1. Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes? 
Paul A. Bunn, MD, John D. Minna, MD, Alexander Augustyn, PhD, Adi F. Gazdar, MD, Youcef Ouadah, BS, Mark A. Krasnow, MD, PhD, Anton Berns, PhD, Elisabeth Brambilla, MD, Natasha Rekhtman, MD, PhD, Pierre P. Massion, MD, Matthew Niederst, PhD, Martin Peifer, PhD, Jun Yokota, MD, Ramaswamy Govindan, MD, John T. Poirier, PhD, Lauren A. Byers, MD, Murry W. Wynes, PhD, David G. McFadden, MD, PhD, David MacPherson, PhD, Christine L. Hann, MD, PhD, Anna F. Farago, MD, PhD, Caroline Dive, PhD, Beverly A. Teicher, PhD, Craig D. Peacock, PhD, Jane E. Johnson, PhD, Melanie H. Cobb, PhD, Hans-Guido Wendel, MD, David Spigel, MD, Julien Sage, PhD, Ping Yang, MD, PhD, M. Catherine Pietanza, MD, Lee M. Krug, MD, John Heymach, MD, PhD, Peter Ujhazy, MD, PhD, Caicun Zhou, MD, PhD, Koichi Goto, MD, Afshin Dowlati, MD, Camilla Laulund Christensen, PhD, Keunchil Park, MD, PhD, Lawrence H. Einhorn, MD, Martin J. Edelman, MD, Giuseppe Giaccone, MD, PhD, David E. Gerber, MD, Ravi Salgia, MD, PhD, Taofeek Owonikoko, MD, PhD, Shakun Malik, MD, Niki Karachaliou, MD, David R. Gandara, MD, Ben J. Slotman, MD, PhD, Fiona Blackhall, MD, PhD, Glenwood Goss, MD, FRCPC, Roman Thomas, MD, Charles M. Rudin, MD, PhD, Fred R. Hirsch, MD, PhD 
Journal of Thoracic Oncology 
Volume 11, Issue 4, Pages (April 2016)
DOI: /j.jtho
Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

2. Figure 1
Genomic alterations in small cell lung cancer (SCLC). (A) Tumor samples are arranged from left to right. Alterations of SCLC candidate genes are annotated for each sample according to the color panel below the image. The somatic mutation frequencies for each candidate gene are plotted on the right panel. Mutation rates and type of base pair substitution are displayed in the top and bottom panel, respectively. Significant candidate genes are highlighted in bold (*corrected q values < 0.05, †P < 0.05, ‡P < 0.01). The respective level of significance is displayed as a heatmap on the right panel. Genes that are also mutated in murine SCLC tumors are denoted with a § symbol. Mutated cancer census genes of therapeutic relevance are denoted with a + symbol. (B) Somatic copy number alterations determined for 142 human SCLC tumors by single-nucleotide polymorphism arrays. Significant amplifications (red) and deletions (blue) were determined for the chromosomal regions and are plotted as q values (significance < 0.05). TP53, tumor protein p53 gene; RB1, retinoblastoma 1 gene; COL22A1, collagen type XXI alpha 1 gene; RGS7, regulator of G-protein signaling 7 gene; FPR1, formyl peptide receptor 1 gene; EP300, E1A binding protein p300 gene; CREBBP, CREB binding protein gene; ASPM, abnormal spindle microtubule assembly gene; ALMS1, ALMS1, centrosome and basal body associated protein gene; PDE4DIP, phosphodiesterase 4D interacting protein gene; XRN1, 5′-3′ exoribonuclease 1 gene; PTGFRN, prostaglandin F2 receptor inhibitor gene; TP73, tumor protein p73 gene; RBL1, retinoblastoma-like 1 gene; RBL2, retinoblastoma-like 2 gene; FMN2, formin 2 gene; PTEN, phosphatase and tensin homolog gene; KIT, KIT proto-oncogene receptor tyrosine kinase gene; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; BRAF, B-Raf proto-oncogene, serine/threonine kinase gene.
Reprinted from George et al.,4 with permission.
Journal of Thoracic Oncology  , DOI: ( /j.jtho )
Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

