Therapy For Small Cell Lung Cancer Research Articles

Preclinical Studies of Metformin Reveal Radiosensitization for Human Small Cell Lung Cancer In Vitro But Apparent Antagonism In Vivo

Metformin is an oral agent used for non-insulin dependent diabetes mellitus that may potentially enhance radiosensitivity for several types of cancer, including non-small cell lung cancer. Clinical studies of metformin in cancer are now underway. However, despite the need for more effective treatments for small cell lung cancer (SCLC), few studies of metformin and radiation in SCLC have been reported. We therefore investigated the efficacy of metformin combined with radiation therapy for SCLC.

Rapamycin Rescues ABT-737 Efficacy in Small Cell Lung Cancer

Overexpression of the antiapoptotic protein Bcl-2 is observed in the majority of small cell lung cancer (SCLC) cases and is associated with resistance to chemotherapy. While targeting Bcl-2 in hematologic malignancies continues to show signs of promise, translating the BH3 mimetic ABT-737 (or ABT-263; navitoclax) to the clinic for solid tumors has remained problematic, with limited single-agent activity in early-phase clinical trials. Here, we used patient-derived xenograft (PDX) models of SCLC to study ABT-737 resistance and demonstrated that responses to ABT-737 are short lived and coincide with decreases in HIF-1α-regulated transcripts. Combining the mTOR inhibitor rapamycin with ABT-737 rescued this resistance mechanism, was highly synergistic in vitro, and provided durable tumor regressions in vivo without notable hematologic suppression. In comparison, tumor regressions did not occur when ABT-737 was combined with etoposide, a gold-standard cytotoxic for SCLC therapy. Rapamycin exposure was consistently associated with an increase in the proapoptotic protein BAX, whereas ABT-737 caused dose-dependent decreases in BAX. As ABT-737 triggers programmed cell death in a BAX/BAK-dependent manner, we provide preclinical evidence that the efficacy of ABT-737 as a single agent is self-limiting in SCLC, but the addition of rapamycin can maintain or increase levels of BAX protein and markedly enhance the anticancer efficacy of ABT-737. These data have direct translational implications for SCLC clinical trials.

The Janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo.

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-activated kinases (JAK) inhibitor, AZD1480, for treatment of SCLC in vitro and in vivo. JAK1 and 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 was studied. Antitumor effects of AZD1480 in tumor xenografts were assessed. AZD1480 significantly inhibited growth of six out of 13 SCLC cells with IC50s ranging from 0.73 to 3.08 μmol/L. 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 an 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. JAK inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation.

The development of targeted therapy in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive cancer usually with distal metastasis and very poor prognosis. Chemotherapy is the treatment of choice for SCLC in all stages and an initial good response, but there is a high chance of disease relapse with an overall poor median survival for both stages. With increasing translational research and a better understanding of the molecular basis of cancer, a number of molecular targets have been identified in various preclinical studies. Targeted drugs have less toxicity than chemotherapy drugs, but no targeted agents have been approved for use in the treatment of SCLC patients to date. This review focuses on targeted therapies in SCLC.

Assessing the relative effectiveness and tolerability of treatments in small cell lung cancer: A network meta-analysis

Background: The combination of Cisplatin plus Etoposide (EP) is currently the standard treatment for small cell lung cancer (SCLC). However, a large number of alternative treatments (monotherapies and combinations) have been studied in randomized controlled trials (RCTs) to identify more effective treatments. Aim of the present study was to assess the relative effectiveness and tolerability of these treatments. Methods: PubMed, EMBASE and Cochrane Central Register of Controlled Trials were systematically searched to identify all RCTs that compared treatments for SCLC. Then, effectiveness of the treatments relative to the combination of Cisplatin plus Etoposide, reference treatment) was estimated by performing a network of treatments analysis. The analysis evaluated two efficacy outcomes (complete response – CR and objective response rate – ORR) and two tolerability outcomes (neutropenia and febrile neutropenia). All RCTs that provided data for calculating the odds ratios (OR) for the selected outcomes were considered. The network analysis involved direct and indirect analyses. Results: We identified 71 articles eligible for inclusion, involving 91 different treatments. In total, 16,026 patients were included in the analysis. In the direct analysis the combination of Cisplatin plus Cyclophosphamide plus Etoposide plus Epirubicin showed better response than EP for the ORR outcome, but with worse tolerability (presence of neutropenia). The indirect analysis revealed that the combination of Cisplatin plus Doxorubicin plus Etoposide (plus Vincrisitine) showed better response that EP for the ORR outcome. Conclusions: No therapy shows better response for the two efficacy outcomes (CR and ORR); though, Cisplatin plus Doxorubicin plus Etoposide plus Vincrisitine might be a promising therapy for SCLC. The results should be interpreted with caution because the network was dominated by indirect comparisons. Large scale head-to-head RCTs are needed to confirm the present findings.

