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不可切除胰腺癌的分子靶向药物治疗进展
DOI: 10.12449/JCH240234
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摘要: 胰腺癌作为消化系统最常见的恶性肿瘤之一，其发病率及死亡率正逐年上升，大多数胰腺癌患者因分期较晚而失去了手术机会。尽管以吉西他滨、氟尿嘧啶为主的化疗方案在一定程度上延长了患者的生存期，但仍有部分患者因无法耐受化疗而失去治疗机会。随着精准医疗时代的来临，分子靶向药物治疗展现出的优异疗效使其成为对抗肿瘤的重要治疗手段之一，但由于胰腺癌高度的异质性及复杂的免疫微环境，针对胰腺癌的分子靶向治疗并未取得显著效果，因此亟需探寻新的治疗靶点及药物攻克这一难题。本综述基于胰腺癌常见分子靶点及肿瘤免疫相关靶点探究在不可切除胰腺癌中分子靶向药物治疗研究的最新进展，为胰腺癌患者提供新的治疗策略。Abstract: Pancreatic cancer is one of the most prevalent malignant tumors of the digestive system， and its incidence and mortality rates are increasing year by year. Most patients with pancreatic cancer are unable to receive surgery due to the advanced stage. Although chemotherapy regimens based on gemcitabine and fluorouracil have prolonged the survival time of patients to some extent， some patients cannot tolerate chemotherapy and hence lose the opportunity for treatment. With the advent of the era of precision medicine， molecular-targeted therapy has exhibited an excellent therapeutic efficacy and has thus become one of the most important treatment techniques for tumors； however， due to the high heterogeneity of pancreatic cancer and its complicated tumor microenvironment， molecular-targeted therapy for pancreatic cancer has not achieved notable results. Therefore， it is imperative to seek new therapeutic targets and medications to overcome this issue. This article reviews the latest advances in the research on molecular-targeted therapy for unresectable pancreatic cancer based on common molecular targets and tumor immunity-related therapeutic targets， in order to provide new treatment strategies for patients with pancreatic cancer.
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Key words:
- Pancreatic Neoplasms /
- Molecular Targeted Therapy /
- Immunotherapy
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胆汁淤积性肝病是各种原因引起胆酸盐循环发生障碍，蓄积于肝细胞而引起肝细胞毒性［1］，并可导致肝内慢性炎症反应，损伤胆管细胞和肝细胞，最终可发展为肝衰竭和恶性转化［2］。胆汁淤积的发生涉及雌激素、遗传及环境等多种因素。
环境污染物邻苯二甲酸二（2-乙基己基）酯（di-2-ethylhexyl phthalate，DEHP）是邻苯二甲酸酯增塑剂之一，生活中被广泛应用于各种塑料制品中［3］。已有研究［4］报道DEHP在输液管中浸出造成的毒性增加胆汁淤积的风险。此外，动物研究［5］也发现DEHP可导致小鼠肝脏DNA损伤可能促进胆汁淤积的发生，本课题组前期研究［6］已证实DEHP暴露可诱导小鼠发生胆汁淤积，但DEHP对胆汁淤积性肝病炎症反应的作用尚未完全阐明。因此，本研究探索DEHP暴露导致胆汁淤积性肝病和炎症损伤的机制，为临床发现新的药物治疗靶点奠定基础。
1. 材料与方法
1.1 实验动物
8周龄（26～30 g）雌性ICR小鼠购买于北京维通利华实验动物技术有限公司，生产许可证编号：SCXK（京）2019-0010，使用许可证编号：SYXK（皖）2020-001。小鼠饲养在适宜的环境中：温度（25±1）℃，湿度55%±5%，适应性饲养7天进行实验。
