McMahon P.M.,Massachusetts General Hospital |
Kong C.Y.,Massachusetts General Hospital |
Bouzan C.,Massachusetts General Hospital |
Weinstein M.C.,Harvard University |
And 9 more authors.
Journal of Thoracic Oncology
Introduction: A randomized trial has demonstrated that lung cancer screening reduces mortality. Identifying participant and program characteristics that influence the cost-effectiveness of screening will help translate trial results into benefits at the population level. Methods: Six U.S. cohorts (men and women aged 50, 60, or 70 years) were simulated in an existing patient-level lung cancer model. Smoking histories reflected observed U.S. patterns. We simulated lifetime histories of 500,000 identical individuals per cohort in each scenario. Costs per quality-adjusted life-year gained ($/QALY) were estimated for each program: computed tomography screening; stand-alone smoking cessation therapies (4-30% 1-year abstinence); and combined programs. Results: Annual screening of current and former smokers aged 50 to 74 years costs between $126,000 and $169,000/QALY (minimum 20 pack-years of smoking) or $110,000 and $166,000/QALY (40 pack-year minimum), when compared with no screening and assuming background quit rates. Screening was beneficial but had a higher cost per QALY when the model included radiation-induced lung cancers. If screen participation doubled background quit rates, the cost of annual screening (at age 50 years, 20 pack-year minimum) was below $75,000/QALY. If screen participation halved background quit rates, benefits from screening were nearly erased. If screening had no effect on quit rates, annual screening costs more but provided fewer QALYs than annual cessation therapies. Annual combined screening/cessation therapy programs at age 50 years costs $130,500 to $159,700/QALY, when compared with annual stand-alone cessation. Conclusions: The cost-effectiveness of computed tomography screening will likely be strongly linked to achievable smoking cessation rates. Trials and further modeling should explore the consequences of relationships between smoking behaviors and screen participation. Copyright © 2011 by the International Association for the Study of Lung Cancer. Source
Liu Y.,Beth Israel Deaconess Medical Center |
Liu Y.,Lowe Center for Thoracic Oncology |
Liu Y.,Ludwig Center |
Marks K.,Agios Pharmaceuticals |
And 62 more authors.
coordinates cell growth, polarity, motility, and metabolism. In non-small cell lung carcinoma, LKB1 is somatically inactivated in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach to defi ne novel therapeutic targets in KRAS-driven LKB1 -mutant lung cancers. High-throughput RNA interference screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identifi cation of Dtymk, encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 defi ciency in mouse and human lung cancer lines. Global metabolite profi ling showed that Lkb1- null cells had a striking decrease in multiple nucleotide metabolites as compared with the Lkb1 -wild-type cells. Thus, LKB1 -mutant lung cancers have defi cits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors. SIGNIFICANCE: Using cell lines derived from the lung cancers occurring in genetically engineered mice, we conducted an integrative genome-wide short hairpin RNA and metabolite screen to identify DTYMK as a potential therapeutic target in Kras/Lkb1 -mutant lung cancer. We believe that DTYMK is tractable for the development of novel therapeutics, and show an integrative approach to target identifi cation that reduces false-positive candidates and should have broad applicability for the development of targeted therapeutics. © 2013 American Association for Cancer Research. Source
Cardarella S.,Lowe Center for Thoracic Oncology |
Cardarella S.,Brigham and Womens Hospital |
Cardarella S.,Harvard University |
Ogino A.,Lowe Center for Thoracic Oncology |
And 17 more authors.
Clinical Cancer Research
Purpose: BRAF mutations are found in a subset of non-small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. Experimental Design: Using DNA sequencing, we successfully screened 883 patients with NSCLC for BRAF mutations between July 1, 2009 and July 16, 2012. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild-type controls consisted of patients with NSCLC without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biologic properties of selected non-V600E BRAF mutations identified from patients with NSCLC. Results: Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18) and 257 were wild-type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of 36 patients with BRAF mutations were smokers. There were no distinguishing clinical features between BRAF-mutant and wildtype patients. Patients with advanced NSCLC with BRAF mutations and wild-type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E-mutated tumors had a shorter PFS to platinum-based chemotherapy compared with those with non-V600E mutations, although this did not reach statistical significance (4.1 vs. 8.9 months; P = 0.297). We identified five BRAF mutations not previously reported in NSCLC; two of five were associated with increased BRAF kinase activity. Conclusions: BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC. © 2013 American Association for Cancer Research. Source
Chen Z.,Harvard University |
Chen Z.,Ludwig Center at Dana Farber Harvard Cancer Center |
Akbay E.,Harvard University |
Akbay E.,Ludwig Center at Dana Farber Harvard Cancer Center |
And 17 more authors.
Clinical Cancer Research
Purpose: To extend the results of a phase III trial in patients with non-small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion. Experimental Design: We conducted a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib to the standard-of-care cytotoxic agents docetaxel or pemetrexed. Results: Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared with chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared with chemotherapy-treated mice. Pemetrexed produced superior overall survival compared with docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. In addition, in the EML4-ALK-driven mouse lung adenocarcinoma model, HSP90 inhibition can overcome both primary and acquired crizotinib resistance. Furthermore, HSP90 inhibition, as well as the second-generation ALK inhibitor TAE684, demonstrated activity in newly developed lung adenocarcinoma models driven by crizotinib-insensitive EML4-ALK L1196M or F1174L. Conclusions: Our findings suggest that crizotinib is superior to standard chemotherapy in ALK inhibitor-naive disease and support further clinical investigation of HSP90 inhibitors and secondgeneration ALK inhibitors in tumors with primary or acquired crizotinib resistance. © 2013 AACR. Source
Liu Q.,Harvard University |
Xu C.,Ludwig Center at Dana Farber Harvard Cancer Center |
Kirubakaran S.,Harvard University |
Zhang X.,Harvard University |
And 27 more authors.
mTOR is a highly conserved serine/threonine protein kinase that serves as a central regulator of cell growth, survival, and autophagy. Deregulation of the PI3K/Akt/mTOR signaling pathway occurs commonly in cancer and numerous inhibitors targeting the ATP-binding site of these kinases are currently undergoing clinical evaluation. Here, we report the characterization of Torin2, a second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. Torin2 inhibited mTORC1- dependent T389 phosphorylation on S6K (RPS6KB1) with an EC50 of 250 pmol/L with approximately 800-fold selectivity for cellular mTOR versus phosphoinositide 3-kinase (PI3K). Torin2 also exhibited potent biochemical and cellular activity against phosphatidylinositol-3 kinase-like kinase (PIKK) family kinases includingATM(EC50, 28 nmol/L), ATR (EC50, 35 nmol/L), and DNA-PK (EC50, 118 nmol/L; PRKDC), the inhibition of which sensitized cells to Irradiation. Similar to the earlier generation compound Torin1 and in contrast to other reported mTOR inhibitors, Torin2 inhibited mTOR kinase and mTORC1 signaling activities in a sustained manner suggestive of a slow dissociation from the kinase. Cancer cell treatment with Torin2 for 24 hours resulted in a prolonged block in negative feedback and consequent T308 phosphorylation on Akt. These effects were associated with strong growth inhibition in vitro. Single-agent treatment with Torin2 in vivo did not yield significant efficacy against KRAS-driven lung tumors, but the combination of Torin2 with mitogen-activated protein/extracellular signal- regulated kinase (MEK) inhibitor AZD6244 yielded a significant growth inhibition. Taken together, our findings establish Torin2 as a strong candidate for clinical evaluation in a broad number of oncologic settings wheremTOR signaling has a pathogenic role. © 2013 American Association for Cancer Research. Source