3. Figure 2
Genetically engineered mouse models for small cell lung cancer (SCLC) and its origins. (A and C) Berns laboratory (p53/Rb1 double conditional knockout); (B and D) Sage laboratory (p53/Rb/p130 triple conditional knockout). (A) Whole lung section demonstrating multiple in situ lesions arising in large airways and a few small invasive carcinomas. (B) SCLC with area of necrosis and Azzopardi effect adjacent to a focus of large cell neuroendocrine carcinoma. (C) High-power view of SCLC morphology. (D) Combined SCLC carcinoma with focal areas of poorly differentiated non-SCLC (NSCLC).
Modified from Gazdar et al.,46 with permission.
Journal of Thoracic Oncology  , DOI: ( /j.jtho )
Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

4. Figure 3
Immunotherapies against small cell lung cancer (SCLC). As in other cancers, blockade of immune checkpoints is thought to be a promising strategy in SCLC. For instance, blockade of cytotoxic T-lymphocyte–associated antigen 4 or the interactions between programmed death-1 (PD-1) (at the surface of T cells) and programmed death ligand-1 (PD-L1) (expressed on tumor cells or in the tumor microenvironment) with specific antibodies (Abs) may enhance the anticancer effects of T cells (T). Similarly, blockade of myeloid checkpoints such the CD47 receptor could enhance the activity of macrophages against SCLC cells. Finally, a number of epitopes may be specific to neuroendocrine SCLC cells (e.g. CD56/neural cell adhesion molecule [NCAM] or the ganglioside antigen fucosyl-monosialotetrahexosylganglioside [Fuc-GM1]) and could be targeted with chimeric antigen receptor (CAR) T cells or monoclonal antibodies (which could lead to the activation of antibody-dependent cell-mediated toxicity via natural killer [NK] cells). Note that these strategies may be used as single agents or in combination with each other or with chemotherapy.
Journal of Thoracic Oncology  , DOI: ( /j.jtho )
Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

5. Figure 4
Some of the many areas of current therapeutic interest in small cell lung cancer. Cell surface targets include a number of receptor tyrosine kinases implicated in proliferative signaling, invasion, and angiogenesis; factors regulating neuroendocrine differentiation that are being explored as targets for antibody drug conjugates; immunologic regulators; and targets for tumor-specific vaccine strategies. Intracellular pathways of particular interest include metabolic and apoptotic regulators, cell cycle checkpoint controls, developmental signaling pathways, the MYC family of transcriptional regulators, and epigenetic modifiers of histones that affect chromosomal accessibility and gene expression. FAK, focal adhesion kinase; RET, ret proto-oncogene; FGFR1, fibroblast growth factor receptor 1; VEGFR, vascular endothelial growth factor receptor; DLL3, delta-like 3 (Drosophila); CXCR4, chemokine (C-X-C motif) receptor 4; PD-L1, programmed death ligand-1; Fuc-GM1, fucosyl-monosialotetrahexosylganglioside; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; mTOR, mammalian target of rapamycin; BCL2, B-cell lymphoma 2; ASCL1, achaete-scute family bHLH transcription factor 1; NEUROD1, neuronal differntiation 1; DLL4, delta-like 4 (Drosophila); WNT, wingless-type MMTV integration site family member; WEE1, WEE1 G2 checkpoint kinase; CHK1, checkpoint kinase 1; PARP1, poly-ADP ribose polymerase 1; MYCL1, v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog; NMYC, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived; MYC, v-myc avian myelocytomatosis viral oncogene homolog; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; LSD1, lysine (K)-specific demethylase 1A; MLL2, myeloid/lymphoid or mixed-lineage leukemia.
Journal of Thoracic Oncology  , DOI: ( /j.jtho )
Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions