National Lung Cancer Partnership Research Articles

WE‐AB‐202‐01: Evaluating the Toxicity Reduction with CT‐Ventilation Functional Avoidance Radiation Therapy

Purpose:CT‐ventilation is an exciting new imaging modality that uses 4DCTs to calculate lung ventilation. Studies have proposed to use 4DCT‐ventilation imaging for functional avoidance radiotherapy which implies designing treatment plans to spare functional portions of the lung. Although retrospective studies have been performed to evaluate the dosimetric gains to functional lung; no work has been done to translate the dosimetric gains to an improvement in pulmonary toxicity. The purpose of our work was to evaluate the potential reduction in toxicity for 4DCT‐ventilation based functional avoidance.Methods:70 lung cancer patients with 4DCT imaging were used for the study. CT‐ventilation maps were calculated using the patient's 4DCT, deformable image registrations, and a density‐change‐based algorithm. Radiation pneumonitis was graded using imaging and clinical information. Log‐likelihood methods were used to fit a normal‐tissue‐complication‐probability (NTCP) model predicting grade 2+ radiation pneumonitis as a function of doses (mean and V20) to functional lung (>15% ventilation). For 20 patients a functional plan was generated that reduced dose to functional lung while meeting RTOG 0617‐based constraints. The NTCP model was applied to the functional plan to determine the reduction in toxicity with functional planningResults:The mean dose to functional lung was 16.8 and 17.7 Gy with the functional and clinical plans respectively. The corresponding grade 2+ pneumonitis probability was 26.9% with the clinically‐used plan and 24.6% with the functional plan (8.5% reduction). The V20‐based grade 2+ pneumonitis probability was 23.7% with the clinically‐used plan and reduced to 19.6% with the functional plan (20.9% reduction).Conclusion:Our results revealed a reduction of 9–20% in complication probability with functional planning. To our knowledge this is the first study to apply complication probability to convert dosimetric results to toxicity improvement. The results presented in the current work provide seminal data for prospective clinical trials in functional avoidance.YV discloses funding from State of Colorado. TY discloses National Lung Cancer Partnership; Young Investigator Research grant

TU‐G‐BRA‐04: Changes in Regional Lung Function Measured by 4D‐CT Ventilation Imaging for Thoracic Radiotherapy

Purpose:To test the hypothesis: 4D‐CT ventilation imaging can show the known effects of radiotherapy on lung function: (1) radiation‐induced ventilation reductions, and (2) ventilation increases caused by tumor regression.Methods:Repeat 4D‐CT scans (pre‐, mid‐ and/or post‐treatment) were acquired prospectively for 11 thoracic cancer patients in an IRB‐approved clinical trial. A ventilation image for each time point was created using deformable image registration and the Hounsfield unit (HU)‐based or Jacobian‐based metric. The 11 patients were divided into two subgroups based on tumor volume reduction using a threshold of 5 cm3. To quantify radiation‐induced ventilation reduction, six patients who showed a small tumor volume reduction (<5 cm3) were analyzed for dose‐response relationships. To investigate ventilation increase caused by tumor regression, two of the other five patients were analyzed to compare ventilation changes in the lung lobes affected and unaffected by the tumor. The remaining three patients were excluded because there were no unaffected lobes.Results:Dose‐dependent reductions of HU‐based ventilation were observed in a majority of the patient‐specific dose‐response curves and in the population‐based dose‐response curve, whereas no clear relationship was seen for Jacobian‐based ventilation. The post‐treatment population‐based dose‐response curve of HU‐based ventilation demonstrated the average ventilation reductions of 20.9±7.0% at 35–40 Gy (equivalent dose in 2‐Gy fractions, EQD2), and 40.6±22.9% at 75–80 Gy EQD2. Remarkable ventilation increases in the affected lobes were observed for the two patients who showed an average tumor volume reduction of 37.1 cm3 and re‐opening airways. The mid‐treatment increase in HU‐based ventilation of patient 3 was 100.4% in the affected lobes, which was considerably greater than 7.8% in the unaffected lobes.Conclusion:This study has demonstrated that 4D‐CT ventilation imaging shows the known effects of radiotherapy on lung function: radiation‐induced ventilation reduction and ventilation increase caused by tumor regression, providing validation for 4D‐CT ventilation imaging.This study was supported in part by a National Lung Cancer Partnership Young Investigator Research grant.

Abstract 743: Potent anti-tumor activity of the MEK1/2 inhibitor MEK162 in human non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN) cell lines

Abstract BACKGROUND: MAPK pathway dysregulation is frequently seen in cancer. For NSCLC, this may be due to driver mutations or gene amplification in EGFR, KRAS, or BRAF, though tumors without such mutations frequently display pathway hyperactivity. Aberrant EGFR signaling in SCCHN may lead to hyperactivity of the MAPK or PI3K pathways. MEK162 (ARRY-438162) is a potent, tight binding, uncompetitive MEK inhibitor currently in clinical development for treatment of solid tumors. MEK162 has an IC50 of 10nM against purified MEK1/2. We evaluated whether MEK162 would inhibit NSCLC and SCCHN cell lines and whether specific molecular alterations predicted anti-tumor activity. We also evaluated the combination of MEK162 in combination with BYL719, a potent PI3K alpha inhibitor. METHODS: The 50% inhibitory concentration (IC50) of MEK162, alone or in combination with BYL719, was determined in 40 human NSCLC and 30 SCCHN cell lines in vitro. Effects on MAPK and PI3K/AKT pathway signaling were studied by western blot analysis. Effects of MEK162 alone or in combination with BYL719 on cell cycle progression were also determined by flow cytometry. RESULTS: Using previously published cut-offs for sensitivity in cell lines, among NSCLC cell lines, 20/40 (50%) were sensitive to MEK162 (IC50 ≤ 500nM), 9/40 were intermediately sensitive (IC50 500nM-1µM), and 11/40 were resistant (IC50 ≥ 1µm). Using the same cut-offs, 80% (24/30) of SCCHN cell lines were sensitive, 2/30 were intermediately sensitive, and 4/30 were resistant to MEK162. MEK162 exposure resulted in increased cells in G0/G1 and decreased cells in S-phase. MEK162 decreased phosphorylated ERK (p-ERK) in all cell lines treated and resulted in an increase in phosphorylated AKT (p-AKT), presumably as a compensatory result from MAPK pathway inhibition. Combined treatment with MEK162 and BYL719 resulted in synergistic growth inhibition for all cell lines and decreased levels of both p-ERK and p-AKT levels at 24 hours. CONCLUSION: MEK162 potently inhibited growth of human NSCLC and SCCHN cell lines in most cell lines tested and led to synergistic inhibition when combined with BYL719. The compensatory increase in pAKT seen with MEK162 was abrogated with dual treatment with MEK162 and BYL719, demonstrating that synergy may be mediated by simultaneous blockade of MAPK and PI3K/AKT pathways. These data provide a preclinical rationale for evaluating MEK162, alone or in combination with BYL719, in metastatic NSCLC and SCCHN. Supported by 1K23CA149079, P50 CA090440, V Foundation for Cancer Research, Jonsson Comprehensive Cancer Center, Wolfen Family Lung Cancer Research Program, Stiles Program in Oncology, National Lung Cancer Partnership and One Ball Matt Memorial Golf Tournament. Citation Format: Deborah JL Wong, Edward B. Garon, Danielle D. Silveira, Naeimeh Kamranpour, Sharon Pitts, Meenal Chalukya, Habib Hamidi, Steven Dubinett, Ronald Linnartz, Richard S. Finn, Dennis J. Slamon. Potent anti-tumor activity of the MEK1/2 inhibitor MEK162 in human non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN) cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 743. doi:10.1158/1538-7445.AM2014-743

TH-A-WAB-03: Radiation Dose Changes Pulmonary Function Measured by 4D-CT Ventilation Imaging

Purpose: The purpose of this study was to quantify mid‐and post‐treatment changes in 4D‐CT ventilation and test the hypothesis: temporal changes of 4D‐CT ventilation in lung regions receiving high doses are greater than those in regions receiving low or no doses. Methods: In an IRB‐approved clinical trial, repeat 4D‐CT scans were acquired for eight thoracic cancer patients treated with conventionally‐fractionated or hypo‐fractionated radiotherapy at the following time points: pre‐treatment (8 patients), mid‐treatment (6) and post‐treatment (7). Ventilation images were created for each time point using deformable registration for spatial mapping of the peak‐exhale 4D‐CT image to the peak‐inhale image and computation of Jacobian‐based ventilation metric. To quantify the ventilation change between pre‐treatment (baseline) and mid‐or post‐treatment, rigid registration was performed and the ventilation values were normalized by the mean value in high‐functional (>50th percentile ventilation value) lung regions receiving low doses (biologically effective dose <30 Gy). Statistical significance was tested using a Wilcoxon test. Results: Absolute ventilation changes in the high dose ROI were found to be greater than those in the low dose ROI consistently for all patients at all time points, except for one case. Overall, the mean absolute ventilation change in the high dose ROI was 22.6±17.7%, which was significantly greater than that in the low dose ROI (5.0±3.7%) (p<0.01). Several patients showed clear correlations between 4D‐CT ventilation changes and anatomic changes observed in CT images. For example, patient 3 demonstrated increased ventilation, which was correlated with central airway re‐opening and tumor regression. Conclusion: An 8‐patient study demonstrated significantly greater changes of 4D‐CT ventilation in lung regions receiving high doses than those in regions receiving low or no doses, providing a validation for 4D‐CT ventilation imaging. Future studies will focus on detailed analysis of correlations between 4D‐CT ventilation changes and anatomic changes. National Lung Cancer Partnership Young Investigator Research Grant; NIH/NCI2 R01 CA 093626

WE‐C‐WAB‐04: Comparison of 4D‐CT Ventilation Imaging with SPECT Ventilation Imaging for Thoracic Cancer Patients

Purpose: A novel lung ventilation imaging technique based on 4D‐CT can be used for functional avoidance to spare high‐functional lung regions, and early prediction or assessment of pulmonary toxicity in radiotherapy. However, there has been minimal validation showing inconsistent results in human subjects. The purpose of this study was to compare 4D‐CT ventilation images with SPECT ventilation images as clinical reference. Methods: In an IRB‐approved clinical trial, 4D‐CT ventilation and SPECT ventilation images were acquired in the supine position for 12 thoracic cancer patients. 4D‐CT ventilation was calculated by deformable image registration of 4D‐CT images, followed by analysis of the resultant displacement vector field to quantify regional volume change (Jacobian), a surrogate for ventilation. SPECT ventilation scans were performed by inhalation of 99mTc‐DTPA aerosols. We evaluated the physiologic accuracy of 4D‐CT ventilation by: (1) comparing 4D‐CT ventilation values in SPECT ventilation defect regions with those in non‐defect regions; (2) quantifying Dice similarity coefficients (DSCs) for the spatial overlap of low‐functional lung regions determined by 4D‐CT ventilation and SPECT ventilation; (3) comparing a ventral‐to‐dorsal gradient of 4D‐CT ventilation with that of SPECT ventilation. Results: Five patients showed severe depositions of SPECT DTPA aerosols in central airways, and hence were excluded from the analysis. The 4D‐CT ventilation value in SPECT ventilation defect regions was found to be significantly lower than that in non‐defect regions (0.14±0.06 vs. 0.19±0.07, p=0.01). The DSC for the spatial overlap of low‐functional lung regions was weak (0.29±0.11). 4D‐CT ventilation demonstrated a ventral‐to‐dorsal gravitational gradient, which was consistent with SPECT ventilation. Conclusion: A 12‐patient study demonstrated reasonable correlations between 4D‐CT ventilation and SPECT ventilation as clinical reference, indicating the potential for 4D‐CT ventilation imaging to achieve high physiologic accuracy. However, poor DSCs suggest the need for further studies to improve 4D‐CT ventilation imaging and/or a validation study design. National Lung Cancer Partnership Young Investigator Research Grant; NIH/NCI 2 R01 CA 093626

Comparison of medical oncologists' approach to non-small cell lung cancer patients compared with breast cancer.

