Biology Of Small Cell Lung Cancer Research Articles

Unravelling the biology of SCLC: implications for therapy

Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints.Preclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaete-scute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody-drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.

P1.07-028 Dual Role of the Focal Adhesion Kinase in Small-Cell Lung Cancer

Small cell-lung cancer (SCLC) is a devastating illness with five-year overall survival as low as 5%. The molecular steps leading to SCLC development and progression are still poorly understood and this has translated into the absence of targeted therapies. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase which regulates integrin and growth factor signaling pathways involved in cell proliferation, survival, migration, and invasion. FAK is overexpressed and/or activated in many cancers, including SCLC. We hypothesized that FAK overexpression/activation in SCLC contributes to its aggressive behavior and that FAK may represent a therapeutic target in SCLC. Two SCLC cell lines growing in suspension (NCI-H82, NCI-H146), and adherent SCLC cell lines (NCI-H196, NCI-H446) were treated with PF-228. NCI-H446 and H82 cells were stably transfected with FAK shRNA and/or FRNK using lentivirus vector. Cell proliferation was evaluated by WST-1 assay; cell cycle by flow cytometry with propidium iodide and bromodeoxyuridine; apoptosis by caspase 3 staining in flow cytometry and by cleaved PARPp85 Western blotting (WB); motility by wound healing assay; and invasion by Boyden chambers. FAK expression/activity was evaluated by WB. While PF-228 did not modify total FAK expression, it decreased FAK phosphorylation (Y397). Inhibition of FAK activity by PF-228 decreased cell proliferation, DNA synthesis, induced cell cycle arrest in G2/M phases, and increased apoptosis in dose-dependently. PF-228 also decreased motility in the adherent H196-H446 cells. To confirm the specificity of the antitumoral effects of PF-228, we stably transfected SCLC cells with FAK shRNA and FRNK and then analyzed the phenotypic changes induced by these approaches. Knockdown of total FAK protein by transfection of FAK shRNA inhibited FAK activity, but did not have any effect on cell proliferation, DNA synthesis, and cell cycle. However, reintroduction of FRNK in cells stably transfected with FAK shRNA inhibited cell proliferation and DNA synthesis. Expression of FRNK decreased cell proliferation and DNA synthesis in SCLC cells. Inhibition of FAK activity by PF-228 in SCLC cell lines demonstrates that FAK activity is required for cell proliferation, cycle progression, survival, and motility, suggesting that FAK inhibition may represent a suitable therapeutic target for SCLC. Inhibition of FAK by a genomic approach suggests that FAK has a dual role in SCLC biology, namely (i) a pro-tumoral effect related to the kinase domain, which induces downstream signals (ii) an anti-tumoral effect mediated by the non-kinase C-terminal domain (FRNK domain), which keeps inactive other pro-tumoral effectors.

Immunohistochemical profiling of receptor tyrosine kinases, MED12, and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker.

The limited number of available treatments for patients with small-cell lung cancer (SCLC) has prompted us to further investigate the biology of SCLC by molecular profiling. We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC, who had undergone surgery at 16 institutions between January 2003 and January 2013, and analyzed the association between disease-specific survival and protein expression of c-kit, c-Met, epidermal growth factor receptor, human EGFR-related 2, vascular endothelial growth factor receptor II, anaplastic lymphoma kinase, mediator complex subunit 12 (MED12), and transforming growth factor beta receptor II (TGF-βRII) by immunohistochemistry (IHC). Of the 125 evaluable samples, all tumors expressed MED12, and 123 samples (98.4%) expressed TGF-βRII. MED12 was highly expressed in the nucleus in 92% of the positive samples while TGF-βRII was highly expressed in the cytoplasm in 55% of the positive samples. High c-kit expression was an independent favorable prognostic marker confirmed by multivariate analysis (hazard ratio: 0.543, 95% confidence interval: 0.310–0.953, p = 0.033). Both the relapse free-survival and overall survival of patients who underwent adjuvant chemotherapy were statistically longer in those with high c-kit expression (n = 38) than those with intermediate, low, or no c-kit expression (n = 19) (not reached vs 11.6 months, p = 0.021; not reached vs 25.9 months, p = 0.028). IHC for c-kit may offer a prognostic marker for early-stage SCLC, and the results for MED12 and TGF-βRII may suggest the biological characteristics of SCLC. Further investigation of the roles of their related molecules in early stage SCLC is required.

Abstract PL04-04: Developing circulating tumor cell derived explant models (CDX)

Abstract Serial biopsies of solid tumors can be challenging, not always without risk to the patient and do not capture intratumoral heterogeneity. ‘Liquid Biopsies’ in the form of Circulating Tumor DNA (ctDNA) and Circulating Tumor Cells (CTCs) offer minimally invasive means to stratify patients for therapy and to routinely monitor therapy responses and anticipate emergent therapy resistance. Whilst technically more challenging than ctDNA, CTCs offer a wider range of biomarker application allowing RNA and protein measurements within single and pools of CTCs following enrichment from the blood. In addition, we have focussed on the development of CTC derived explant models (CDX), particularly in small cell lung cancer (SCLC), where biopsies are particularly difficult to obtain (and often small and necrotic) to study the biology of this aggressive disease and to test new therapies. We have generated 17 SCLC CDX models to date where CTCs, enriched using negative depletion of blood cells, are grown subcutaneously in immune-compromised mice. The take rate is ∼45% and is broadly correlated to the number of CellSearch detected EpCam positive CTCs measured in a paired blood sample. CDX models are derived from SCLC patients at presentation before chemotherapy, where most patients are initially chemosensitive but ∼20% are chemorefractory. For some patients, a matched CDX has been derived following chemotherapy response and subsequent relapse with progressive disease and where a biopsy is rarely acquired. CDX histopathology mimics the diagnostic biopsy of the donor patient and recapitulates the donor patient's response to chemotherapy. CDX can be passaged with maintained growth characteristics and as few as 5-10 CDX cells can re-establish the tumor consistent with a high frequency of tumor initiating cells. We are exploiting CDX models to explore the biology of SCLC, mechanisms of tumor cell dissemination and chemotherapy resistance. The CDX models are also being used to facilitate drug development. Therapies that show promise in CDX models can be rapidly translated to the clinic where the high prevalence of CTCs in SCLC patients provide minimally invasive, proof of mechanism pharmacodynamic biomarkers and CTC number as a surrogate of tumor response. Once passaged in vivo, tumor cells from disaggregated CDX can be cultured ex vivo over 2-3 weeks for initial and more rapid drug screening. SCLC CDX are also being used to assess the importance of vascular mimicry (VM) - a manifestation of tumor cell plasticity that endows endothelial cell behaviour, and we have shown that VE-Cadherin plays a functional role in SCLC VM, altering tumor growth kinetics and intratumor delivery of cisplatin. The generation of s.c CDX from NSCLC patients is proving more challenging. We have generated a CDX from a NSCLC patient with no CellSearch EpCam positive CTCs in their 7.5ml blood sample but whose blood did contain >150 CTCs/ml blood detected by filtration using an immunofluorescence assay for Epithelial to Mesenchymal Transition. The resultant CDX and the majority of this patient's CTCs were mesenchymal. Alternative approaches including intrathoracic implantation of enriched NSCLC CTCs are being explored. Subcutaneous CDX have been successfully derived from advanced melanoma patients and can now complement other approaches and extend studies where metastatic melanoma biopsies are unforthcoming. In summary, the development of CDX models yields new opportunities to study advanced disease and examine treatment response and resistance. We are currently developing approaches that will allow the genetic manipulation of CDX cultures to underpin mechanistic studies and we are exploring the generation of CDX across other tumor types. Citation Format: Caroline Dive, Kris Frese, Melanie Galvin, Alice Lallo, Cassandra Hodgkinson, Christopher Morrow, Kathryn Simpson, Francesca Trappani, Stuart Williamson, Lynsey Priest, Romina Girotti, Crispin Miller, Ged Brady, Richard Marais, Fiona Blackhall. Developing circulating tumor cell derived explant models (CDX). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr PL04-04.

Therapies in the pipeline for small-cell lung cancer.

