Therapy For Lung Cancer Patients Research Articles

High Potency VEGFRs/MET/FMS Triple Blockade by TAS-115 Concomitantly Suppresses Tumor Progression and Bone Destruction in Tumor-Induced Bone Disease Model with Lung Carcinoma Cells.

Approximately 25–40% of patients with lung cancer show bone metastasis. Bone modifying agents reduce skeletal-related events (SREs), but they do not significantly improve overall survival. Therefore, novel therapeutic approaches are urgently required. In this study, we investigated the anti-tumor effect of TAS-115, a VEGFRs and HGF receptor (MET)-targeted kinase inhibitor, in a tumor-induced bone disease model. A549-Luc-BM1 cells, an osteo-tropic clone of luciferase-transfected A549 human lung adenocarcinoma cells (A549-Luc), produced aggressive bone destruction associated with tumor progression after intra-tibial (IT) implantation into mice. TAS-115 significantly reduced IT tumor growth and bone destruction. Histopathological analysis showed a decrease in tumor vessels after TAS-115 treatment, which might be mediated through VEGFRs inhibition. Furthermore, the number of osteoclasts surrounding the tumor was decreased after TAS-115 treatment. In vitro studies demonstrated that TAS-115 inhibited HGF-, VEGF-, and macrophage-colony stimulating factor (M-CSF)-induced signaling pathways in osteoclasts. Moreover, TAS-115 inhibited Feline McDonough Sarcoma oncogene (FMS) kinase, as well as M-CSF and receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation. Thus, VEGFRs/MET/FMS-triple inhibition in osteoclasts might contribute to the potent efficacy of TAS-115. The fact that concomitant dosing of sunitinib (VEGFRs/FMS inhibition) with crizotinib (MET inhibition) exerted comparable inhibitory efficacy for bone destruction to TAS-115 also supports this notion. In conclusion, TAS-115 inhibited tumor growth via VEGFR-kinase blockade, and also suppressed bone destruction possibly through VEGFRs/MET/FMS-kinase inhibition, which resulted in potent efficacy of TAS-115 in an A549-Luc-BM1 bone disease model. Thus, TAS-115 shows promise as a novel therapy for lung cancer patients with bone metastasis.

Effects of anatomical changes on pencil beam scanning proton plans in locally advanced NSCLC patients

Daily anatomical variations can cause considerable differences between delivered and planned dose. This study simulates and evaluates these effects in spot-scanning proton therapy for lung cancer patients. Robust intensity modulated treatment plans were designed on the mid-position CT scan for sixteen locally advanced lung cancer patients. To estimate dosimetric uncertainty, deformable registration was performed on their daily CBCTs to generate 4DCT equivalent scans for each fraction and to map recomputed dose to a common frame. Without adaptive planning, eight patients had an undercoverage of the targets of more than 2GyE (maximum of 14.1GyE) on the recalculated treatment dose from the daily anatomy variations including respiration. In organs at risk, a maximum increase of 4.7GyE in the D1 was found in the mediastinal structures. The effect of respiratory motion alone is smaller: 1.4GyE undercoverage for targets and less than 1GyE for organs at risk. Daily anatomical variations over the course of treatment can cause considerable dose differences in the robust planned dose distribution. An advanced planning strategy including knowledge of anatomical uncertainties would be recommended to improve plan robustness against interfractional variations. For large anatomical changes, adaptive therapy is mandatory.

SU‐F‐T‐133: Uniform Scanning Proton Therapy for Lung Cancer: Toxicity and Its Correlation with Dosimetry

Purpose:To analyze the toxicity of uniform scanning proton therapy for lung cancer patients and its correlation with dose distribution.Methods:In this study, we analyzed the toxicity of 128 lung cancer patients, including 18 small cell lung cancer and 110 non small cell lung cancer patients. Each patient was treated with uniform scanning proton beams at our center using typically 2–4 fields. The prescription was typically 74 Cobalt gray equivalent (CGE) at 2 CGE per fraction. 4D Computerized Tomography (CT) scans were used to evaluate the target motion and contour the internal target volume, and repeated 3 times during the course of treatment to evaluate the need for plan adaptation. Toxicity data for these patients were obtained from the proton collaborative group (PCG) database. For cases of grade 3 toxicities or toxicities of interest such as esophagitis and radiation dermatitis, dose distributions were reviewed and analyzed in attempt to correlate the toxicity with radiation dose.Results:At a median follow up time of about 21 months, none of the patients had experienced Grade 4 or 5 toxicity. The most common adverse effect was dermatitis (81%: 52%‐Grade 1, 28%‐Grade 2, and 1% Grade 3), followed by fatigue (48%), Cough (46%), and Esophagitis (45%), as shown in Figure 1. Severe toxicities, such as Grade 3 dermatitis or pain of skin, had a clear correlation with high radiation dose.Conclusion:Uniform scanning proton therapy is well tolerated by lung cancer patients. Preliminary analysis indicates there is correlation between severe toxicity and high radiation dose. Understanding of radiation resulted toxicities and careful choice of beam arrangement are critical in minimizing toxicity of skin and other organs.

Circulating cell-free nucleic acids and platelets as a liquid biopsy in the provision of personalized therapy for lung cancer patients

Lung cancer is the predominant cause of cancer-related mortality in the world. The majority of patients present with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Treatment for NSCLC is evolving from the use of cytotoxic chemotherapy to personalized treatment based on molecular alterations. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of circulating cell-free nucleic acids (cfNA), consisting of both circulating cell-free (tumoral) DNA (cfDNA–ctDNA) and RNA (cfRNA), as a liquid biopsy in lung cancer. The development of sensitive and accurate techniques such as Next-Generation Sequencing (NGS); Beads, Emulsion, Amplification, and Magnetics (BEAMing); and Digital PCR (dPCR), have made it possible to detect the specific genetic alterations (e.g. EGFR mutations, MET amplifications, and ALK and ROS1 translocations) for which targeted therapies are already available. Moreover, the ability to detect and quantify these tumor mutations has enabled the follow-up of tumor dynamics in real time. Liquid biopsy offers opportunities to detect resistance mechanisms, such as the EGFR T790M mutation in the case of EGFR TKI use, at an early stage. Several studies have already established the predictive and prognostic value of measuring ctNA concentration in the blood. To conclude, using ctNA analysis as a liquid biopsy has many advantages and allows for a variety of clinical and investigational applications.

Highlights of This Issue

Preclinical evaluation of targeted therapies does not follow simple criteria and often heavily relies on the use of patient-derived xenograft (PDX), which present major disadvantages: potential failure of tumor transplantation, long waiting-time to response evaluation, and extensive laboratory cost. Alternative clinical decision-making tools, therefore, are needed. This study compares PDX-based treatment response of targeted therapies in lung cancer patients with the result of a specific in silico response prediction (ISRP) tool and provides evidence for a substantial agreement between an ISPR and PDX response prediction. The ISPR allows fast and cheap individual-targeted response prediction in parallel for several substances.The heterogeneity of programmed cell death ligand 1 (PD-L1) expression may not be accurately represented by analysis of a single tumor. Mansfield and colleagues assessed the distribution of PD-L1 expression in paired, resected multifocal lung cancers and used mate pair next-generation sequencing to define the lineage relationship of these lesions. The expression of PD-L1 was heterogeneous among independent primary lung cancers, but there were high levels of agreement among related, intrapulmonary metastases. These data highlight that a single biopsy may not accurately capture PD-L1 expression status and emphasize the need for novel methods of patient selection for immunotherapy.PD-L1 status and tumor-infiltrating lymphocyte (TIL) recruitment have been suggested to be the most theoretical biomarker to predict the good responder of anti-PD-1/PD-L1 inhibitors. To prove this concept, Ock and colleagues analyzed the immunogenomic properties in The Cancer Genome Atlas (N = 9,677) according to the classification of tumor into four groups based on PD-L1 expression and TIL status, assessed by CD8A expression. Tumor microenvironment immune types (TMIT) I, high PD-L1, and CD8A expressions were significantly associated with a high number of somatic mutations as well as neoantigen, PD-L1 amplification, and infection with Epstein-Barr virus or human papillomavirus.The increased expression of phosphodiesterase (PDE) 5 in various human malignancies, coupled with the success of PDE5 inhibitors in different diseases, has led to interest in investigating the role of this enzyme in cancer. Catalano and colleagues showed that PDE5 overexpression increased motile and invasive properties of breast cancer cells. In patients, PDE5 is differentially expressed according to molecular subtypes, with a positive correlation with tumor grading, and high levels predict a worse prognosis. This study holds promise for PDE5 as a valuable candidate with prognostic significance and an attractive target for future therapy in breast cancers.

Dynamic changes in circulating miRNA levels in response to antitumor therapy of lung cancer

ABSTRACTPurpose: Expression levels of cancer-associated microRNAs were reported to be altered in serum/plasma samples from lung cancer patients compared with healthy subjects. The purpose of this study was to estimate the value of five selected miRNAs plasma levels as markers of response to antitumor therapy in lung cancer patients. Materials and Methods: Expression levels of miR-19b, miR-126, miR-25, miR-205, and miR-125b have been evaluated by quantitative reverse transcription PCR versus control miR-16 in blood plasma samples from 23 lung cancer (LC) patients. Plasma samples were obtained from LC patients before treatment (untreated-UT), within 30 days after completing two courses of chemotherapy (postchemotherapy-PC) and 15 days after surgery (postoperative-PO). Results: Repeated Measures ANOVA demonstrated that miR-19b expression levels were decreased in PC and increased in PO samples. These changes were characterized by a significant quadratic trend (p = 0.03). Expression levels of miR-125b increased both after chemotherapy and again after surgery and demonstrated a significant linear trend (p = 0.03). The miR-125b/miR-19b ratio changed during the course of the antitumor treatment with a significant linear trend (p = 0.04). Individual analysis in the groups of patients with partial response to chemotherapy and patients with stable or progressive disease showed different trends for miR-19b, miR-125b, and miR-125b/miR-19b ratio between the groups. The Kaplan–Meier survival curves demonstrated an association of miR-125b/miR-19b ratio value with the survival time without the tumor relapse (p < 0.1). Conclusions: Dynamic change of trends for miR-19b and miR-125b expression levels and miR-125b/miR-19b ratio in the blood plasma have shown a potentiality to discriminate types of response to antitumor therapy in lung cancer patients. Further in-depth investigation is needed to establish a direct link the miRNAs expression levels in blood plasma with therapy response and patient's survival.

Radiosensitizing effect of PSMC5, a 19S proteasome ATPase, in H460 lung cancer cells

The function of PSMC5 (proteasome 26S subunit, ATPase 5) in tumors, particularly with respect to cancer radioresistance, is not known. Here, we identified PSMC5 as a novel radiosensitivity biomarker, demonstrating that radiosensitive H460 cells were converted to a radioresistance phenotype by PSMC5 depletion. Exposure of H460 cells to radiation induced a marked accumulation of cell death-promoting reactive oxygen species, but this effect was blocked in radiation-treated H460 PSMC5-knockdown cells through downregulation of the p53-p21 pathway. Interestingly, PSMC5 depletion in H460 cells enhanced both AKT activation and MDM2 transcription, thereby promoting the degradation of p53 and p21 proteins. Furthermore, specific inhibition of AKT with triciribine or knockdown of MDM2 with small interfering RNA largely restored p21 expression in PSMC5-knockdown H460 cells. Our data suggest that PSMC5 facilitates the damaging effects of radiation in radiation-responsive H460 cancer cells and therefore may serve as a prognostic indicator for radiotherapy and molecular targeted therapy in lung cancer patients.

O2-6-2 - A randomized phase II trial of triplet or doublet antiemetic therapy in lung cancer patients receiving MEC (NLCTG1002)

O2-6-2 - A randomized phase II trial of triplet or doublet antiemetic therapy in lung cancer patients receiving MEC (NLCTG1002)