6601 Background: Despite recent advances in the management of non-small cell lung cancer (NSCLC), treatment disparities persist. Evidence suggests that primary care physicians (PCPs) have less awareness of the benefit of adjuvant chemotherapy for lung cancer compared to breast cancer. They may also be less inclined to refer advanced stage NSCLC patients for further treatment and closely manage pain. This study’s goal was to refine this focus on treatment comparisons with a survey of medical oncologists. Methods: Online case scenarios were provided to medical oncologists identified through participating state and institutional organizations. Medical oncologists were randomized to receive one of four scenarios on the basis of cancer type (lung v. breast) and smoking status (30 pack/year smoker v. lifetime non-smoker). Medical oncologists’ treatment approaches were compared. Results: Two hundred seventy-one medical oncologists participated in the survey. The majority were male (71%) with a mean of 16.5 practice years; 28% worked within an academic setting. There were no significant differences in adjuvant chemotherapy use for early stage patients (98.3% lung v. 98.4% breast) or second-line chemotherapy for progressive disease (93.7% lung v. 95.9% breast). Almost all medical oncologists reported that they would offer an available clinical trial to a patient who had progressive disease but a good performance status (PS), regardless of cancer type. However, more medical oncologists were “very likely” to start third line chemotherapy for advanced stage breast cancer (33.6%) compared to advanced stage NSCLC (18.4%; p=.01). Conclusions: Medical oncologists report consistent first- and second-line adjuvant treatment patterns for NSCLC compared to breast cancer. However, they are less likely to consider third-line chemotherapy for advanced stage NSCLC, suggesting subtle treatment disparities. This study was supported by an award by GlaxoSmithKline (GSK) and by a grant from the National Lung Cancer Partnership and its North Carolina affiliate.

Incidence, characteristics, and survival of patients with EGFR-mutant lung cancers with EGFR T790M at diagnosis identified in the lung cancer mutation consortium (LCMC).

8085 Background: Somatic T790M mutations are detected in 62% of EGFR-mutant lung cancers with acquired resistance to EGFR TKIs, and have rarely been identified in the tumor at diagnosis and/or within the germline DNA. Multiplexed genotyping by the LCMC permitted us to evaluate the incidence of T790M at diagnosis, co-mutations, and survival of patients with this driver. Methods: The 14 member LCMC prospectively tested tumors of patients with lung adenocarcinomas in CLIA laboratories for mutations in EGFR and 9 other genes. We assayed T790Mby Sequenom, Snapshot, or Sanger sequencing. Germline DNA was not collected. Results: In the 987 tumors tested, 209 had mutations in EGFR alone: 25 T790M (2.5%) , 157 sensitizing EGFR mutations (exon 19 del, L858R, L861Q, G719X) without T790M, 23 exon 20 ins, 4 other mutations. 13 additional cases harbored mutations in EGFR and another driver; 2 with both T790M and PIK3CA. In each of the 27 EGFR-mutant cases with T790M, a coincident EGFR mutation was detected (18 exon 19 del, 9 L858R, 1 exon 20 ins). EGFR T790M was found more often than EGFR exon 20 ins or mutations in HER2 (1.9%), BRAF (1.6%), or PIK3CA (0.7%). Patients with T790M: 77% women, 81% never smokers, median age 55 (range 38-79), stage IV at diagnosis 81%, PS 0/1 100%. Characteristics did not differ from persons with sensitizing mutations and no T790M. Median survival from the diagnosis of metastatic disease for patients with EGFR-mutant lung cancers was 3.5 yrs with T790Mand 4.0 yrs without (p=0.926). Conclusions: T790M mutations were detected at diagnosis in 3% of adenocarcinomas and always coincident with another EGFR mutation. Cases with T790M represent 13% of all cases of EGFR- mutant lung cancer. Characteristics and survival for patients with EGFR- mutant lung cancers with T790M at diagnosis were similar to individuals with sensitizing mutations and no T790M. The observed incidence of T790M exceeded that of the other actionable targets HER2, BRAF, and PIK3CA. Trials should study this unique population identified by routine multiplexed genotyping. Supported by 1RC2CA148394-01 and the National Lung Cancer Partnership. Clinical trial information: NCT01014286.