Small-cell lung cancer (SCLC) represents ~15% of all cases of lung cancer and is characterized by a rapid tumour doubling time, early onset disease dissemination and high sensitivity to chemotherapy. We searched MEDLINE and OVID databases for articles in English published from January 1980 to February 2015. Platinum-based chemotherapy, thoracic radiotherapy and prophylactic cranial irradiation are standard of care. Benefit from second-line chemotherapy is limited. The role of platinum/irinotecan chemotherapy in the Western population and the role of maintenance therapies remain to be established. Knowledge of the biology of SCLC has expanded exponentially and many potential therapeutic targets have been identified. The use of circulating tumour cells can help investigating molecular alterations occurring within tumour cells, understanding drug resistance mechanisms and evaluating new treatments.

Seeking New Approaches to Patients With Small Cell Lung Cancer.

The fundamental approach to the treatment of small cell lung cancer (SCLC) has not changed in the last several decades, with most advances being restricted to improved radiation approaches. The standard first-line chemotherapy regimen in the United States and Europe remains cisplatin or carboplatin plus etoposide in the treatment of limited stage (LS-SCLC) and extensive stage (ES-SCLC) disease. Radiation therapy is administered to those patients with LS-SCLC, whose cancer is confined to the chest in a single tolerable radiation field. This article will summarize a number of exciting observations regarding the biology of SCLC and how a deeper understanding of newly integrated targets and target pathways may lead to new and better therapeutic approaches in the near future.

Cancer stem cells in small cell lung cancer.

Small cell lung cancer (SCLC) is one of the most aggressive lung tumors, with poor survival rates. Although patients may initially respond to treatment, this is followed by rapid development of drug resistance and disease progression. SCLC patients often present with metastasis at time of diagnosis, ruling out surgery as a treatment option. Currently, treatment options for this disease remain limited and platinum-based chemotherapy is the treatment of choice. A better understanding of the biology of SCLC could allow us to identify new therapeutic targets. Cancer stem cell (CSC) theory is currently crucial in cancer research and could provide a viable explanation for the heterogeneity, drug resistance, recurrence and metastasis of several types of tumors. Some characteristics of SCLC, such as aggressiveness, suggest that this kind of tumor could be enriched in CSCs, and drug resistance in SCLC could be attributable to the existence of a CSC subpopulation in SCLC. Herein we summarize current understanding of CSC in SCLC, including the evidence for CSC markers and signaling pathways involved in stemness. We also discuss potential ongoing strategies and areas of active research in SCLC, such as immunotherapy, that focus on inhibition of signaling pathways and targeting molecules driving stemness. Understanding of signaling pathways and the discovery of new therapeutic markers specific to CSCs will lead to new advances in therapy and improvements in prognosis of SCLC patients. Therefore, evaluation of these CSC-specific molecules and pathways may become a routine part of SCLC diagnosis and therapy.

Small cell lung cancer (SCLC): no treatment advances in recent years.

Small cell lung cancer (SCLC) is an aggressive malignancy with a distinct natural history and dismal prognosis. Given its predisposition for early dissemination, patients are commonly diagnosed with metastatic disease and chemotherapy is regarded as the cornerstone of approved treatment strategies. However, over the last 30 years there has been a distinct paucity of significant breakthroughs in SCLC therapy. Thus, SCLC is characterized as a recalcitrant neoplasm with limited therapeutic options. By employing well-established research approaches, proven to be efficacious in non-small cell lung cancer (NSCLC), a growing amount of data has shed light on the molecular biology of SCLC and enhanced our knowledge of the "drivers" of tumor cell survival and proliferation. New therapeutic targets have emerged, but no significant improvement in patients' survival has been demonstrated thus far. In a sense, the more we know, the more we fail. Nowadays this is starting to change and methodical research efforts are underway. It is anticipated that the next decade will see a revolution in the treatment of SCLC patients with the application of effective precision medicine and immunotherapy strategies.

Seeking New Approaches to Patients With Small Cell Lung Cancer

The fundamental approach to the treatment of small cell lung cancer (SCLC) has not changed in the last several decades, with most advances being restricted to improved radiation approaches. The standard first-line chemotherapy regimen in the United States and Europe remains cisplatin or carboplatin plus etoposide in the treatment of limited stage (LS-SCLC) and extensive stage (ES-SCLC) disease. Radiation therapy is administered to those patients with LS-SCLC, whose cancer is confined to the chest in a single tolerable radiation field. This article will summarize a number of exciting observations regarding the biology of SCLC and how a deeper understanding of newly integrated targets and target pathways may lead to new and better therapeutic approaches in the near future.