1.2 试剂
总胆汁酸（TBA）试剂盒购买于浙江伊利康生物技术有限公司，ALP和GGT购买于南京建成生物工程研究所；DEHP、胆酸（cholic acid，CA）、甘氨胆酸（glycocholic acid，GCA）、牛磺胆酸（taurocholic acid，TCA）、牛磺鹅去氧胆酸（taurochenodesoxycholic acid，TCDCA）、鹅去氧胆酸（chenodeoxycholic acid，CDCA）、去氧胆酸（deoxycholic acid，DCA）、熊去氧胆酸（ursodeoxycholic acid，UDCA）、甘氨鹅去氧胆酸（glycine chenodeoxycholic acid，GCDCA）、牛磺熊去氧胆酸（tauroursodeoxycholic acid，TUDCA）、甘氨石胆酸（glycine cholic acid，GLCA）和甘氨猪去氧胆酸（glycine hyodeoxycholic acid，GHDCA）购买于美国默克公司；玉米油购自上海阿拉丁生化有限公司；CCK-8溶液、DMSO购买于上海碧云天生物技术有限公司；血清购买于浙江天杭生物科技股份有限公司；胰酶细胞消化液购买于Biosharp生物科技公司；DMEM培养基购买于Hyclone；实时定量PCR扩增试剂盒购买于翌圣生物科技（上海）股份有限公司；实时定量PCR引物购买于北京擎科生物科技股份有限公司。
1.3 动物分组与处理
将雌性ICR小鼠随机分为对照组、DEHP组（200 mg·kg-1·d-1），每组8只，共灌胃4周。取材前禁食6 h，收集血液和肝组织用于后续实验。
1.4 生化检测
使用生化分析仪检测血清中TBA以及肝脏TBA的含量。
1.5 肝组织病理学观察
将小鼠新鲜肝组织放入4%多聚甲醛溶液中浸泡处理，室温放置摇床固定24 h。进行脱水包埋并切片固定后，用苏木精-伊红（HE）染色，在显微镜下观察并拍照。
1.6 液相色谱-三重四级杆质谱
使用液相色谱-三重四级杆质谱仪（liquid chromatography-triple quadrupole mass spectrometer，LC-MS/MS）（AB SCIEX公司，型号：TRIPLE QUAD™ 4500 SYSTEM）检测小鼠中胆汁酸组分水平。色谱柱：100 mm×3.0 mm（Phenomenex公司，型号：00D-4462-Y0、2.6 µm C18 100A）；流动相：A相为含有0.1%冰乙酸的4 mmol/L乙酸铵溶液，B相为甲醇；柱温为40 ℃；流速为0.4 mL/min；进样量为10 μL。
1.7 细胞培养
小鼠肝细胞系AML-12细胞来源于中国科学院典型培养物保藏委员会细胞库。AML-12细胞培养在含有10%胎牛血清、5 μg/mL胰岛素-转铁蛋白-亚硒酸钠、地塞米松40 ng/mL，青霉素100 U/mL，链霉素100 μg/mL的DMEM-F12完全培养基中，并放置于恒温培养箱中（37 ℃，5% CO2）培养。当细胞密度达到80%～90%时，使用胰酶消化细胞后进行传代。
1.8 CCK-8实验检测细胞增殖
将处于对数生长期的肝细胞接种于96孔板，每孔1×104个细胞。按实验设计进行分组并给药。培养24 h后，弃掉上清，向每孔中添加CCK-8工作溶液110 μL（CCK-8试剂∶细胞培养基=1∶10），继续孵育0.5～4 h后使用酶标仪测定450 nm处的光密度（OD）值，计算细胞存活率。细胞存活率（%）=（处理组细胞OD值－阴性对照组OD值）/（对照组细胞OD值－阴性对照组OD值）×100%。
1.9 实时定量PCR检测相关基因
采用TRlzol法提取RNA，将所有提取的RNA样品的浓度定量在1 000 ng/µL，逆转录成cDNA，之后进行扩增反应，选取18S（18S ribosomal RNA）作为内参基因，计算相应基因的相对表达水平。相关引物信息见表1。
表 1 基因的引物序列Table 1. Primers sequence of genes基因名称 引物序列（5'-3'） 18S F：GTAACCCGTTGAACCCCATT R：CCATCCAATCGGTAGTAGCG IL-1β F：AACTGCACTACAGGCTCCGAG R：TGCTTGGTTCTCCTTGTACAAAGC TNF-α F：AAAAGATGGGGGGCTTCCAGAA R：CCATTTGGGAACTTCTCATCCCTT IL-6 F：TCTATACCACTTCACAAGTCGGA R：GAATTGCCATTGCACAACTCTTT 1.10 统计学方法
采用SPSS 25.0软件进行统计分析。计量资料以
2. 结果
2.1 DEHP暴露导致小鼠胆汁淤积的发生
与对照组相比，DEHP组小鼠肝体比显著增加（t=-4.396，P<0.01）；血清与肝脏TBA水平显著升高（t值分别为-5.109、-7.974，P<0.01）；血清ALP和GGT水平显著升高（t值分别为-8.504、-3.792，P值均<0.05）（图1）。
2.2 DEHP暴露对小鼠肝脏胆汁酸组分的影响
LC-MS/MS结果显示与对照组相比，CA、CDCA、TCDCA、DCA及UDCA均显著升高（t值分别为-2.802、-3.177、-2.633、-2.874和-2.311，P值均<0.05）。其余肝脏胆汁酸组分无明显变化（图2）。
2.3 DEHP暴露对肝脏炎症因子的影响
肝组织HE染色结果显示，对照组小鼠肝组织完整，DEHP组小鼠肝组织可见汇管区扩大、胆管变形，胆管周围并伴有炎性细胞浸润。进一步对肝脏炎症因子进行检测发现，DEHP组小鼠炎性因子IL-1β、IL-6和TNF-α mRNA水平较对照组显著升高（t值分别为-2.539、-2.823和-4.636，P值均<0.05）（图3）。
