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

Bunn, Paul A.; Minna, John D.; Augustyn, Alexander; Gazdar, Adi F.; Ouadah, Youcef; Krasnow, Mark A.; Berns, Anton; Brambilla, Élisabeth; Rekhtman, Natasha; Massion, Pierre P.; Niederst, Matthew J.; Peifer, Martin; Yokota, Jun; Govindan, Ramaswamy; Poirier, John T.; Byers, Lauren A.; Wynes, Murry W.; McFadden, David G.; MacPherson, David; Hann, Christine L.; Farago, Anna F.; Dive, Caroline; Teicher, Beverly A.; Peacock, Craig D.; Johnson, Jane E.; Cobb, Melanie H.; Wendel, Hans Guido; Spigel, David R.; Sage, Julien; Yang, Ping; Pietanza, M. Catherine; Krug, Lee M.; Heymach, John V.; Ujházy, Peter; Zhou, Caicun; Goto, Kōichi; Dowlati, Afshin; Christensen, Camilla L.; Park, Keunchil; Einhorn, Lawrence H.; Edelman, Martin J.; Giaccone, Giuseppe; Gerber, David E.; Salgia, Ravi; Owonikoko, Taofeek K.; Malik, Shakun; Karachaliou, Niki; Gandara, David R.; Slotman, Ben J.; Blackhall, Fiona; Goss, Glenwood D.; Thomas, Roman K.; Rudin, Charles M.; Hirsch, Fred R.

doi:10.1016/j.jtho.2016.01.012

Cited by 154 publications

(131 citation statements)

References 156 publications

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“…Dowlati and colleagues did not detect any dysregulation of MYC function, something that cannot be easily explained (2,4). Interestingly, the authors highlight the potential benefit from tyrosine kinase inhibitors targeting the rearranged during transfection (RET) receptor for SCLC patients that carry RET somatic mutations (4).…”

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confidence: 99%

“…This problem has now been overcome with the development of new model systems, mainly genetically engineered mouse models (GEMMs) that give us the opportunity to understand the biology and molecular biology of SCLC. It is widely accepted that SCLC is a high-grade neuroendocrine carcinoma with several molecular and cellular abnormalities (2). Tumor suppressor genes, such as retinoblastoma 1 (RB1) and tumor protein p53 (TP53), are inactivated in the majority of patients with SCLC (2).…”

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confidence: 99%

“…The family of the FGF receptors is a promising target for personalized therapies in various types of tumors and several drugs targeting the FGF pathway are in clinical testing (2). In addition, a lot of work is ongoing with the scope to identify other amplification biomarkers than FGFR1 as better predictors of response to FGFR inhibition (2).…”

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confidence: 99%

See 2 more Smart Citations

Unraveling the genomic complexity of small cell lung cancer

Karachaliou¹,

Sosa²,

Rosell³

2016

Transl. Lung Cancer Res.

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confidence: 99%

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confidence: 99%

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Unraveling the genomic complexity of small cell lung cancer

Karachaliou¹,

Sosa²,

Rosell³

2016

Transl. Lung Cancer Res.

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“…A number of excellent reviews have recently discussed the key clinical features of SCLC and the current lack of efficient treatment despite a large number of clinical trials in the past three decades (1)(2)(3)(4). New therapeutic approaches, including immunotherapies, are promising but at the time this review is written, there are still no approved targeted therapies for SCLC [reviewed in (5)(6)(7)(8)]. …”

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confidence: 99%

Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

Shue¹,

Lim²,

Sage³

2018

Transl. Lung Cancer Res.

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Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer characterized by its fast growth and aggressive nature. SCLC development is strongly associated with heavy cigarette smoking. In a majority of cases, SCLC tumors have already metastasized to distant sites at the time of first diagnosis. Except in rare cases when tumors are diagnosed early, treatment options are limited and usually consist of several rounds of chemotherapy with cisplatin/ carboplatin and etoposide. While this chemotherapy regimen often results in significant response and tumor shrinkage, relapse is usually quite rapid. A number of excellent reviews have recently discussed the key clinical features of SCLC and the current lack of efficient treatment despite a large number of clinical trials in the past three decades (1-4). New therapeutic approaches, including immunotherapies, are promising but at the time this review is written, there are still no approved targeted therapies for SCLC [reviewed in (5-8)].Here we discuss emerging data in the field on the role of tumor heterogeneity in the growth of SCLC and the response of these tumors to therapy, and how mouse models have been used to identify such tumor heterogeneity and investigate its role. We use the term "intertumoral" heterogeneity to describe how SCLC tumors in patients or mice evolve differently at the genetic and epigenetic level during tumor progression and metastasis. We use the term "intratumoral" heterogeneity to describe the different subpopulations of cells within tumors at any given time; in Abstract: Small cell lung carcinoma (SCLC) is a fast-growing, highly metastatic form of lung cancer. A major difference between SCLC and other forms of lung cancer is that SCLC tumors often respond well to chemotherapy initially; unfortunately, resistant tumors rapidly recur. In addition, despite a large number of clinical trials with a variety of therapeutic agents, little progress has been achieved in the past three decades in improving the survival of SCLC patients. These clinical observations indicate that SCLC tumors have a high degree of plasticity and rapid adaptability to changes in growth conditions. Here we consider recent evidence pointing to several levels of heterogeneity in SCLC that may explain the ability of these tumors to adjust to different microenvironment and therapeutics. In particular, we review new data pointing to the existence of several subpopulations of tumor cells that interact with each other to promote tumor growth.We also discuss how SCLC tumors that look similar at the histopathological level may actually represent distinct subtypes of tumors and how these differences impact the response to specific therapeutic agents.A better understanding of genetic and cellular heterogeneity will guide the development of personalized approaches to help SCLC patients.

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“…Besides the inherent differences in mouse models and human subjects, another possible reason for the high drug attrition rates in late stage SCLC clinical studies could be due to the fact that it has been challenging to recapitulate the multitude of genetic aberrations found in human tumors of SCLC in genetically engineered mouse models (GEMMs) (4). For example, the complexity of genetic and epigenetic changes brought about by carcinogens in tobacco smoke may not be reflected in these GEMMs, resulting in the simplification of oncogenic pathways involved and an oversight of possible bypass mechanisms employed by tumors to escape cell death.…”

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confidence: 99%