Small cell lung cancer: will recent progress lead to improved outcomes?

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with a unique natural history characterized by a short doubling time, high growth fraction, and early development of widespread metastases. Although a chemotherapy- and radiation-sensitive disease, SCLC typically recurs rapidly after primary treatment, with only 6% of patients surviving 5 years from diagnosis. This disease has been notable for the absence of major improvements in its treatment: Nearly four decades after the introduction of a platinum-etoposide doublet, therapeutic options have remained virtually unchanged, with correspondingly little improvement in survival rates. Here, we summarize specific barriers and challenges inherent to SCLC research and care that have limited progress in novel therapeutic development to date. We discuss recent progress in basic and translational research, especially in the development of mouse models, which will provide insights into the patterns of metastasis and resistance in SCLC. Opportunities in clinical research aimed at exploiting SCLC biology are reviewed, with an emphasis on ongoing trials. SCLC has been described as a recalcitrant cancer, for which there is an urgent need for accelerated progress. The NCI convened a panel of laboratory and clinical investigators interested in SCLC with a goal of defining consensus recommendations to accelerate progress in the treatment of SCLC, which we summarize here.

Abstract IA05: Circulating tumor cells in lung cancer: Biomarkers, biology, and mouse models to study drug resistance

Abstract SCLC patients (∼75%) respond well initially to standard chemotherapy (platinum/etoposide) but drug resistant disease relapse ensues rapidly. Most Small Cell Lung Cancer (SCLC) patients present with metastases, consequently tumor resection is rare and tumor biopsy is rarely obtained at disease relapse to explore drug resistance mechanisms. Targeted therapies have yet to impact SCLC patient outcomes, new drug targets and biomarkers measured in minimally invasive samples are required. Using EpCam dependent CellSearch technology, we showed that CTCs are prevalent in SCLC and CTC number is an independent prognosticator. SCLC CTC number is pharamcodynamic and CTCs are amenable to biomarker assay development (protein expression, omic profiling, FISH etc.) to be applied in clinical trials. We also developed unique patient CTC derived mouse models (CDX) to study SCLC biology, search for new drug targets, develop biomarkers and explore drug resistance mechanisms. Successful CDX engraftment has been observed so far in ∼45% cases. The molecular landscape of CDX can be compared to that of single, isolated CTCs from the same patient. CDX are readily passaged and their response to cisplatin/etoposide closely mimics the donor patient. CDX offer unparalleled opportunity to interrogate drug resistance mechanisms as paired models can be generated at presentation (chemosensitive) and again at relapse (drug resistance). Our data demonstrate that serial blood sampling with CDX and CTC molecular analysis could facilitate delivery of precision medicine to improve outcomes in SCLC. A program of evaluation of novel therapeutics in CDX models, the development of orthotopic CDX SCLC and NSCLC CDX are underway. Citation Format: Caroline Dive, Chris Morrow, Ged Brady, Fiona Blackhall. Circulating tumor cells in lung cancer: Biomarkers, biology, and mouse models to study drug resistance. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA05.

Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor

Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy.

MET and Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving c-MET gene and their implications as a potential target in SCLC.

Updated Data on Clinical and Molecular Profile of Surgically Resected Small Cell Lung Cancer: Intergroup Study with Fight002 and Hot1301

ABSTRACT Aim: NCCN and Japanese guidelines suggest surgery for patients with c-stage I small-cell lung cancer (SCLC), and ESMO guidelines recommend surgery for patients with c-stage II (T1,2 N0,1). However, the clinical impact of surgery with other variables on patients with early stage SCLC has yet to be determined. Therefore, clarification of the clinical and molecular profile of surgically resected SCLC is required. We expanded the number of patients and updated the clinical data which had been presented at ASCO 2014 (abstract #7590). Methods: We reviewed the clinical courses of 156 patients with SCLC who had undergone surgery at 17 institutes from January 2003 to January 2013. 125 formalin-fixed paraffin-embedded tissue samples were subjected to immunohistochemistry using 8 antibodies and to next-generation sequencing (NGS) systems using MiSeq and TruSight Tumor Sequencing Panel (Illumina) loading 26 genes. (UMIN registration No. 000010116 /10117). Results: Median relapse-free survival (RFS) and overall survival (OS) were 15.6 (95%CI: 6.8-24.5), and 33.3 (20.9-45.8) months, respectively. Multivariate analysis revealed that OS was longer in patients without history of malignancy (HR: 0.459, 95%CI: 0.248-0.847, p=0.013), with preoperative diagnosis (HR: 0.529, 95%CI: 0.293-0.953, p=0.034), and with c-stage II and under (HR: 0.117, 95%CI: 0.047-0.288, p Conclusions: These results support the ESMO guidelines for the management of c-stage II small-cell lung cancer, and indicate that history of malignancy might be a major decisive factor for surgery. The results of immunohistochemistry assist us in gaining a better understandingof the biology of SCLC. Disclosure: All authors have declared no conflicts of interest.

Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer.

Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor with early dissemination and dismal prognosis, accounts for 15-20% of lung cancer cases and ∼200,000 deaths each year. Most cases are inoperable, and biopsies to investigate SCLC biology are rarely obtainable. Circulating tumor cells (CTCs), which are prevalent in SCLC, present a readily accessible 'liquid biopsy'. Here we show that CTCs from patients with either chemosensitive or chemorefractory SCLC are tumorigenic in immune-compromised mice, and the resultant CTC-derived explants (CDXs) mirror the donor patient's response to platinum and etoposide chemotherapy. Genomic analysis of isolated CTCs revealed considerable similarity to the corresponding CDX. Most marked differences were observed between CDXs from patients with different clinical outcomes. These data demonstrate that CTC molecular analysis via serial blood sampling could facilitate delivery of personalized medicine for SCLC. CDXs are readily passaged, and these unique mouse models provide tractable systems for therapy testing and understanding drug resistance mechanisms.

Discovery of New Membrane-Associated Proteins Overexpressed in Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with no early detection strategy or targeted therapy currently available. We hypothesized that difference gel electrophoresis (DIGE) may identify membrane-associated proteins (MAPs) specific to SCLC, advance our understanding of SCLC biology, and discover new biomarkers of SCLC. MAP lysates were prepared from three SCLCs, three non-small-cell lung cancers, and three immortalized normal bronchial epithelial cell lines and coanalyzed by DIGE. Subsequent protein identification was performed by mass spectrometry. Proteins were submitted to Ingenuity Pathway Analysis. Candidate biomarkers were validated by Western blotting (WB) and immunohistochemistry (IHC). Principal component analysis on the global DIGE data set demonstrated that the four replicates derived from each of the nine cell lines clustered closely, as did samples within the same histological group. One hundred thirty-seven proteins were differentially expressed in SCLC compared with non-small-cell lung cancer and immortalized normal bronchial epithelial cells. These proteins were overrepresented in cellular/tissue morphology networks. Dihydropyrimidinase-related protein 2, guanine nucleotide-binding protein alpha-q, laminin receptor 1, pontin, and stathmin 1 were selected as candidate biomarkers among MAPs overexpressed in SCLC. Overexpression of all candidates but RSSA in SCLC was verified by WB and/or IHC on tissue microarrays. These proteins were significantly associated with SCLC histology and survival in univariables analyses. DIGE analysis of a membrane-associated subproteome discovered overexpression of dihydropyrimidinase-related protein 2, guanine nucleotide-binding protein alpha-q, RUVB1, and stathmin 1 in SCLC. Results were verified by WB and/or IHC in primary tumors, suggesting that investigating their functional relevance in SCLC progression is warranted. Association with survival requires further validation in larger clinical data sets.

Small Cell Lung Cancer: Therapies and Targets

Small cell lung cancer (SCLC) remains a fatal disease due to limited therapeutic options. Systemic chemotherapy is the bedrock of treatment for both the limited and extensive stages of the disease. However, the established management paradigm of platinum-based chemotherapy has reached an efficacy plateau. A modest survival improvement, approximately 5%, was witnessed with the addition of cranial or thoracic radiation to systemic chemotherapy. Other strategies to improve outcome of platinum-based chemotherapy in the last two decades have met with minimal success. The substitution of irinotecan for etoposide in the frontline treatment of SCLC achieved significant efficacy benefit in Japanese patients, but similar benefit could not be reproduced in other patient populations. Salvage treatment for recurrent or progressive SCLC is particularly challenging, where topotecan remains the only agent with regulatory approval to date. Ongoing evaluation of biologic agents targeting angiogenesis, sonic hedgehog pathway, DNA repair pathway, and immune checkpoint modulators hold some promise for improved outcome in SCLC. It is hoped that the coming decade will witness the application of new molecular biology and genomic research techniques to improve our understanding of SCLC biology and identification of molecular subsets that can be targeted appropriately using established and emerging biological agents similar to the accomplishments of the last decade with non-small cell lung cancer (NSCLC).