图 3 小鼠肝脏HE染色和炎症因子表达水平Figure 3. HE staining and expression of inflammatory factors in mouse liver2.4 DEHP暴露对肝细胞的影响
结合肝脏HE染色的结果，DEHP暴露导致肝脏发生损伤，本研究进一步在体外探究DEHP暴露对肝细胞的影响，不同浓度的DEHP处理24 h对肝细胞存活率与0 µmol/L相比有显著性差异（F=29.575，P<0.01）（图4a）；进一步检测肝细胞炎性因子的表达情况，发现DEHP处理后IL-1β、IL-6和TNF-α mRNA水平均显著升高（P值均<0.05）（图4b），这与体内结果相一致；同时选择250 µmol/L浓度进行后续实验。
注： a，不同剂量DEHP处理24 h肝细胞存活率；b，肝细胞炎症因子mRNA水平。图 4 DEHP暴露对肝细胞炎症因子水平的影响Figure 4. Effects of DEHP exposure on levels of inflammatory cytokines in hepatocytes2.5 DEHP联合胆汁酸共培养对肝细胞的影响
结合LC-MS/MS检测结果DEHP暴露导致不同组分胆汁酸发生改变，进一步探究某一种组分改变对于肝细胞的影响，选用CDCA和DCA与DEHP进行联合刺激肝细胞，观察炎性因子表达的情况。肝细胞的存活率随着CDCA和DCA浓度的增加而降低，当浓度为125 µmol/L时，细胞存活率均达到80%以下（图5a、b），因此选择125 µmol/L的CDCA和DCA分别与DEHP共同培养肝细胞，结果发现与DEHP组相比，CDCA联合DEHP刺激上调了细胞炎症因子IL-1β mRNA水平（P<0.01），对IL-6和TNF-α的表达有促进作用，但无统计学差异（图5c）；DCA联合DEHP刺激可显著增加细胞炎症因子IL-1β和IL-6的mRNA水平（P值均<0.01），同样可上调TNF-α的表达，但无统计学差异（图5d）。
注： a，不同剂量CDCA处理24 h细胞存活率；b，不同剂量DCA处理24 h细胞存活率；c，125 µmol/L CDCA和250 µmol/L DEHP处理肝细胞炎症因子mRNA水平；d，125 µmol/L DCA和250 µmol/L DEHP处理肝细胞炎症因子mRNA水平。图 5 胆汁酸联合DEHP共培养对肝细胞炎症因子水平的影响Figure 5. Effects of bile acids combined with DEHP on the levels of inflammatory cytokines in hepatocytes3. 讨论
DEHP作为邻苯二甲酸酯的一种，可通过饮食、吸入、医疗设备与生物液体等多种途径直接接触摄入体内［7-8］，引起生殖毒性、神经损伤、炎症、过敏和内分泌紊乱等危害［9］。因此，研究DEHP暴露对于人体所造成的危害具有重要的意义。胆汁淤积性肝病是因胆汁生成、分泌及排泄障碍导致肝内外胆汁淤积的临床常见疾病，血清胆汁酸浓度升高是诊断的必要条件，其中TBA>10 μmol/L可作为胆汁淤积的诊断标准［10］。因此，针对DEHP诱导胆汁淤积动物模型对于深入研究环境因素与胆汁淤积性肝病之间的关系和机制研究具有重要意义。
本研究发现，DEHP给小鼠灌胃28天后，DEHP组小鼠肝体比明显增加且血清TBA、ALP和GGT水平显著升高，表明DEHP暴露可导致胆汁淤积性肝病的发生。Gourlay等［11］发现DEHP在人和大鼠的血液中具有促炎作用，在本研究中也发现DEHP暴露组小鼠肝脏出现明显病理变化并伴有炎性细胞浸润且肝脏中的炎症因子表达显著性升高；体外DEHP处理肝细胞后也上调了肝细胞中炎症因子的表达。胆汁酸具有促进营养物质和脂溶性维生素吸收和代谢的重要功能，还具有调节机体糖、脂、能量代谢、内分泌以及解毒作用。本研究发现DEHP暴露小鼠肝脏中CA、CDCA、TCDCA、DCA以及UDCA等代谢发生紊乱。有研究［12］表明，不同的胆汁酸成分损害肝脏的能力存在差异，本研究中升高的天然胆汁酸成分对小鼠肝脏毒性强弱程度依次为DCA>CDCA>CA>UDCA。体外实验进一步探讨了胆汁酸是否影响DEHP的促炎作用，选用DCA和CDCA分别与DEHP联合作用于肝细胞，结果显示，相较于单独DEHP暴露，DCA和CDCA分别与DEHP共同刺激可导致肝细胞炎症因子IL-1β、IL-6和TNF-α的转录水平显著升高，这提示毒性胆汁酸可促进DEHP的促炎作用。
DEHP作为一种被广泛使用的塑化剂，对人体健康的危害不容忽视。在既往研究［9］中，通过临床出生队列分析发现DEHP暴露增加了胆汁淤积发生的风险但并未进一步在小鼠模型中进行验证。本课题组前期研究［6］首次构建DEHP暴露导致小鼠胆汁淤积性肝病的模型，而本研究中进一步探究DEHP诱发小鼠胆汁淤积和肝损伤机制研究。综上所述，DEHP暴露可导致小鼠胆汁淤积肝病的发生并诱发肝脏炎症，这可能与DEHP暴露引起毒性胆汁酸生成进而加剧炎性因子分泌有关。本课题组后续将进一步探究临床药物对于DEHP导致胆汁淤积性肝病的治疗效果，为临床治疗胆汁淤积性肝病提供更多的实验依据。