부산, 경남지역 폐암 환자의 방사선치료 이용에 대한 임상 결정 모델 연구

Abstract Radiation therapy for lung cancer is an effective treatment during monotherapy or combination therapy. Studies have reported that the optimum utilization rate of radiation therapy is estimated at 61% to 74%. Radiation therapy in Korea has been investigated to be low; further studies are needed.This study was intended to assess the appropriateness of the use of radiation and to reveal the use of radiation therapy-related factors by examining radiation therapy in lung cancer patients of Busan and South Gyeongnam Province. This study was aimed at the population diagnosed with lung cancer in Busan and South Gyeongnam Province. To conduct the study, 1036 patients enrolled in two hospitals were collected and 897 appropriate as subjects were selected.We compared the optimum utilization rate and actual rate of radiation therapy, and revealed the adequacy and related factors for use of radiotherapy. Of 897 patients, 503 (56%) were treated with medical therapy and 394 (44%) weregiven radiotherapy.The radiotherapy utilization rate of all lung cancer patients was 42%. The proportion of non-small cell lung cancer by histologic type was 33% and that of small cell lung cancer was 90%. Factors related to radiation therapy used in cancer were age, histological type, clinical stage, doctor refereed to, and clinical examination. Compared to radiation utilization by region (site), curative chest therapy was 42%; palliative treatment was 26%. In the comparison of histologic types, utilization of small-cell lung cancer is lower; the lowest especially in the stage Ⅲ. Utilization of radiation therapy in Busan and South Gyeongnam Province was lower than the reasonable one. Utilization difference could be explained by patient factors, tumor factors, and health service factors. To improve utilization,development ofoutreach service programs and activation of the multidisciplinary team are required.

Clinical results of photodynamic therapy in tracheobronchial malignancy

Photodynamic therapy (PDT) has been adopted as an alternative therapy for lung cancer patients who could not receive surgery due to their poor condition. It also has expanded its roles in lung cancer treatment for palliative treatment for increasing symptoms.We retrospectively reviewed medical records of patients of tracheobronchial cancers who received photodynamic therapy in our institute. Outcomes of the treatment results were evaluated, and survival analysis was performed via Kaplan–Meier analysis.We performed 25 cases of photodynamic therapy for tracheobronchial cancer patients between 2003 and 2013. A total of 21 patients were involved. Average ages at the time of treatment were 68.1. In those 25 cases, 8 cases achieved complete remission, and 15 cases remained partial remission. There were 2 cases of no response. Seven patients died during the follow-up periods, but none of these were related with complications. Only two minor complications were observed during the follow-up periods. One was granulation at the site of PDT, and the other was hemoptysis. Average overall survival periods for the therapeutic group were 50.1months and those of the palliative group were 29.3months.Photodynamic therapy was safe and feasible for palliative therapy in tracheobronchial cancer with acceptable complication rates. Also, it could be a treatment option for double primary lung cancer in inoperable patients.

Pulmonary Interstitial Changes Is a Predictive Factor for Radiation Pneumonitis After Stereotactic Body Radiation Therapy for Lung Cancer Patients

Pulmonary Interstitial Changes Is a Predictive Factor for Radiation Pneumonitis After Stereotactic Body Radiation Therapy for Lung Cancer Patients

Implementation of Amplicon Parallel Sequencing Leads to Improvement of Diagnosis and Therapy of Lung Cancer Patients

The Network Genomic Medicine Lung Cancer was set up to rapidly translate scientific advances into early clinical trials of targeted therapies in lung cancer performing molecular analyses of more than 3500 patients annually. Because sequential analysis of the relevant driver mutations on fixated samples is challenging in terms of workload, tissue availability, and cost, we established multiplex parallel sequencing in routine diagnostics. The aim was to analyze all therapeutically relevant mutations in lung cancer samples in a high-throughput fashion while significantly reducing turnaround time and amount of input DNA compared with conventional dideoxy sequencing of single polymerase chain reaction amplicons. In this study, we demonstrate the feasibility of a 102 amplicon multiplex polymerase chain reaction followed by sequencing on an Illumina sequencer on formalin-fixed paraffin-embedded tissue in routine diagnostics. Analysis of a validation cohort of 180 samples showed this approach to require significantly less input material and to be more reliable, robust, and cost-effective than conventional dideoxy sequencing. Subsequently, 2657 lung cancer patients were analyzed. We observed that comprehensive biomarker testing provided novel information in addition to histological diagnosis and clinical staging. In 2657 consecutively analyzed lung cancer samples, we identified driver mutations at the expected prevalence. Furthermore we found potentially targetable DDR2 mutations at a frequency of 3% in both adenocarcinomas and squamous cell carcinomas. Overall, our data demonstrate the utility of systematic sequencing analysis in a clinical routine setting and highlight the dramatic impact of such an approach on the availability of therapeutic strategies for the targeted treatment of individual cancer patients.

SU‐E‐J‐169: The Dosimetric and Temporal Effects of Respiratory‐Gated Radiation Therapy in Lung Cancer Patients

Purpose:To evaluate the dosimetric and temporal effects of high dose rate treatment mode for respiratory‐gated radiation therapy in lung cancer patients.Methods:Treatment plans from five lung cancer patients (3 nongated (Group 1), 2 gated at 80EX‐80IN (Group 2)) were retrospectively evaluated. The maximum tumor motions range from 6–12 mm. Using the same planning criteria, four new treatment plans, corresponding to four gating windows (20EX–20IN, 40EX–40IN, 60EX–60IN, and 80EX–80IN), were generated for each patient. Mean tumor dose (MTD), mean lung dose (MLD), and lung V20 were used to assess the dosimetric effects. A MATLAB algorithm was developed to compute treatment time by considering gantry rotation time, time to position collimator leaves, dose delivery time (scaled relative to the gating window), and communication overhead. Treatment delivery time for each plan was estimated using a 500 MU/min dose rate for the original plans and a 1500 MU/min dose rate for the gated plans.Results:Differences in MTD were less than 1Gy across plans for all five patients. MLD and lung V20 were on average reduced between −16.1% to −6.0% and −20.0% to −7.2%, respectively for non‐gated plans when compared with the corresponding gated plans, and between − 5.8% to −4.2% and −7.0% to −5.4%, respectively for plans originally gated at 80EX–80IN when compared with the corresponding 20EX‐20IN to 60EX– 60IN gated plans. Treatment delivery times of gated plans using high dose rate were reduced on average between −19.7% (−1.9min) to −27.2% (−2.7min) for originally non‐gated plans and −15.6% (−0.9min) to −20.3% (−1.2min) for originally 80EX‐80IN gated plans.Conclusion:Respiratory‐gated radiation therapy in lung cancer patients can reduce lung toxicity, while maintaining tumor dose. Using a gated high‐dose‐rate treatment, delivery time comparable to non‐gated normal‐dose‐rate treatment can be achieved.This research is supported by Siemens Medical Solutions USA, Inc

Statin use and survival from lung cancer: a population-based cohort study.

Preclinical evidence from lung cancer cell lines and animal models suggest that statins could have anticancer properties. We investigated whether statin users had reduced risk of cancer-specific mortality in a population-based cohort of lung cancer patients. Newly diagnosed lung cancer patients, from 1998 to 2009, were identified from English cancer registry data and linked to the UK Clinical Practice Research Datalink, providing prescription records, and to Office of National Statistics mortality data up to 2012. Cox regression models were used to calculate HRs for cancer-specific mortality and 95% confidence intervals (CI) by statin use before and after diagnosis, and to adjust these HRs for potential confounders. In 3,638 lung cancer patients, there was some evidence that statin use after diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR, 0.89; 95% CI, 0.78-1.02; P = 0.09). Associations were more marked after 12 prescriptions (adjusted HR, 0.81; 95% CI, 0.67-0.98; P = 0.03) and when lipophilic statins were investigated (adjusted HR, 0.81; 95% CI, 0.70-0.94; P = 0.01), but were attenuated in some sensitivity analyses. Furthermore, in 11,051 lung cancer patients, statin use before diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR, 0.88; 95% CI, 0.83-0.93; P < 0.001). There was some evidence that lung cancer patients who used statins, and particularly simvastatin, had reduced rates of cancer-specific mortality. These findings should first be confirmed in observational studies, but provide some support for conducting randomized controlled trials of simvastatin as adjuvant cancer therapy in lung cancer patients.

Autologous cytokine-induced killer cell therapy in lung cancer patients: A retrospective study

Cytokine-induced killer (CIK) cells have the ability to kill tumor cells in vitro and in vivo. This study aimed to evaluate the clinical effect of adjuvant immunotherapy with CIK cells on the prognosis of lung cancer patients. In the present study, we investigated the clinical outcomes of autologous CIK cell immunotherapy for patients with lung cancer in a case–control study. Our study included 60 patients who received chemotherapy combined with autologous CIK cell adoptive immunotherapy in CIK treatment group and 60 patients who received chemotherapy alone in the control group. Progression-free survival (PFS) and overall survival (OS) of these two groups were evaluated. After 14 days of incubation in vitro, the percentages of CD3+, CD3+CD8+, CD3+CD56+ and CD3−CD56+ were significantly increased (P<0.05). The clinical symptoms of 60 patients were apparently improved. No severe toxicity and side effects were observed in the CIK treatment group. The 3-year, 5-year PFS rates were 44.7% and 26.8% and the 3-year, 5-year OS rates were 74% and 62% in the CIK group, respectively, which were significantly improved compared to that in the control group. The median PFS and OS in the CIK group were significantly improved than those in the control group (PFS, 24 months vs. 14 months, P=0.014; OS, 72 months vs. 44 months, P=0.006). Our results indicated that autologous CIK cells can efficiently improve the immunological status and prolong PFS and OS in patients with lung cancer.

Abstract B43: Targeting tumor microenvironment for treatment of K-ras mutant lung cancer

Abstract Activating mutations of K-ras are one of the most common molecular alterations associated with lung cancer development. Several attempts to develop therapies directly targeting K-ras have been failed thus far, clearly state the need for new strategies to bring clinical benefits to patients displaying such a molecular profile. Using a conditional K-ras mutant lung cancer mouse model (CC-LR) we previously showed that K-ras mutated lung tumors have intrinsic inflammatory characteristics associated with NF-κB pathway activation. Therefore, CC-LR mice were crossed with IKK-β f/f mice to develop a K-ras mutant mouse with lack of NF-κB activity in airway epithelium. This changed the bronchoalveolar lavage fluid (BALF) cellular component of the CC-LR mice (mostly by reduction of macrophages), and resulted in a ∼70% (3.4-fold) reduction in lung surface tumor number. Lung of CC-LR mice also shows high protein level of IL-6 (downstream to NF-κB activation) and increased STAT3 gene expression (downstream signal to IL-6) plus infiltration of myeloid and Th17 cells. Accordingly, we genetically ablated IL-6 in the CC-LR mice. This significantly inhibited lung cancer development (1.7-fold, 41%) suggesting a role for IL-6 mediated signaling in tumor promotion probably through STAT3 pathway activation. IL-6 and STAT3 are required for differentiation of Th17 cells from naïve T cells. Th17 cells mostly produce IL-17A that binds to the IL-17 receptor (IL-17R). IL-17R signaling is required for lung CXC chemokine expression and myeloid cell recruitment. Furthermore, IL-17A induces more production of IL-6 by epithelial cells. So, CC-LR mice were crossed with IL-17A KO mice. Lack of IL-17A in CC-LR mice resulted in a ∼70% (3.4-fold) tumor reduction. It also decreased the expression of pro-inflammatory mediators and reduced recruitment of myeloid cells. These reults suggest that K-ras initiated airway inflammation through NF-κB mediated activation of the IL-6/STAT3/Th17 signaling promotes lung tumorigenesis, and introduce IL-6 as a potential druggable target for lung cancer patients who harbor K-ras mutations. This prompted us to block IL-6 pathway using a monoclonal anti-IL-6 immunotherapy in our K-ras mutant model. Six week old CC-LR mice were injected intraperitoneally with 20 mg/kg dose of an anti-IL-6 monoclonal IgG1 antibody, twice a week, for a period of 8 weeks. Flowcytometry and qPCR analysis of total lung in non-treated CC-LR mice showed 2-fold increase in the population of tumor associated macrophage (TAM) and Arginase-1 mRNA expression (3 fold) during tumor progression from age 6 weeks to 14 weeks suggesting that epithelial signal initiated by K-ras mutation dictates an inflammatory type 2 pro-tumor fate for lung microenvironment. We further found that anti-IL-6 treatment suppressed tumor development by ∼78% (4.6-fold) in CC-LR mice with a significant reduction in the expression levels of Ki-67, VEGF, MMP9, CD31 and phospho-STAT3 in lung tissue. It also reduced TGFβ and KC protein levels in BALF with a significant decrease in Arginase1 mRNA expression (3-fold) and TAM population (5-fold) in total lung homogenate. We conclude that K-ras mutation drives an immunosuppressive pro-tumor response and blocking IL-6 shifts this to an anti-tumor lung microenvironment. Therefore we propose pharmacological targeting of IL-6 as a potential therapeutic strategy alone or in combination with conventional cytotoxic therapy for lung cancer patients with K-ras mutation. Funded by: American Cancer Society, RSG-11-115-01-CNE, and American Lung Association/LUNGevity Foundation, LCD-114696-N Citation Format: Mauricio da Silva Caetano, Seon Hee Chang, Amber M. Cumpian, Soudabeh Daliri, Maria Miguelina De La Garza, Cesar E. Ochoa, Chen Dong, Seyed Javad Moghaddam. Targeting tumor microenvironment for treatment of K-ras mutant lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B43. doi: 10.1158/1557-3125.RASONC14-B43

