung cancer (NSCLC) cells treated with EGFR tyrosine kinase and MEK inhibitors. NanoPro showed the same dynamic ERK phosphorylation as western blotting with good assay reproducibility using 1,000 times less protein. The IEF separation in NanoPro system enables multiple protein phosphorylation isoforms to be resolved and detected simultaneously. With NanoPro, we identified a specific on-target MEK response pattern to MEK inhibitor PD325901, which was not detectable by western blotting. We also revealed a MEK2 signal that may be associated with NSCLC cell sensitivity to EGFR inhibitor erlotinib, and distinguish erlotinib-sensitive from -intrinsic as well as -acquired resistant cells. Moreover, NanoPro could differentiate human ERK1 isoforms from the mouse isoforms based on their pI differences and demonstrated that erlotinib effectively inhibited ERK phosphorylation in targeted human xenograft cancer cells but not in surrounding mouse stromal cells. With 8 ug of tumor aspirates, we precisely quantified the response of 18 signaling molecules to erlotinib and MEK1 inhibitor treatments in a NSCLC patient.
NanoPro’s higher sensitivity, better resolution of protein phosphorylation status and reduced tissue requirement warrant NanoPro’s investigation for future drug development and evaluation of drug effects of targeted therapies.
doi:10.1158/1535-7163.MCT-13-0074
PMCID: PMC3823739  PMID: 23979919
Lung cancer; Methodology for proteomics; Novel assay technology; Xenograft models; Cellular responses to anticancer drugs
24.  Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors 
Objective
To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed.
Participants
Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies.
Evidence
Three unbiased literature searches of electronic databases were performed to capture articles published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation.
Consensus Process
Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4).
Conclusions
The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
doi:10.5858/arpa.2012-0720-OA
PMCID: PMC4162344  PMID: 23551194
25.  Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors 
Objective
To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed.
Participants
Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies.
Evidence
Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation.
Consensus Process
Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4).
Conclusions
The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
doi:10.1097/JTO.0b013e318290868f
PMCID: PMC4159960  PMID: 23552377

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