Abstract 4664: Result of TORI L-03, a randomized, multicenter phase II clinical trial of erlotinib (E) or E + fulvestrant (F) in previously treated advanced non-small cell lung cancer (NSCLC).

Abstract Background: EGFR inhibition is an established therapy for previously treated NSCLC. Estrogen receptors (ER) and aromatase are expressed in most NSCLC specimens in both men and women. In preclinical models, estrogen stimulates NSCLC growth, an effect blocked by F, a pure ER antagonist. Preclinical models show enhanced anti-tumor effects by combining EGFR inhibitors with F. Methods: We conducted a Phase II clinical study to evaluate whether addition of F enhances antitumor efficacy of E. Men and women with advanced NSCLC and &amp;gt; 1 prior chemotherapy regimen (unless patient refused) were randomized 2:1 to receive E (150 mg PO qd) + F (500 mg IM q2wk x 3, then q4wk) or E alone. Stratification for gender and ECOG (0, 1 vs. 2) was performed. Response rate (RR) was the primary endpoint. Secondary endpoints included progression free survival (PFS), overall survival (OS) and correlation between clinical endpoints and tumor tissue and blood-based biomarkers. Results: 106 patients (pts) were randomized from March 2006 to June 2010. 100 (evaluated population) received E +/- F. E + F was well tolerated, with adverse events well balanced between arms. For E + F and E respectively, RR (23.6% vs. 14.8%, p = 0.35), PFS [1.9 vs. 1.8 months, hazard ratio (HR) 0.85, 95% confidence interval 0.55, 1.33] and OS [9.4 vs. 5.7 months, HR 0.96 (0.6, 1.55)] were similar between arms. EGFR mutational data could be obtained on 69 pts. EGFR mutations were more prevalent in the E arm (35% vs. 20%). EGFR mutations strongly predicted best response, PFS and OS (p &amp;lt; 0.0002 for each). RR, PFS and OS were similar among EGFR mutants between arms in this small subset (17 patients). Among the 52 pts with EGFR WT tumors, 3 partial responses (PR) were seen with E + F vs. none for E alone. Clinical benefit rate [CBR (RR + stable disease): 54.8% vs. 8.3%, p = 0.0056] was significantly higher among pts with WT tumors treated with E + F. Trends were observed in favor of E + F in PFS [2.0 vs. 1.6 months, HR 0.56 (0.29, 1.07)] and OS [7.4 vs. 5.9 months, HR 0.69 (0.36, 1.31)]. Conclusion: E + F was well tolerated in previously treated NSCLC pts, including men and pre- and post-menopausal women. The study showed a high RR (23.6%) for E + F, that was not adequately explained by EGFR mutations. Among EGFR WT pts, a significantly higher CBR that included 3 PRs was seen with trends towards improved PFS and OS with E + F as compared to E alone. Evaluation of tumor tissue biomarkers (including ER-α and -β, aromatase), blood estrogen levels and EGFR ligands known to be induced by ER signaling is ongoing to determine NSCLC subpopulations most likely to benefit from antiestrogens. [Supported by 1K23CA149079, P50 CA090440, V Foundation for Cancer Research, Jonsson Comprehensive Cancer Center, Wolfen Family Lung Cancer Research Program, Stiles Program in Oncology, National Lung Cancer Partnership and One Ball Matt Memorial Golf Tournament] Citation Format: Edward B. Garon, Jill M. Siegfried, Steven M. Dubinett, Robert M. Elashoff, David J. Park, Rupesh J. Parikh, Ravi Patel, Eddie H. Hu, Karen L. Reckamp, Brad Adams, Diego Martinez, He-Jing Wang, Fairooz Kabbinavar, Sanja Dacic, Meghan Brennan, Isett Laux, Diana C. Marquez-Garban, Laura P. Stabile, Dennis J. Slamon, Richard J. Pietras. Result of TORI L-03, a randomized, multicenter phase II clinical trial of erlotinib (E) or E + fulvestrant (F) in previously treated advanced non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4664. doi:10.1158/1538-7445.AM2013-4664