The PARAMOUNT trial: Implications for Maintenance Therapy in Lung Cancer Patients

243 ISSN 1758-1966 10.2217/LMT.13.28 © 2013 Future Medicine Ltd Lung Cancer Manage. (2013) 2(4), 243–246 The maintenance strategic approach has been extensively investigated in hematologic malignancies and then in solid tumors. Among thoracic cancers, small-cell lung cancer has been the setting for several clinical trials of maintenance treatment. The most recent systematic review pooled the available trials evaluating maintenance therapy in small-cell lung cancer, producing a thorough picture of efficacy related to different pharmacological strategies. Despite an overall survival (OS) advantage reported for maintenance chemo therapy and interferon treatment, the results are not clinically relevant [1,2,101]. Maintenance therapy has only recently been accepted as a treatment strategy for advanced non-smallcell lung cancer (NSCLC) with the main goal of prolonging a favorable clinical state after induction first-line platinum-based combination chemo therapy in respect of an adequate tolerability and without impairing quality of life (QoL). This renewed interest has been raised with the availability of active and tolerable new drugs. Among these, pemetrexed, a new cytotoxic agent, is a potent inhibitor of thymidylate synthase and other folate-dependent enzymes. Based on its mechanism of action, pemetrexed was the first chemotherapeutic to be studied as a targeted agent. In fact, due to the evidence of the differential expression of thymidylate synthase between adenocarcinoma and squamous NSCLC, pemetrexed reported an increased efficacy in nonsquamous histology, and thus it is now registered only for the treatment of this histotype worldwide [3,4]. With adequate vitamin supplementation, pemetrexed was shown to be active and well tolerated, with grade ≥3 toxicities, when administered as a single agent, not exceeding 5–10% [5]. First, pemetrexed was tested as switch maintenance within the randomized Phase III trial JMEN. Advanced NSCLC patients of any histology not progressing after four cycles of platinum-based doublets, not including pemetrexed, were randomized to pemetrexed or placebo. Pemetrexed showed a statistically better progressionfree survival (PFS) and OS than placebo, which were more significant for nonsquamous histology [6]. These results led to the design of the PARAMOUNT study, a double-blind, multicenter, Phase III, randomized, placebocontrolled trial. The primary end point was PFS, chosen because this measure is not

Present status and upcoming prospects of hedgehog pathway inhibitors in small cell lung cancer therapy

Lung cancer is an important etiology of malignant mortality worldwide with global statistics indicating over 1 million deaths annually. Although there have been advances in cytotoxic chemotherapy, the prognosis after treatment still remains poor. Remarkably, recent studies on the molecular level are creating the possibility to hamper lung cancer by inhibiting the hedgehog pathway. Currently, hedgehog pathway inhibitors include IWP-2, cyclopamine and aprotinin. However, Vismodegib is a new upcoming prospect which has shown positive results while undergoing clinical trials. If approved, it may lead to a novel class of anti-cancer therapy for patients seeking treatment for small cell lung cancer.

Abstract 3257: Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor, PF-4989216.

Abstract Aberrant PI3K/AKT signaling occurs commonly in cancer. Gene mutation, amplification, and copy number gains in the catalytic p110α of PI3K have been shown in a variety of human cancers. Tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylates the 3-phosphoinositides and is frequently mutated, deleted, or down-regulated in many human cancers to constitutively activate the PI3K pathway. Small cell lung cancer (SCLC) patients have poor prognosis; response to second-line chemotherapy for patients with refractory disease is less than 10%, and survival is 3-4 months. Multiple phase III trials have been conducted, however the survival of SCLC patients has not significantly improved over the years. In this study, we characterized a selective PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway may be a potential therapy for SCLC. PF-4989216 inhibits phosphorylation of PI3K downstream molecules and subsequently leads to induction in apoptosis and cell cycle block, as well as inhibition of cell proliferation, transformation, and xenograft tumor growth in SCLCs harboring a PIK3CA mutation. Moreover, our results suggest that there may be different mechanisms of tumorigenesis between PIK3CA mutation and PTEN loss in SCLCs, and indicate that PF-4989216 is a potential cancer drug candidate for small-cell lung cancer patients harboring a PIK3CA mutation. Citation Format: Marlena Walls, Sangita M. Baxi, Pramod P. Mehta, Elizabeth Epps, Heather Estrella, Kevin KC Liu, JinJiang Zhu, Chunze Li, Tod Smeal, Min-Jean Yin. Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor, PF-4989216. [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 3257. doi:10.1158/1538-7445.AM2013-3257

Anti‐angiogenic activity of alpha7‐nicotinic receptor antagonists in human small cell lung cancer

Small cell lung cancer (SCLC), a highly angiogenic tumor displays a 90% association with smoking. Nicotine promotes angiogenesis in lung cancer via alpha7‐nicotinic acetylcholine receptors (α7‐nAChRs). We conjectured that α7‐nAChR antagonists should suppress nicotine‐induced angiogenesis and may have potential applications for the therapy of SCLC. Here we show that the synthetic α7‐nAChR antagonist MG624 suppresses nicotine‐induced proliferation of human microvascular endothelial cells from the lung (HMEC‐L). MG624 displayed potent anti‐angiogenic activity in the Matrigel, rat aortic ring, and chicken chorioallantoic membrane models and in human SCLC tumors xenografted in athymic mice. The administration of MG624 did not cause any discomfort, gross toxicity or lethargy in mice. Chromatin immunprecipitation assays show that MG624 decreases the recruitment of Egr‐1 on FGF2 promoter thereby decreasing its transcription and suppressing nicotine‐induced angiogenesis. Currently, our laboratory is testing the anti‐angiogenic activity of other well characterized α7‐nAChR antagonists like MLA and COG. Our results suggest that α7‐nAChR based anti‐angiogenic agents may be useful for the therapy of human SCLC.

Capsaicin: a novel dietary therapeutic agent in human small cell lung cancers

Capsaicin, spicy ingredient of chili peppers, is used to topically treat pain and inflammation associated with a variety of diseases. However, emerging evidence shows that it can induce apoptosis in different transformed cell types in vitro and in animal models. The present study examines the apoptotic activity of capsaicin in human small cell lung cancer (SCLC). Here we show that capsaicin induced apoptosis in a panel of human SCLC in a concentration‐dependent and time‐dependent manner. Most importantly, capsaicin caused robust apoptosis in a panel of human SCLC cell lines, but did not affect normal human lung epithelial cells. The dietary administration of capsaicin decreased the growth H69 and DMS53 human SCLC tumors xenotransplanted in nude mice. The apoptotic activity of capsaicin was reversed with the generalized TRPV antagonist ruthenium red, indicating that TRPV receptors are involved in capsaicin induced apoptosis. However, antagonists to TRPV1, namely capsazepine and SB‐366791, did not affect the apoptotic activity of capsaicin, suggesting the involvement of TRPV1‐independent mechanism. In contrast, depletion of TRPV6 by siRNA ablated the apoptotic activity of capsaicin. Our findings suggest that capsaicin may have potential applications as a novel agent for management and therapy of human SCLCs.

Doubling Down with Inhibitors of Notch and Hedgehog Signaling Pathways

Doubling Down with Inhibitors of Notch and Hedgehog Signaling Pathways

P2-004 - Comparison of Efficacy in Chemotherapy for Large-Cell Neuroendocrine Carcinoma of the Lung and Small-Cell Lung Cancer

