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Review
. 2016 Apr;11(4):453-74.
doi: 10.1016/j.jtho.2016.01.012. Epub 2016 Jan 30.

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Paul A Bunn Jr  1 , John D Minna  2 , Alexander Augustyn  2 , Adi F Gazdar  2 , Youcef Ouadah  3 , Mark A Krasnow  3 , Anton Berns  4 , Elisabeth Brambilla  5 , Natasha Rekhtman  6 , Pierre P Massion  7 , Matthew Niederst  8 , Martin Peifer  9 , Jun Yokota  10 , Ramaswamy Govindan  11 , John T Poirier  6 , Lauren A Byers  12 , Murry W Wynes  13 , David G McFadden  2 , David MacPherson  14 , Christine L Hann  15 , Anna F Farago  8 , Caroline Dive  16 , Beverly A Teicher  17 , Craig D Peacock  18 , Jane E Johnson  2 , Melanie H Cobb  2 , Hans-Guido Wendel  6 , David Spigel  19 , Julien Sage  3 , Ping Yang  20 , M Catherine Pietanza  6 , Lee M Krug  6 , John Heymach  12 , Peter Ujhazy  20 , Caicun Zhou  21 , Koichi Goto  22 , Afshin Dowlati  23 , Camilla Laulund Christensen  24 , Keunchil Park  25 , Lawrence H Einhorn  26 , Martin J Edelman  27 , Giuseppe Giaccone  28 , David E Gerber  2 , Ravi Salgia  29 , Taofeek Owonikoko  30 , Shakun Malik  17 , Niki Karachaliou  31 , David R Gandara  32 , Ben J Slotman  33 , Fiona Blackhall  34 , Glenwood Goss  35 , Roman Thomas  9 , Charles M Rudin  6 , Fred R Hirsch  36
Affiliations
Review

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Paul A Bunn Jr et al. J Thorac Oncol. 2016 Apr.
No abstract available

Keywords: Gene mutations; Immunotherapy; Neuroendocrine; Small cell lung cancer; Therapy.

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Figures

Figure 1
Figure 1. Genomic alterations in SCLC
A, Tumor samples are arranged from left to right. Alterations of SCLC candidate genes are annotated for each sample according to the colour 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 1 symbol. Mutated cancer census genes of therapeutic relevance are denoted with a 1 symbol. B, Somatic copy number alterations determined for 142 human SCLC tumors by single nucleotide polymorphism (SNP) arrays. Significant amplifications (red) and deletions (blue) were determined for the chromosomal regions and are plotted as q-values (significance,0.05). George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47-53
Figure 2
Figure 2. GEMMs for SCLC and its origins
A and C, Berns laboratory, (p53/Rb1 double CKO); B and D, Sage laboratory, (p53/Rb/p130 triple CKO). 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 LCNEC. C, High power view of SCLC morphology. D, Combined SCLC carcinoma, with focal areas of poorly differentiated NSCLC. NSCLC, non–small-cell lung carcinoma; SCLC, small-cell lung carcinoma. Gazdar AF, Savage TK, Johnson JE, et al. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J Thorac Oncol 2015;10:553-564.
Figure 3
Figure 3. 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.
Figure 4
Figure 4. Immunotherapies against SCLC
Similar to other cancers, blockade of immune checkpoints is thought to be a promising strategy in SCLC. For instance, blockade of CTLA-4 or the interactions between PD-1 (at the surface of T cells) and PD-L1 (expressed on tumor cells or in the tumor microenvironment) with specific antibodies (Ab) may enhance the anti-cancer effects of T cells (T). Similarly, blockade of myeloid checkpoints such the CD47 receptor could enhance the activity of macrophages (M) against SCLC cells. Finally, a number of epitopes may be specific to neuroendocrine SCLC cells (e.g. CD56/NCAM or the ganglioside antigen 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 NK cells). Note that these strategies may be used as single agents or in combination with each other or with chemotherapy.
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