Newhook Timothy E, Lindberg James M, Adair Sara J, Kim Alison J, Stelow Edward B, Rahma Osama E, Parsons J Thomas, Bauer Todd W
Department of Surgery, University of Virginia, Charlottesville, VA, USA.
Department of Pathology, University of Virginia, Charlottesville, VA, USA.
Ann Surg Oncol. 2016 Jun;23(6):1993-2000. doi: 10.1245/s10434-016-5116-4. Epub 2016 Feb 4.
Most patients with pancreatic ductal adenocarcinoma (PDAC) die within 5 years following resection plus adjuvant gemcitabine (Gem) from outgrowth of occult metastases. We hypothesized that inhibition of the KRAS pathway with the MEK inhibitor trametinib would inhibit the outgrowth of occult liver metastases in a preclinical model.
Liver metastases harvested from two patients with PDAC (Tumors 608, 366) were implanted orthotopically in mice. Tumor cell lines were derived and transduced with lentiviruses encoding luciferase and injected into spleens of mice generating microscopic liver metastases. Growth kinetics of liver metastases were measured with bioluminescent imaging and time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) were determined.
Trametinib (0.3 mg/kg BID) significantly prolonged OS versus control (Tumor 608: 114 vs. 43 days, p < 0.001; Tumor 366: not reached vs. 167 days, p = 0.0488). In vivo target validation demonstrated trametinib significantly reduced phosphorylated-ERK and expression of the ERK-responsive gene DUSP6. In a randomized, preclinical trial, mice were randomized to: (1) control, (2) adjuvant Gem (100 mg/kg IP, Q3 days) × 7 days followed by surveillance, or (3) adjuvant Gem followed by trametinib. Sequential Gem-trametinib significantly decreased metastatic cell outgrowth and increased TTP and PFS.
Treatment of mice bearing micrometastases with trametinib significantly delayed tumor outgrowth by effectively inhibiting KRAS-MEK-ERK signaling. In a randomized, preclinical, murine trial adjuvant sequential Gem followed by trametinib inhibited occult metastatic cell outgrowth in the liver and increased PFS versus adjuvant Gem alone. An adjuvant trial of sequential Gem-trametinib is being planned in patients with resected PDAC.
大多数胰腺导管腺癌（PDAC）患者在接受切除加辅助吉西他滨（Gem）治疗后的5年内，会因隐匿性转移灶的生长而死亡。我们假设，在临床前模型中，用MEK抑制剂曲美替尼抑制KRAS通路会抑制隐匿性肝转移灶的生长。
从两名PDAC患者（肿瘤608、366）获取的肝转移灶原位植入小鼠体内。衍生肿瘤细胞系并用编码荧光素酶的慢病毒转导，然后注入小鼠脾脏以产生微小肝转移灶。通过生物发光成像测量肝转移灶的生长动力学，并确定疾病进展时间（TTP）、无进展生存期（PFS）和总生存期（OS）。
与对照组相比，曲美替尼（0.3mg/kg，每日两次）显著延长了OS（肿瘤608：114天对43天，p<0.001；肿瘤366：未达到对167天，p=0.0488）。体内靶点验证表明，曲美替尼显著降低了磷酸化ERK和ERK反应基因DUSP6的表达。在一项随机临床前试验中，小鼠被随机分为：（1）对照组，（2）辅助Gem（100mg/kg腹腔注射，每3天一次）×7天，然后进行监测，或（3）辅助Gem后给予曲美替尼。序贯Gem-曲美替尼显著减少了转移细胞的生长，并增加了TTP和PFS。
用曲美替尼治疗携带微转移灶的小鼠，通过有效抑制KRAS-MEK-ERK信号传导，显著延迟了肿瘤生长。在一项随机临床前小鼠试验中，辅助序贯Gem后给予曲美替尼，与单独使用辅助Gem相比，抑制了肝脏中隐匿性转移细胞的生长并增加了PFS。正在计划对切除的PDAC患者进行序贯Gem-曲美替尼的辅助试验。