ABSTRACT Introduction Large-cell neuroendocrine carcinoma (LCNEC) of the lung is the high-grade neuroendocrine tumor which account for ∼3% of all lung cancer. Although it has been reported that the platinum-containing chemotherapy was effective for LCNEC, the standard chemotherapy has not been established for LCNEC. Accordingly, patients with LCNEC have been administered chemotherapy which was the standard therapy for small-cell lung cancer (SCLC). To evaluate the efficacy of chemotherapy for the LCNEC, we assessed tumor response to chemotherapy and survival in patients with LCNEC and SCLC. Patients and methods Patients with histologically or cytologically confirmed metastatic or recurrent LCNEC or ED-SCLC who received chemotherapy in our institution were eligible. The efficacy of chemotherapy was retrospectively evaluated on the basis of the overall response rate (ORR) and the overall survival. Results From January 1999 to August 2011, 14 patients with metastatic or recurrent LCNEC received chemotherapy in our institution. On the other hand, 122 patients with ED-SCLC were administered chemotherapy in the same period. Gender, age and performance status were similar in the LCNEC and ED-SCLC groups. There were more never smokers in the LCNEC group than the ED-SCLC group. Patients with the ED-SCLC group had more number of metastatic sites than patients with the LCNEC group. In the first-line chemotherapy, 79% of patients with LCNEC and 92% with ED-SCLC received platinum-containing chemotherapy. The ORR of first-line chemotherapy was 57 and 58% for the LCNEC and ED-SCLC groups, respectively (P = 1.00). The median survival time was 11.8 months (95% CI: 4.0–14.3) in the LCNEC group and 11.8 months (95% CI; 10.5–14.1) in the ED-SCLC group, respectively. There was no statistical significance between both groups. Conclusion The efficacy of chemotherapy for LCNEC was similar to that for ED-SCLC in terms of tumor response and survival.

Suppression of metastases of small cell lung cancer cells in mice by a peptidic CXCR4 inhibitor TF14016

CXCL12 is a chemokine essential for the organ-specific spread of a variety of cancers including small cell lung cancer (SCLC). Here, we examined the anti-metastatic efficacy of TF14016, a small peptidic inhibitor of CXCL12 receptor CXCR4, in SCLC. Treatment of mice with TF14016 significantly suppressed pulmonary metastases of CXCR4-expressing SCLC in size and number. Furthermore, histological examination revealed that the expression of vascular endothelial cell growth factor and the density of CD31-positive microvessels in metastatic foci were both significantly reduced in TF14016-treated mice. Collectively, CXCR4 could be an attractive target for anti-metastatic and anti-angiogenic therapy in SCLC.

Targeted therapies in small cell lung cancer.

Lung cancer is the leading cause of cancer-related mortality. Small cell lung cancer (SCLC) accounted for 12.95% of all lung cancer histological types in 2002. Despite trends toward modest improvement in survival, the outcome remains extremely poor. Chemotherapy is the cornerstone of treatment in SCLC. More than two-thirds of patients who succumb to lung cancer in the United States are over 65 years old. Elderly patients tolerate chemotherapy poorly and need novel therapeutic agents. Targeted drugs have less toxicity than chemotherapy drugs, but no targeted agents have been approved for use in the treatment of SCLC patients to date. Certain new targeted agents, including gefitinib, bevacizumab and Bcl-2 inhibitors, offer a promise of improved outcomes, however negative results are more commonly reported than positive. This review focuses on targeted therapies in SCLC.

The clinical analysis of small cell lung cancer treatment with recombinant human endostatin injection and cis-platinum complexes

Objective To explore the clinical effect of small cell lung cancer(SCLC) treatment with recombinant human endostatin injection and cis-platinum complexes.Methods 100 patients with SCLC were divided into 2groups.The experiment group used cis-platinum complexes while the control group used recombinant human endostatin injection.Results The effective rate of experiment group was obviously higher than the control group ( 74.0％ vs60.0％,x2=2.16,P ＜ 0.05 ).The median survival time of experiment group was better than control group( t=2.02,P ＜ 0.05 ).The diverse of untoward effect of two groups had no difference ( P ＞ 0.05).Conclusion Recombinant human endostatin injection and cis-platinum complexes were better therapy for SCLC,which had stable effect,no severe untoward effect and overcome the drug-fast of cis-platinum complexes. Key words: Carcinoma; small cell; Endostatin; Cis-platinum

Curcumin Blocks Small Cell Lung Cancer Cells Migration, Invasion, Angiogenesis, Cell Cycle and Neoplasia through Janus Kinase-STAT3 Signalling Pathway

Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development. However, little is known about its anti-tumor mechanism in small cell lung cancer (SCLC). In this study, we found that curcumin can inhibit SCLC cell proliferation, cell cycle, migration, invasion and angiogenesis through suppression of the STAT3. SCLC cells were treated with curcumin (15 µmol/L) and the results showed that curcumin was effective in inhibiting STAT3 phosphorylation to downregulate of an array of STAT3 downstream targets ,which contributed to suppression of cell proliferation, loss of colony formation, depression of cell migration and invasion. Curcumin also suppressed the expression of proliferative proteins (Survivin, Bcl-XL and Cyclin B1), and invasive proteins (VEGF, MMP-2, MMP-7 and ICAM-1).Knockdown of STAT3 expression by siRNA was able to induce anti-invasive effects in vitro. In contrast, activation of STAT3 upstream of interleukin 6 (IL-6) leads to the increased cell proliferation ,cell survival, angiogenesis, invasion, migration and tumor growth. Our findings illustrate the biologic significance of IL-6/JAK/STAT3 signaling in SCLC progression and providenovel evidence that the pathway may be a new potential target for therapy of SCLC. It was concluded that curcumin is a potent agent in the inhibition of STAT3 with favorable pharmacological activity,and curcumin may have translational potential as an effective cancer therapeutic or preventive agent for SCLC.

A phase II study of second-line bendamustine in relapsed or refractory small cell lung cancer (SCLC).

7094 Background: Bendamustine is an alkylating agent with a nitrogen mustard group and purine-like benzimidazole group. Bendamustine in combination with carboplatin has shown efficacy as first line therapy in extensive stage SCLC with RR 73%, TTP 5.2 months and OS 8.3 months [Köster, et al, JCO 2007]. This study aims to investigate the efficacy and safety of single agent bendamustine as 2nd or 3rd line therapy in patients with extensive-stage disease, small-cell lung cancer (ED-SCLC). Methods: This is an open-label, single-arm, multicenter phase II trial. Eligible patients had previously treated ED-SCLC, up to 2 prior regimens, ECOG performance status 0-2, evaluable/measurable disease, and adequate marrow, renal and hepatic function. Patients with stable treated brain metastases were allowed. Patients were treated with bendamustine (120mg/m2 IV days 1 and 2 every 3 weeks) for up to 6 cycles. Evaluation occurred every 2 cycles. Primary endpoint was TTP; secondary endpoints include RR, PFS, OS, and toxicity. Results: 48 patients were enrolled; 56% were male and 96% were Caucasian. 33 patients were evaluable for response. There was 1 CR, 9 PR, 13 SD (48% disease control rate) and 10 PD. Median TTP was 3.37 months (95% CI 2.30 to 4.47 months). At the time of analysis, 13 patients were alive and with a median overall survival of 4.77 months (95% CI 3.67 to 6.07 months). 5 patients (10.4%) required dose reductions due to AEs, 2 due to fatigue, 1 due to neutropenia, 1 due to pancytopenia and 1 due to pneumonia. Grade 3/4 AEs included fatigue (18.8%), dyspnea (14.5%), infection without neutropenia (12.5%), anemia (8.3%), neutropenia (8.3%), and diarrhea (8.3%). Conclusions: These data indicate that single agent bendamustine appears to be well tolerated and effective in the second or third line setting for patients with SCLC.

A Systematic Analysis of Efficacy of Second-Line Chemotherapy in Sensitive and Refractory Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) patients unresponsive or relapsing within 90 days after frontline chemotherapy have poor prognosis and are treated with regimens different from the first-line regimen. Potential differences in the efficacy of second-line therapy for refractory and sensitive SCLC have not been well studied. Studies that enrolled sensitive and refractory (relapse < 90 days or > 90 days) SCLC patients for second-line therapy were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library), and meeting abstracts databases. A systematic analysis was conducted using Comprehensive Meta Analysis (version 2.2.048) software to calculate the odds ratio of response and 95% confidence interval. Median overall survival time for sensitive and resistant SCLC patients was compared by two-sided Student's t test. We tested for significant heterogeneity by Cochran's chi-square test and I-square index. Twenty-one studies published between 1984 and 2011 were eligible for this analysis with a total of 1692 patients enrolled; 912 with sensitive and 780 with refractory SCLC. The overall response rate was 17.9% with a higher response rate of 27.7% (range, 0%-77%) for sensitive SCLC versus 14.8% (range, 0%-70%) for refractory patients; p=0.0001. Pooled overall odds ratio of response was 2.235 (95% confidence interval: 1.518-3.291; p=0.001) favoring patients with sensitive disease. Median overall survival time was 6.7 months with a weighted survival of 7.7 and 5.4 months for sensitive and refractory SCLC, respectively (p = 0.0035). Refractory SCLC patients derive modest clinical benefit from second-line chemotherapy. However, response and survival outcomes are superior with chemosensitive disease.