Con: The Case for Expanded Lung Cancer Research Support

Con: The Case for Expanded Lung Cancer Research Support

Abstract 2923: Estrogen signaling modulates cisplatin resistance in the treatment of human non-small cell lung cancer

Abstract Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Non-small cell lung cancer (NSCLC) accounts for more than 85% of lung cancers. Standard initial chemotherapy for patients with advanced NSCLC is a platinum-based regimen, with data showing that these therapies elicit a modest improvement in patient survival. However, a major limitation to cisplatin therapy is development of drug resistance, leading to cancer progression and reduced patient survival. Cisplatin acts by interacting with DNA to form adducts that, in turn, activate signaling pathways for cell death (apoptosis). DNA damage-mediated apoptotic signals, however, can be blocked, and the resistance that ensues is a major drawback of cisplatin therapy. Resistance mechanisms, such as increased DNA adduct repair, may be modulated by interactions with other signaling pathways for cell survival, and emerging data suggest that estrogens may play a role in this process. To understand how estrogens modulate cisplatin resistance in vitro, we used two models of human NSCLC, A549 and H23 cells, that proliferate in response to estradiol-17β (E2) and express estrogen receptors and aromatase (enzyme that produces estrogens locally). Cisplatin markedly reduces tumor cell growth and enhances apoptosis in both models. However, the antitumor action of cisplatin is significantly blocked when cells are treated with estrogen in vitro. Using qRT-PCR and Western immunoblot analysis of excision repair cross-complementing-1 (ERCC1) protein (repairs cisplatin-induced DNA damage), we find that ERCC1 mRNA and protein levels are significantly increased in the presence of estrogen, thereby suggesting a potential mechanism for estrogen-induced cisplatin resistance. Analyses of the 5’-regulatory region of the human ERCC1 gene revealed putative half-estrogen responsive elements in close proximity with sp1 and AP1 sites. Chromatin immunoprecipitation assays showed binding of estrogen receptors to these promoter sites. Furthermore, treatment of human NSCLC xenografts in vivo with an aromatase inhibitor (exemestane) alone or combined with standard cisplatin chemotherapy elicits a significant reduction in tumor progression as compared to paired controls. A new strategy to block NSCLC progression may be use of cisplatin with simultaneous suppression of estrogen signaling (such as use of aromatase inhibitors). [Supported by NIH Lung Cancer SPORE, National Lung Cancer Partnership and Stiles Program funds]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2923.

Abstract 3231: Chronic nicotine stimulates lung adenocarcinoma in vivo and in vitro via modulation of nicotinic acetylcholine receptor regulated excitatory and inhibitory neurotransmission characteristic of nicotine addiction

Abstract Nicotine addiction is characterized by changes of nicotinic acetylcholine receptors (nAChRs) in the brain to increase the production of excitatory neurotransmitters noradrenaline/adrenaline while reducing inhibitory neurotransmitter γ-aminobutyric acid (GABA). We tested the hypothesis that nAChR-regulated neurotransmitters regulate lung adenocarcinoma (AC) and that nAChR changes in AC cells analogous to nicotine addiction in the brain contribute to the development and progression of this cancer. Mice carrying xenografts of the human AC cell line NCI-H322 received no treatment or were given nicotine in the drinking water for 30 days with and without intraperitoneal injections of GABA. Xenograft sizes were measured. Noradrenaline and adrenaline in serum and cAMP in blood cells and tumor cells were measured by immunoassays. Protein expression of α7nAChR, α4β2nAChR, p-CREB, p-ERK1/2, glutamate decarboxylase 65 (GAD65) and GABA in xenografts were analyzed by Western blotting. Nicotine increased xenograft sizes and upregulated receptor protein of both nAChRs in xenografts while increasing noradrenaline, adrenaline and cAMP in the blood. Xenograft expression of GAD65 and GABA were suppressed by nicotine while p-CREB, p-ERK and cAMP were induced. GABA reversed all these effects of nicotine. In vitro exposure of AC cells for 7 days to nicotine upregulated and sensitized the α7nAChR, resulting in a significant increase in noradrenaline/adrenaline production in response to agonist and enhancement of its cAMP-dependent signaling responses. At the same time, the α4nAChR was desensitized by chronic nicotine causing a significant reduction in GABA production. Nicotine-induced predominance of stimulatory noradrenaline and deficiency in inhibitory GABA in AC cells analogues to the nicotine addicted brain may therefore contribute to the development and progression of AC in smokers and GABA may be useful for the marker-guided prevention and adjuvant therapy of AC. Supported by a grant from the National Lung Cancer Partnership and LUNGevity Foundation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3231.

Abstract 4124: Chronic estrogen and NNK stimulate small airway epithelial cells via modulation of nicotinic acetylcholine receptors

Abstract Small airway epithelial cell-derived adenocarcinoma is the most common human lung cancer and is particularly prevalent in women. We have previously reported that the proliferation of immortalized human small airway epithelial cells HPL1D is stimulated by a single dose of the tobacco carcinogen NNK via cAMP signaling activated by binding of NNK to the beta-1-adrenergic receptor (β1-AR) and that estrogen enhances this response. In the current study we show that γ-aminobutyric acid (GABA) blocks this cooperative signaling of NNK and estrogen in HPL1D cells by inhibiting the activation of adenylyl cyclase. In addition, HPL1D cells produced the stress neurotransmitters noradrenaline and adrenaline in response to binding of a single dose of NNK to the α7 nicotinic acetylcholine receptor (α7nAChR). Since both stress neurotransmitters are beta-adrenergic agonists, this response further enhanced cAMP-dependent stimulatory signaling. On the other hand, GABA production by these cells was reduced by a single dose of NNK via desensitization of the α4β2 nAChR. Exposure to NNK, estrogen or the combination of both agents for 7 days upregulated and sensitized the α7nAChR, resulting in an enhanced noradrenergic response to agonist. At the same time, chronic NNK and estrogen suppressed the production of GABA by desensitizing its regulatory α4β2nAChR. The resulting predominance of stimulatory cAMP signaling over inhibitory GABA signaling may contribute to the development and progression of small airway-derived adenocarcinoma in women who smoke and offer a novel target for the marker-guided prevention of this cancer. Supported by a grant from the National Lung Cancer Partnership and LUNGevity Foundation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4124.

2008 Meeting of the National Lung Cancer Partnership: A Summary of Meeting Highlights

Herein are highlights from National Lung Cancer Partnership's Annual Meeting, held May 30, 2008 in Chicago. Aiming to improve the match between lung cancer patients and their drug treatments, speakers described potential predictive and prognostic biomarkers. Approaches included: (1) in non-small cell lung cancer, testing for predictive links between tumor expression levels of DNA synthesis (RRM1) and repair (ERCC1) enzymes and response to gemcitabine and cisplatin respectively, and looking for a prognostic link with ERCC1 expression; (2) validating a predictive "meta-gene profile" from gene expression microarray studies to distinguish drug-responsive from unresponsive lung cancer tumors; and (3) developing proteomics profiling to distinguish lung cancer patients, including squamous and nonsquamous cell carcinoma patients, who respond to epidermal growth factor receptor tyrosine kinase inhibitors from those who do not. The notion that cancer stem cells are fundamental in the development and progression of solid tumors including lung cancers was also discussed. Potential strategies for using this information to identify useful targets for next-generation therapies were suggested.

2007 Annual Meeting of the National Lung Cancer Partnership: A Summary of Meeting Highlights

This report presents highlights from The National Lung Cancer Partnership's Annual Meeting, held in June 2007 in Chicago. It discusses recent refinements in the histologic, genetic, and epigenetic subtyping of lung cancers and suggests reasons why certain therapies benefit only a subset of lung cancer patients. It also describes new molecular data about the subtype-specific differences in drug resistance among bronchioloalveolar-associated non-small cell lung cancers and discusses strategies to avoid or tackle specific drug-resistant tumors. Finally, it describes new findings about epigenetic differences-specifically in DNA hypermethylation-among lung tumors, including some male/female differences, which may prove useful as biomarkers for diagnosis, prognosis, and prediction of response to treatments.