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[1] XIA CF, DONG XS, LI H, et al. Cancer statistics in China and United States, 2022: Profiles, trends, and determinants[J]. Chin Med J(Engl), 2022, 135( 5): 584- 590. DOI: 10.1097/CM9.0000000000002108. [2] PARK W, CHAWLA A, O’REILLY EM. Pancreatic cancer: A review[J]. JAMA, 2021, 326( 9): 851- 862. DOI: 10.1001/jama.2021.13027. [3] CONROY T, HAMMEL P, HEBBAR M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer[J]. N Engl J Med, 2018, 379( 25): 2395- 2406. DOI: 10.1056/NEJMoa1809775. [4] ZHANG ZN, ZHANG H, LIAO X, et al. KRAS mutation: The booster of pancreatic ductal adenocarcinoma transformation and progression[J]. Front Cell Dev Biol, 2023, 11: 1147676. DOI: 10.3389/fcell.2023.1147676. [5] STRICKLER JH, SATAKE H, GEORGE TJ, et al. Sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer[J]. N Engl J Med, 2023, 388( 1): 33- 43. DOI: 10.1056/nejmoa2208470. [6] SI OU, JÄNNE PA, LEAL TA, et al. First-in-human phase I/IB dose-finding study of adagrasib(MRTX849) in patients with advanced KRASG12C solid tumors(KRYSTAL-1)[J]. J Clin Oncol, 2022, 40( 23): 2530- 2538. DOI: 10.1200/JCO.21.02752. [7] WATERS AM, DER CJ. KRAS: The critical driver and therapeutic target for pancreatic cancer[J]. Cold Spring Harb Perspect Med, 2018, 8( 9): a031435. DOI: 10.1101/cshperspect.a031435. [8] KEMP SB, CHENG N, MARKOSYAN N, et al. Efficacy of a small-molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer[J]. Cancer Discov, 2023, 13( 2): 298- 311. DOI: 10.1158/2159-8290.CD-22-1066. [9] SHIN JE, AN HJ, PARK HS, et al. Efficacy of dabrafenib/trametinib in pancreatic ductal adenocarcinoma with BRAF NVTAP deletion: A case report[J]. Front Oncol, 2022, 12: 976450. DOI: 10.3389/fonc.2022.976450. [10] LI HS, YANG K, WANG Y. Remarkable response of BRAFV600E-mutated metastatic pancreatic cancer to BRAF/MEK inhibition: A case report[J]. Gastroenterol Rep(Oxf), 2022, 10: goab031. DOI: 10.1093/gastro/goab031. [11] SALAMA AKS, LI S, MACRAE ER, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: Results of the NCI-MATCH trial subprotocol H[J]. J Clin Oncol, 2020, 38( 33): 3895- 3904. DOI: 10.1200/JCO.20.00762. [12] SUBBIAH V, LASSEN U, ÉLEZ E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer(ROAR): A phase 2, open-label, single-arm, multicentre basket trial[J]. Lancet Oncol, 2020, 21( 9): 1234- 1243. DOI: 10.1016/S1470-2045(20)30321-1. [13] COCCO E, SCALTRITI M, DRILON A. NTRK fusion-positive cancers and TRK inhibitor therapy[J]. Nat Rev Clin Oncol, 2018, 15( 12): 731- 747. DOI: 10.1038/s41571-018-0113-0. [14] DOEBELE