Abstract 5662: The development of SCLC specific nanoparticle-mediated p53 gene therapy

Abstract Lung cancer is the most common cause of cancer-related deaths worldwide. Small cell lung cancer (SCLC) is a highly malignant and aggressive type of lung cancer with widespread metastases and poor prognosis. SCLC is characterized by chemoresistance and radioresistance with an average survival period of &amp;lt;1 year. Clinically, over 70% of SCLC cases harbor mutations in two key tumor suppressor genes, p53 and Rb, whose deletion or inactivation is associated with SCLC pathogenesis. Therefore the reinstatement of wild-type (WT) p53 expression provides an attractive gene therapy strategy for SCLC. We investigated restoration of WT p53 in p53-mutant SCLC cells, using non-viral, poly(β-amino ester) (PBAE) nanoparticles for gene delivery. PBAE nanoparticles possess numerous advantages over conventional viral carriers such as low risk of insertional mutagenesis, low immunogenicity, increased cargo capacity, and capabilities for cell targeting. PBAEs encapsulate DNA to form biodegradable cationic nanoparticles and have been studied in a variety of cancer cell types and in primary endothelial cells. This is the first study of PBAE-mediated gene therapy in SCLC. Two out of 112 PBAEs initially screened, 456 and 457, were validated for gene expression efficiency using a green fluorescent protein (GFP)-based reporter in the H446 SCLC cell line using microscopy and flow cytometry. Both 456 and 457 exhibited transfection efficiency of &amp;gt;40%; comparable to commercially available transfection reagents. We initiated efficacy assays by validating whether H446 cells possess mutant p53 and are a suitable target for p53 restoration; p53 status in H446 and H460 cells (WT control) was confirmed by direct sequencing. A plasmid encoding WT p53-GFP under the control of the CMV promoter (CMV-p53-GFP) was used to reconstitute exogenous expression of WT p53. An 8 h incubation with 456:CMV-p53-GFP complex induced WT p53 expression in H446 cells (p53-mutant) but not in H460 cells (p53 WT); leading to a moderate p21 induction, subsequent G1-arrest and anti-proliferative effects. A CMV-p53-GFP plasmid without p53 (CMV-GFP) served as a negative control for induction and activity of exogenous p53. Additionally, 456 and 457 exhibited in vivo tumoral transfection of CMV-LUC DNA after an intratumoral or an intravenous injection. These novel in vitro and in vivo effects by PBAEs in H446 cells suggested a possible therapeutic potential for targeted p53 gene therapy in other SCLC cells and mouse models with primary SCLC xenografts. Ongoing studies include genetic characterization of patient-derived primary SCLC xenografts and assessing systemic PBAE-p53 delivery in these xenografts. In parallel, we plan to employ PBAE-p53 delivery in combination with other target genes or with chemo-/radio-therapy in SCLC cell lines and mouse models. We strongly believe that PBAE-based gene therapy would provide higher efficacy and minimal adverse effects for improved SCLC treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5662. doi:1538-7445.AM2012-5662

MG624, an α7‐nicotinic receptor antagonist, inhibits angiogenesis in human small cell lung cancer

Small cell lung cancer (SCLC), a highly angiogenic tumor, displays a 90% association with smoking. Nicotine promotes angiogenesis in lung cancer via alpha‐7‐nicotinic acetylcholine receptors (α7nAChRs). Therefore, α7nAChR antagonists should attenuate nicotine‐induced angiogenesis and be useful for the therapy of SCLC. Here we show that the α7nAChR antagonist MG624 suppresses proliferation of human microvascular endothelial cells from the lung (HMEC‐L) in response to nicotine. MG624 displays potent anti‐angiogenic activity in the Matrigel, rat aortic ring and chicken chorioallantoic membrane models. MG624 also inhibited nicotine‐induced angiogenesis in human SCLC tumors xenografted in athymic mice. The administration of MG624 did not cause any discomfort or lethargy in mice. Chromatin immunprecipitation assays show that MG624 decreases the recruitment of Egr‐1 on FGF2 promoter thereby decreasing its transcription and suppressing nicotine‐induced angiogenesis. Our results suggest that anti‐angiogenic agents like MG624 may be useful for the therapy of human SCLC.