Biology of SCLC: the implications and the progress for the clinical therapy
-
摘要: 肺癌是全球几大恶性肿瘤之一,在我国居于恶性肿瘤发病及死亡首位。小细胞肺癌是肺内分泌肿瘤的一种,具有侵袭性强、易复发、易转移、预后不良等特征。而临床上小细胞肺癌的一线治疗方案仍未取得突破性的进展,主要仍以化疗为主,辅以放疗等综合治疗。虽然,小细胞肺癌对化疗反应敏感,但80%局限期小细胞肺癌及几乎所有广泛期小细胞肺癌都会发生肿瘤复发及进展,且化疗的毒副作用大。生物信息学及分子生物技术的发展为癌症的诊治提供更为广泛的空间,其中生物治疗方法为近年研究的热点之一,尤其是免疫治疗,特别是研究一些免疫检查点抑制剂以达到抗癌的作用。本文旨在阐述小细胞肺癌生物学研究及其治疗进展。Abstract: Lung cancer is one of the most common cancer around the world and the first cause of tumor-related mortality in China. Small-cell lung cancer (SCLC) is the neuroendocrine tumor with the characteristic of high aggressivity and growth fraction, early development of widespread metastases and poor prognosis in patients with SCLC. In the clinical practice, the first-line therapy for SCLC has been unchanged for decades, mainly the usage of chemoradiotherapy for SCLC. Although SCLC patients are sensitive to chemotherapy, recurrence arises rapidly in 80% of limited-stage SCLC and nearly all the extensive-stage SCLC cases. The progress of molecular biotechnology has provided hope for SCLC patients with new therapeutic strategies, especially the immunotherapy with immune-checkpoint blockade. Here, we reviewed the progress made in revealing the biology of SCLC and its implication for the new clinical therapy.
-
Key words:
- Small-cell lung cancer /
- chemoradiotherapy /
- immunotherapy /
- immune-checkpoint blockade
-
[1] Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer, 2015, 136(5): E359-86 doi: 10.1002/ijc.29210 [2] Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-32 doi: 10.3322/caac.21338 [3] Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database[J]. J Clin Oncol, 2006, 24(28): 4539-44 doi: 10.1200/JCO.2005.04.4859 [4] Abajobir AA, Abbafati C, Abbas KM, et al. Global, regional, and National age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the global burden of disease study 2016[J]. Lancet, 2017, 390(10100): 1151-210 doi: 10.1016/S0140-6736(17)32152-9 [5] Nicholson AG, Chansky K, Crowley J, et al. The international association for the study of lung cancer lung cancer staging project: proposals for the revision of the clinical and pathologic staging of small cell lung cancer in the forthcoming eighth edition of the TNM classification for lung cancer[J]. J Thorac Oncol, 2016, 11(3): 300-11 doi: 10.1016/j.jtho.2015.10.008 [6] Fitzmaurice C, Collaboration GB, Allen C, et al. Global, regional, and National cancer incidence, mortality, years of Life lost, years lived with disability, and Disability-Adjusted life-years for 32 cancer groups, 1990 to 2015 a systematic analysis for the global burden of disease study[J]. JAMA Oncol, 2017, 3(4): 524-48 doi: 10.1001/jamaoncol.2016.5688 [7] George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer[J]. Nature, 2015, 524(7563): 47-53 doi: 10.1038/nature14664 [8] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2): 87-108 doi: 10.3322/caac.21262 [9] Silva M, Galeone C, Sverzellati N, et al. Screening with low-dose computed tomography does not improve survival of small cell lung cancer[J]. J Thorac Oncol, 2016, 11(2): 187-93 doi: 10.1016/j.jtho.2015.10.014 [10] Turrisi AT, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide[J]. N Engl J Med, 1999, 340(4): 265-71 doi: 10.1056/NEJM199901283400403 [11] Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial[J]. Lancet Oncol, 2017, 18(8): 1116-25 doi: 10.1016/S1470-2045(17)30318-2 [12] Jackman DM, Johnson BE. Small-cell lung cancer[J]. Lancet, 2005, 366(9494): 1385-96 doi: 10.1016/S0140-6736(05)67569-1 [13] Rossi A, Di Maio M, Chiodini P, et al. Carboplatin-or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data[J]. J Clin Oncol, 2012, 30(14): 1692-8 doi: 10.1200/JCO.2011.40.4905 [14] Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer[J]. N Engl J Med, 2002, 346(2): 85-91 doi: 10.1056/NEJMoa003034 [15] von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan as Second-Line treatment for patients with Small-Cell lung cancer[J]. J Clin Oncol, 2014, 32(35): U160-4012 [16] Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial[J]. Lancet, 2015, 385(9962): 36-42 doi: 10.1016/S0140-6736(14)61085-0 [17] Slotman BJ, van Tinteren H, Praag JO, et al. Radiotherapy for extensive stage small-cell lung cancer - Authors' reply[J]. Lancet, 2015, 385(9975): 1292-3 [18] Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer[J]. N Engl J Med, 2007, 357(7): 664-72 doi: 10.1056/NEJMoa071780 [19] Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2017, 18(5): 663-71 doi: 10.1016/S1470-2045(17)30230-9 [20] Aizer AA, Mak R, Alexander BM. Prophylactic cranial irradiation in patients with extensive-stage small cell lung cancer[J]. Neuro Oncol, 2017, 19(8): 1015-6 doi: 10.1093/neuonc/nox113 [21] Slotman BJ. Time to reconsider prophylactic cranial irradiation in extensive-stage small-cell lung cancer[J]. Lancet Oncol, 2017, 18(5): 566-7 doi: 10.1016/S1470-2045(17)30193-6 [22] Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1[J]. Cancer Discov, 2012, 2(9): 798-811 doi: 10.1158/2159-8290.CD-12-0112 [23] de Bono J, Ramanathan RK, Mina L, et al. Phase I, Dose-Escalation, Two-Part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers[J]. Cancer Discov, 2017, 7(6): 620-9 doi: 10.1158/2159-8290.CD-16-1250 [24] Margueron R, Reinberg D. The polycomb complex PRC2 and its mark in Life[J]. Nature, 2011, 469(7330): 343-9 doi: 10.1038/nature09784 [25] Gardner EE, Lok BH, Schneeberger VE, et al. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis[J]. Cancer Cell, 2017, 31(2): 286-99 doi: 10.1016/j.ccell.2017.01.006 [26] Leijen S, van Geel RM, Pavlick AC, et al. Phase I study evaluating WEE1 inhibitor AZD1775 as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors[J]. J Clin Oncol, 2016, 34(36): 4371-80 doi: 10.1200/JCO.2016.67.5991 [27] Do K, Wilsker D, Ji J, et al. Phase I study of Single-Agent AZD1775 (MK-1775), a wee1 kinase inhibitor, in patients with refractory solid tumors[J]. J Clin Oncol, 2015, 33(30): 3409-15 doi: 10.1200/JCO.2014.60.4009 [28] Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo[J]. Sci Transl Med, 2015, 7(32): 302-6 [29] Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study[J]. Lancet Oncol, 2017, 18(1): 42-51 doi: 10.1016/S1470-2045(16)30565-4 [30] Lu Y, Liu Y, Jiang J, et al. Knocking down the expression of Aurora-A gene inhibits cell proliferation and induces G2/M phase arrest in human small cell lung cancer cells[J]. Oncol Rep, 2014, 32(1): 243-9 doi: 10.3892/or.2014.3194 [31] Mollaoglu G, Guthrie MR, Böhm S, et al. MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to Aurora kinase inhibition[J]. Cancer Cell, 2017, 31(2): 270-85 doi: 10.1016/j.ccell.2016.12.005 [32] Melichar B, Adenis A, Lockhart AC, et al. Safety and activity of alisertib, an investigational Aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study[J]. Lancet Oncol, 2015, 16(4): 395-405 doi: 10.1016/S1470-2045(15)70051-3 [33] Zarogoulidis K, Ziogas E, Boutsikou E, et al. Immunomodifiers in combination with conventional chemotherapy in small cell lung cancer: a phase II, randomized study[J]. Drug Des Devel Ther, 2013, 7(2): 611-7 [34] Antonia SJ, Mirza N, Fricke I, et al. Combination of p53 Cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer[J]. Clin Cancer Res, 2006, 12(3 Pt 1): 878-87 [35] Krug LM, Ragupathi G, Hood C, et al. Vaccination of patients with small-cell lung cancer with synthetic fucosyl GM-1 conjugated to keyhole limpet hemocyanin[J]. Clin Cancer Res, 2004, 10(18 Pt 1): 6094-100 [36] Giaccone G, Debruyne C, Felip E, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer[J]. J Clin Oncol, 2005, 23(28): 6854-64 doi: 10.1200/JCO.2005.17.186 [37] Wei SC, Levine JH, Cogdill AP, et al. Distinct cellular mechanisms underlie Anti-CTLA-4 and Anti-PD-1 checkpoint blockade[J]. Cell, 2017, 170(6): 1120-33 doi: 10.1016/j.cell.2017.07.024 [38] Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial[J]. Ann Oncol, 2013, 24(1): 75-83 doi: 10.1093/annonc/mds213 [39] Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and Platinum versus placebo plus etoposide and Platinum in Extensive-Stage Small-Cell lung cancer[J]. J Clin Oncol, 2016, 34(31): 3740-8 doi: 10.1200/JCO.2016.67.6601 [40] Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial[J]. Lancet Oncol, 2016, 17(7): 883-95 doi: 10.1016/S1470-2045(16)30098-5 [41] Ott PA, Elez E, Hiret S, et al. Pembrolizumab in patients with Extensive-Stage Small-Cell lung cancer: results from the phase Ib KEYNOTE-028 study[J]. J Clin Oncol, 2017, 35(34): 3823-9 doi: 10.1200/JCO.2017.72.5069
点击查看大图
计量
- 文章访问数: 1022
- HTML全文浏览量: 366
- PDF下载量: 11
- 被引次数: 0