Abstract CN02-01: CTCs in small cell lung cancer: Biomarkers and biology.

Abstract Tumor biopsies from lung cancer patients are challenging, particularly so in metastatic disease and development of informative minimally invasive biomarkers are much needed. In this presentation I will review the current status of CTCs in lung cancer as prognostic, predictive and pharmacodynamic biomarkers. The presentation will then focus on Small Cell Lung Cancer (SCLC), an aggressive, neuroendocrine tumor with early dissemination and dismal prognosis accounting for 15-20% lung cancer cases and ∼200,000 deaths globally each year. Most cases are inoperable and biopsies to interrogate SCLC biology are rarely obtained. Improved treatment outcomes for SCLC patients requires new approaches to interrogate the biology and genetics of the disease, appropriate methods to investigate the rapid onset of acquired resistance to current chemotherapy and tractable, patient derived models with which to test new therapies. Circulating tumor cells (CTCs) are prevalent in SCLC. I will describe how we isolate a molecularly profile single CTCs and discuss the development of our new CTC mouse. These new models that can be generated longitudinally from patients at diagnosis and at relapse, together with an analysis of CTC heterogeneity will facilitate a thorough investigation of the mechanisms of acquired drug resistance, and may identify new targets for improved therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN02-01. Citation Format: Caroline Dive. CTCs in small cell lung cancer: Biomarkers and biology. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN02-01.

Genomic Deregulation of the E2F/Rb Pathway Leads to Activation of the Oncogene EZH2 in Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a highly aggressive lung neoplasm with extremely poor clinical outcomes and no approved targeted treatments. To elucidate the mechanisms responsible for driving the SCLC phenotype in hopes of revealing novel therapeutic targets, we studied copy number and methylation profiles of SCLC. We found disruption of the E2F/Rb pathway was a prominent feature deregulated in 96% of the SCLC samples investigated and was strongly associated with increased expression of EZH2, an oncogene and core member of the polycomb repressive complex 2 (PRC2). Through its catalytic role in the PRC2 complex, EZH2 normally functions to epigenetically silence genes during development, however, it aberrantly silences genes in human cancers. We provide evidence to support that EZH2 is functionally active in SCLC tumours, exerts pro-tumourigenic functions in vitro, and is associated with aberrant methylation profiles of PRC2 target genes indicative of a “stem-cell like” hypermethylator profile in SCLC tumours. Furthermore, lentiviral-mediated knockdown of EZH2 demonstrated a significant reduction in the growth of SCLC cell lines, suggesting EZH2 has a key role in driving SCLC biology. In conclusion, our data confirm the role of EZH2 as a critical oncogene in SCLC, and lend support to the prioritization of EZH2 as a potential therapeutic target in clinical disease.

Small-Cell Lung Cancer: Where are we Now and What Can We Expect for the Future?

Neuroendocrine tumors account for approximately 20% of lung cancers; and almost 15% of lung cancers are small-cell lung cancer (SCLC), previously known as oat cell cancer [1]. SCLC is an aggressive form of lung cancer with distinct clinical and biologic characteristics. In 2012, an estimated 33,900 new cases of SCLC occurred in the USA and nearly all cases of SCLC are attributable to cigarette smoking [2]. SCLC was beginning to be added to some lists of ‘curable cancers’ 25 years ago. We had devised a unique staging system, established the effectiveness of several chemotherapeutic agents and radiation therapy, and even discovered the CNS sanctuary that requires a distinct treatment approach [2]. A quarter of a century later, patients with this disease still do not have a significantly better outlook [2]. In this article, we address the scientific advances that have been made in defining the biology of SCLC and that have increased our ability to manage this cancer through personalized therapy. Standard of care for SCLC Compared with non-SCLC (NSCLC), SCLC