RC, DRILON A, PAZ-ARES L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1-2 trials[J]. Lancet Oncol, 2020, 21( 2): 271- 282. DOI: 10.1016/S1470-2045(19)30691-6. [15] HONG DS, DUBOIS SG, KUMMAR S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials[J]. Lancet Oncol, 2020, 21( 4): 531- 540. DOI: 10.1016/S1470-2045(19)30856-3. [16] MOORE MJ, GOLDSTEIN D, HAMM J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group[J]. J Clin Oncol, 2007, 25( 15): 1960- 1966. DOI: 10.1200/JCO.2006.07.9525. [17] LIU Y, GUO YL, WU ZQ, et al. Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: A phase I clinical trial[J]. Cytotherapy, 2020, 22( 10): 573- 580. DOI: 10.1016/j.jcyt.2020.04.088. [18] KOUMARIANOU A, KALTSAS G. Surufatinib-a novel oral agent for neuroendocrine tumours[J]. Nat Rev Endocrinol, 2021, 17( 1): 9- 10. DOI: 10.1038/s41574-020-00439-0. [19] BAGHDADI T AL, HALABI S, GARRETT-MAYER E, et al. Palbociclib in patients with pancreatic and biliary cancer with CDKN2A alterations: Results from the targeted agent and profiling utilization registry study[J]. JCO Precis Oncol, 2019, 3: 1- 8. DOI: 10.1200/PO.19.00124. [20] KATO S, ADASHEK JJ, SHAYA J, et al. Concomitant MEK and cyclin gene alterations: Implications for response to targeted therapeutics[J]. Clin Cancer Res, 2021, 27( 10): 2792- 2797. DOI: 10.1158/1078-0432.CCR-20-3761. [21] BLAIR AB, GROOT VP, GEMENETZIS G, et al. BRCA1/BRCA2 germline mutation carriers and sporadic pancreatic ductal adenocarcinoma[J]. J Am Coll Surg, 2018, 226( 4): 630- 637. DOI: 10.1016/j.jamcollsurg.2017.12.021. [22] KINDLER HL, HAMMEL P, RENI M, et al. Overall survival results from the POLO trial: A phase III study of active maintenance olaparib versus placebo for germline BRCA-mutated metastatic pancreatic cancer[J]. J Clin Oncol, 2022, 40( 34): 3929- 3939. DOI: 10.1200/JCO.21.01604. [23] REISS KA, MICK R, TEITELBAUM U, et al. Niraparib plus nivolumab or niraparib plus ipilimumab in patients with platinum-sensitive advanced pancreatic cancer: A randomised, phase 1b/2 trial[J]. Lancet Oncol, 2022, 23( 8): 1009- 1020. DOI: 10.1016/S1470-2045(22)00369-2. [24] FEIG C, JONES JO, KRAMAN M, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer[J]. Proc Natl Acad Sci U S A, 2013, 110( 50): 20212- 20217. DOI: 10.1073/pnas.1320318110. [25] BOCKORNY B, SEMENISTY V, MACARULLA T, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: The COMBAT trial[J]. Nat Med, 2020, 26( 6): 878- 885. DOI: 10.1038/s41591-020-0880-x. [26] BAILEY P, CHANG DK, NONES K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer[J]. Nature, 2016, 531( 7592): 47- 52. DOI: 10.1038/nature16965. [27] MELISI D, GARCIA-CARBONERO R, MACARULLA T, et al. Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer[J]. Br J Cancer, 2018, 119( 10): 1208- 1214. DOI: 10.1038/s41416-018-0246-z. [28] MELISI D, OH DY, HOLLEBECQUE A, et al. Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer[J]. J Immunother Cancer, 2021, 9( 3): e002068. DOI: 10.1136/jitc-2020-002068. [29] WANG X, ZHANG CS, DONG XY, et al. Claudin 18.2 is a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma[J]. World J Gastrointest Oncol, 2022, 14( 7): 1252- 1264. DOI: 10.4251/wjgo.v14.i7.1252. [30] QI CS, GONG JF, LI J, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: Phase 1 trial interim results[J]. Nat Med, 2022, 28( 6): 1189- 1198. DOI: 10.1038/s41591-022-01800-8. [31] LIU YF, SUN YS, WANG P, et al. FAP-targeted CAR-T suppresses MDSCs recruitment to improve the antitumor efficacy of claudin18.2-targeted CAR-T against pancreatic cancer[J]. J Transl Med, 2023, 21( 1): 255. DOI: 10.1186/s12967-023-04080-z. [32] YANG YM, DONG RH, ZHANG XS, et al.‘Oasis’ in‘death desert’: attach importance to the diagnosis and treatment for pancreatic cancer with microsatellite instability-high/deficient mismatch repair[J]. Chin J Dig Surg, 2023, 22( 5): 588- 592. DOI: 10.3760/cma.j.cn115610-20230505-00194.杨尹默, 董睿涵, 张兴胜, 等.“死亡荒漠”的“绿洲”: 重视微卫星高度不稳定/错配修复缺陷胰腺癌的诊断与治疗[J]. 中华消化外科杂志, 2023, 22( 5): 588- 592. DOI: 10.3760/cma.j.cn115610-20230505-00194. [33] ULLMAN NA, BURCHARD PR, DUNNE RF, et al. Immunologic strategies in pancreatic cancer: Making cold tumors hot[J]. J Clin Oncol, 2022, 40( 24): 2789- 2805. DOI: 10.1200/JCO.21.02616. [34] PADRÓN LJ, MAURER DM, O’HARA MH, et al. Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: Clinical and immunologic analyses from the randomized phase 2 PRINCE trial[J]. Nat Med, 2022, 28( 6): 1167- 1177. DOI: 10.1038/s41591-022-01829-9. [35] CHEN IM, JOHANSEN JS, THEILE S, et al. Randomized phase Ⅱ study of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy for refractory metastatic pancreatic cancer(CheckPAC)[J]. J Clin Oncol, 2022, 40( 27): 3180- 3189. DOI: 10.1200/JCO.21.02511. [36] CHEN BT, MAO XH. Clinical research advance in immunotherapy of pancreatic cancer[J]. Chin J Dig Surg, 2023, 22( 5): 610- 615. DOI: 10.3760/cma.j.cn115610-20230407-00158.