Cancer Metastasis Rev DOI 10.1007/s10555-015-9562-4

Lung cancer and metastasis: new opportunities and challenges Xiangdong Wang 1 & Alex A. Adjei 2

# Springer Science+Business Media New York 2015

Abstract Lung cancer continues to attract special attention since the real number of lung cancer mortality and incidence in 2014 was definitely higher than those estimated numbers according to the report from World Health Organization. The present special issue highly focuses on advanced discovery and development of lung cancer and metastasis and discusses about potential opportunities and challenges to be faced. The present issue explores clinical applications of cancer immunotherapies, gene therapies, radiotherapies, or target-oriented therapies. A new and novel methodology can be used to identify differential interactions of driver genes, cancer-predictive genes, subtype-specific genes, or disease-exclusive genes or gene pairs from imbalanced or heterogeneous datasets. We also demonstrate the importance of lung cancer-specific gene mutations, epigenetics, gene sequencing, heterogeneity, or biomarker discovery. Clinical bioinformatics is emphasized as a critical tool and merging science. Novel therapies are designed and expected on basis of oncogenic molecular aberrations in lung cancer. Keywords Lung cancer . Metastasis . Therapies . Genomics . Biomarkers Lung cancer continues to attract special attention from the public, patients, physicians, and health authorities due to the * Xiangdong Wang [email protected] 1

Zhongshan Hospital, Shanghai Institute of Clinical Bioinformatics, Fudan University Center for Clinical Bioinformatics, Biomedical Research Center, Shanghai, China

2

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

increasing incidence in many parts of the world with its concomitant increased morbidity and mortality. Lung cancer is the most common cancer affecting both men and women after skin cancer. In the USA, incidence rates are about 14 % of all new cancer diagnoses with an estimated 222,200 new cases and a predicted mortality of about 27 % of all cancer deaths with about 158,040 deaths [1]. The worldwide incidence and mortality of lung cancer is estimated at about 1.82 and 1.6 million in 2012, respectively, making it the leading cause of cancer deaths [2]. However, the real number of lung cancer mortality and incidence in 2014 was definitely higher than those estimated numbers according to the report from World Health Organization. In this report, in China alone, there were 600,000 lung cancer deaths out of a total cancer mortality of 2.2 million. There is a rapid rise of lung cancer mortality and incidence in developing countries, even while mortality and incidence in developed countries continues to decline. Novel approaches to lung cancer treatment are needed and are outlined in this particular issue. Cancer immunotherapy has been suggested as an attractive approach to lung cancer therapy. Surface antigens expressed on tumor cells can be efficient and specific therapeutic targets. Antibody-based strategies are emphasized to enhance antitumor immune responses by targeting immune cells, irrespective of tumor antigens, and to increase clinical application of antibodies engineered with molecular genetics and chemical modifications [3]. In recent years, antibodies against immune check point inhibitors have demonstrated early clinical activity, and an antibody against program death receptor 1 (PD-1), nivolumab, has been approved for second-line therapy of squamous cell carcinoma by the US Food and Drug Administration. Drs Zimmermann and Peters in the present issue discuss this and other approaches and suggest that such novel immunotherapies could challenge current standards of care in both first-line cytotoxic chemotherapy and later lines of

Cancer Metastasis Rev

therapy. They further indicate that validated lung cancer genes can be developed into gene therapies (Zimmermann, S., & Peters, S. (2015), Cancer & Metastasis Review, forthcoming). Drs Salama and Schild discuss recent developments in advanced radiotherapy planning and delivery techniques, focusing on stereotactic body radiotherapy or stereotactic ablative radiotherapy for the control of oligometastatic disease [4]. The article clearly and practically describes the understanding of technology-based therapies, selection of patients, latest outcomes from clinical trials, biologic underpinnings of the oligometastatic state, and suggestions to improve the efficiency of the therapy. Furthermore, preclinical studies demonstrate the iterative combined theoretical and experimental strategy suggested to define tumor cellular heterogeneity and dynamically acquired radioresistance in order to predict the effectiveness of different radiation schedules [5]. Identification of driver mutations in lung cancer and its metastasis is a new and important area to improve the systematic discovery of genetic alterations and understand the pathogenesis of the disease by prioritizing genes upstream of functional disease drivers within regulatory networks. The Chen group has proposed a novel approach to detect potential disease genes for lung cancer and have presented their latest findings on reliable disordered regulations and networks in the disease (Shi, Q., Liu, X., Zeng, T., Wang, X., & Chen, L. N. (2015), Cancer & Metastasis Review, forthcoming). Such methodology can be used to identify consensus differential interactions and predict cancer genes, subtype-specific genes, or disease-exclusive genes or gene pairs from imbalanced or heterogeneous datasets. Disease-specific genes and novel biomarkers may increase the accuracy and efficiency of diagnosis and prognosis of patients with lung cancer metastasis. Tumor heterogeneity is an important factor influencing the reliability of tissue biopsy, property of disease-specific biomarkers, design of therapeutic strategies, response and resistance against drugs, or the practice of precision medicine. Multiregion whole-exome and/or whole-genome sequencing were recently used to investigate lung cancer evolution and evolutionary history, intratumor heterogeneity of non-silent mutations and copy number aberrations, extent of genomic diversity and structural variants, regional heterogeneity of lung cancer driver mutation, majority of truncal mutations, dynamics of mutational processes, temporal and spatial dissection of mutation spectra, or divergent genomic instability processes [6, 7]. The present issue pays special attention to the clinical significance of epigenetics and mutations in the development of diagnostic and therapeutic strategies for lung cancer. Wu and Wang emphasize the importance and necessity to integrate information from genomic, proteomic, metabolomic, or epigenetic studies with clinical phenotypes of patients with lung cancer using clinical bioinformatics [8]. Drs Mehta et al. highlight the importance of interactions between permanent genetic and dynamic epigenetic alterations in the initiation and progression of lung cancer [9].