338 BM-1252 (APG-1252): a potent dual specific Bcl-2/Bcl-xL inhibitor that achieves complete tumor regression with minimal platelet toxicity

we investigated the in vitro cytotoxicity of inhibitors against different components of the PI3K/AKT/mTOR pathways in RICTOR-amplified lung cancer cells. Results: The majority of cells possess normal copy numbers of RICTOR but 3 out of 27 non-small cell lung cancer (NSCLC) cell lines, including H23 (adenocarcinoma) and H1703 (squamous), were found to have ratio of RICTOR/control around 2, suggesting RICTOR amplification in those cell lines. Genetic knockdown of RICTOR by using either siRNA or inducible shRNA was associated with growth inhibition of RICTOR-amplified lung cancer cell lines. The growth of xenograft lung tumor was also inhibited by inducible RICTOR knockdown. Among 6 different kinase inhibitors against the PI3K/AKT/mTOR pathways, agents blocking both mTOR1 and mTOR2 were the most active in RICTOR-amplified lung cancer cells. Conclusions: Targeted genetic blockade of RICTOR led to growth inhibition of RICTOR-amplified lung cancer cells, indicating that selective targeting of RICTOR may represent a novel therapeutic strategy for the treatment of this subgroupof lung cancer patients. Our study also provides the rationale for utilizing dual mTOR1/2 inhibitors as a potential therapy for lung cancer patients harboring RICTOR amplification.

Incidence of Radiation Pneumonitis After Multiple Courses of Stereotactic Body Radiation Therapy for Lung Cancer Patients

Stereotactic body radiation therapy (SBRT) is a widely used therapy for primary and metastatic lung cancers. Radiation pneumonitis (RP) is one of the most important and potentially serious complications of SBRT, and recent studies have established the clinical and dosimetric risk factors for the development of RP in single course of SBRT. However, it is not well known how cumulative lung dose of multiple courses of SBRT impacts incidence of RP. The purpose of the present study is to evaluate incidence of RP after multiple courses of SBRT for lung cancers.

Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells

We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history.

Individual profiling of circulating tumor cell composition in patients with non-small cell lung cancer receiving platinum based treatment.

Circulating tumor cells (CTC) could serve as a "liquid biopsy" for individualizing and monitoring treatment in patients with solid tumors as recently shown by our group. We assessed which non-hematopoietic cell types are identifiable in the peripheral blood of patients with non-small cell lung cancer (NSCLC) and correlated those to clinical characteristics. Blood from NSCLC patients (n=43) was processed as previously described. For subtype analyses CTC were negatively enriched by hematopoietic cell depletion. The remaining cell suspension included pre-enriched tumor cells and was spun onto glass slides and further characterized by multi-immunofluorescence staining against epithelial markers pan-cytokeratin (CK) and epithelial cell adhesion molecule (EpCAM), mesenchymal marker N-cadherin, stem cell marker CD133, hematopoietic marker CD45 and nuclear counterstain DAPI. Individual cell type profiles were analyzed and correlated to therapeutic outcome. Among other associations of CTC subtypes with clinical parameters Kaplan-Meier test revealed that an increased CD133-positive to pan-CK-positive cell type ratio (stem cell like to epithelial ratio) and the presence of mesenchymal N-cadherin+ cells, both were significantly associated to shortened PFS (2 vs. 8 months, P=0.003, HR =4.43; 5 vs. 8 months, P=0.03, HR =2.63). Our data suggest that different CTC populations are identifiable in peripheral blood and that these individual cell type profiles might be used to predict outcome to platinum based systemic therapies in lung cancer patients.