陈博滔, 毛先海. 胰腺癌免疫治疗临床研究进展[J]. 中华消化外科杂志, 2023, 22( 5): 610- 615. DOI: 10.3760/cma.j.cn115610-20230407-00158. [37] YAN C, RICHMOND A. Hiding in the dark: Pan-cancer characterization of expression and clinical relevance of CD40 to immune checkpoint blockade therapy[J]. Mol Cancer, 2021, 20( 1): 146. DOI: 10.1186/s12943-021-01442-3. [38] BEATTY GL, CHIOREAN EG, FISHMAN MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans[J]. Science, 2011, 331( 6024): 1612- 1616. DOI: 10.1126/science.1198443. [39] VAN LAETHEM J, BORBATH I, PRENEN H, et al. Mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma(PDAC): Safety data from part of the OPTIMIZE-1 study[Z]. American Society of Clinical Oncology, 2022. [40] LIU HC, DAVILA GONZALEZ D, VISWANATH DI, et al. Sustained intratumoral administration of agonist CD40 antibody overcomes immunosuppressive tumor microenvironment in pancreatic cancer[J]. Adv Sci(Weinh), 2023, 10( 9): e2206873. DOI: 10.1002/advs.202206873. [41] SHANKARA NARAYANAN JS, HAYASHI T, ERDEM S, et al. Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model[J]. J Immunother Cancer, 2023, 11( 1): e006133. DOI: 10.1136/jitc-2022-006133. [42] HAMIDI H, IVASKA J. Every step of the way: Integrins in cancer progression and metastasis[J]. Nat Rev Cancer, 2018, 18( 9): 533- 548. DOI: 10.1038/s41568-018-0038-z. [43] DEAN A, GILL S, MCGREGOR M, et al. Dual αV-integrin and neuropilin-1 targeting peptide CEND-1 plus nab-paclitaxel and gemcitabine for the treatment of metastatic pancreatic ductal adenocarcinoma: A first-in-human, open-label, multicentre, phase 1 study[J]. Lancet Gastroenterol Hepatol, 2022, 7( 10): 943- 951. DOI: 10.1016/S2468-1253(22)00167-4. [44] DAWSON JC, SERRELS A, STUPACK DG, et al. Targeting FAK in anticancer combination therapies[J]. Nat Rev Cancer, 2021, 21( 5): 313- 324. DOI: 10.1038/s41568-021-00340-6. [45] JIANG H, HEGDE S, KNOLHOFF BL, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy[J]. Nat Med, 2016, 22( 8): 851- 860. DOI: 10.1038/nm.4123. [46] WANG-GILLAM A, LIM KH, MCWILLIAMS R, et al. Defactinib, pembrolizumab, and gemcitabine in patients with advanced treatment refractory pancreatic cancer: A phase I dose escalation and expansion study[J]. Clin Cancer Res, 2022, 28( 24): 5254- 5262. DOI: 10.1158/1078-0432.CCR-22-0308. 期刊类型引用(1)
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