Cancer heterogeneity has emerged as a biologic factor that may affect efficacy of therapeutic agents. Rosell and Karachaliou demonstrated the potential association of mutations with cancer metastasis and development of new, more specific therapeutic strategies to minimize cancer morbidity and mortality in the long term (Rosell, R., & Karachaliou, N. (2015), Cancer & Metastasis Review, forthcoming). Phenotypic changes during cancer progression can reflect the sequential accumulation of genetic alterations, which endow cancer cells with the ability to undergo their own divergent evolution and create distinct metastatic species. The chromosome 19 Consortium is a global group of the ChromosomeCentric Human Proteome Project, which aims to explore chromosome 19 functions at both gene and protein levels and biological roles in lung oncogenesis deeply [10]. The most common variation is chromosome 19p loss and 19q gain. Of the related 64 aberrant genes identified, the loss of tumor suppressor gene STK11, MUM1, KISS1R (19p13.3), and BRG1 (19p13.13) may be associated with lung oncogenesis or distant metastasis. Drs Yang et al. performed global analyses of chromosome 1 gene expression and define the disease type-specific, duration-specific, and severity-specific gene expression characteristics in patients with lung cancer (Wang, X. D., Zhang, Y., Nilsson C. L., Berven, F., Andrén P. E., Carlsohn, E., et al. (2015), Cancer & Metastasis Review, forthcoming). The concept of precision medicine was initially emphasized as an important therapeutic strategy in new drug discovery and development [10]. Drs Zhao and Adjei provide an overview of novel therapies that are based on oncogenic molecular aberrations in lung cancer (Zhao, Y., & Adjei, A. A. (2015), Cancer & Metastasis Review, forthcoming). Because of tumor heterogeneity, it will be important to simultaneously target multiple aberrations and alternate signaling pathways which tumors utilize to survive various insults. Nanomedicine is seen as an emerging platform for metastatic lung cancer therapy, which will achieve these goals [11]. In conclusion, lung cancer and metastasis is a leading cause of mortality. Local approaches to treating lung cancer are very successful. What is now needed is a variety of effective systemic approaches that will effectively control metastatic disease in order to increase survival. This volume provides an excellent discussion of these approaches.

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genomic instability processes defines lung cancer evolution. Science, 346(6206), 251–256. doi:10.1126/science.1253462. 7. Zhang, J., Fujimoto, J., Zhang, J., Wedge, D. C., Song, X., Zhang, J., et al. (2014). Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science, 346(6206), 256–259. doi:10.1126/science.1256930. 8. Wu, D. J., Wang, X. D. (2015). Application of clinical bioinformatics in lung cancer-specific biomarkers. Cancer & Metastasis Review. 9. Mehta, A., Romero-Olmedo, A. J., Dobersch S., Barreto G. (2015). Significance of epigenetics in lung cancer diagnosis and therapy. Cancer & Metastasis Review. 10. Dolsten, M., & Søgaard, M. (2012). Precision medicine: an approach to R&D for delivering superior medicines to patients. Clinical and Translational Medicine, 1, 7. doi:10.1186/20011326-1-7. 11. Landesman-Milo, D., Ramishetti, S., Peer, D. (2015). Nanomedicine as an emerging platform for metastatic lung cancer therapy. Cancer & Metastasis Review.

Lung cancer and metastasis: new opportunities and challenges.

Lung cancer continues to attract special attention since the real number of lung cancer mortality and incidence in 2014 was definitely higher than tho...
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