1 Cornerstone Pharmaceuticals, Inc., 1 Duncan Drive, Cranbury, NJ 08512, USA ; 2 Quinnipiac University, 275 Mount Carmel Avenue, Hamden, CT 06518, USA.
Ann Transl Med. 2014 Sep;2(9):91. doi: 10.3978/j.issn.2305-5839.2014.05.08.
Via genetic alterations, malignant transformation and proliferation are associated with extensive alterations of mitochondrial energy metabolism of tumor cells. Thus, inhibition of the altered form of mitochondrial energy metabolism of tumor cells may be an effective therapy for cancers. This study performed translational assessment of mitochondrial dysfunction of pancreatic cancer from in vitro gene microarray and animal efficacy studies, to early clinical studies, via the novel tumor-specific anti-mitochondrial agent, CPI-613.
The gene profiles of BxPC-3 human pancreatic tumor cells and non-transformed NIH-3T3 mouse fibroblast cells (negative control), after CPI-613 or sham treatment, were assessed and compared using microarray technique. The anti-cancer efficacies of CPI-613 and Gemcitabine were assessed and compared in mice with xenograft from inoculation of BxPC-3 human pancreatic tumor cells, based on the degree of tumor growth inhibition and prolongation of survival when compared to vehicle treatment. The anti-cancer activities, according to overall survival (OS), of CPI-613 alone and in combination with Gemcitabine were assessed in patients with Stage IV pancreatic cancer.
Microarray studies indicated that CPI-613 down-regulated the expression of Cyclin D3, E1, E2, F, A2, B1 and CDK2 genes of BxPC-3 pancreatic cancer cells but not non-transformed NIH-3T3 mouse fibroblast cells (negative control). In mice with pancreatic carcinoma xenografts, four weekly intraperitoneal injections of either CPI-613 (25 mg/kg/administration) or Gemcitabine (50 mg/kg/administration) inhibited tumor growth and prolonged survival when compared to vehicle treatment. The degree of tumor growth inhibition was ~2×, and prolongation of survival was ~4×, greater with CPI-613 treatment than with Gemcitabine treatment. In patients with Stage IV advanced pancreatic cancer, CPI-613 at 420-1,300 mg/m(2), given twice weekly for three weeks followed by a week of rest (i.e., 3-week-on-1-week-off) as monotherapy, provided median OS of 15 months in three patients. CPI-613 at 150-320 mg/m(2) given twice weekly on the 3-week-on-1-week-off dosing schedule, coinciding with Gemcitabine (1,000 mg/m(2)) given once weekly on the 3-week-on-1-week-off dosing schedule, provided median OS of 17.8 months in four patients. These median OS values from CPI-613 monotherapy and CPI-613 + Gemcitabine treatment tend to be longer than those in patients treated with Abraxane + Gemcitabine combination or FOLFININOX (median OS ~12 months).
The dysfunctional mitochondria of pancreatic cancer cells was translationable from in vitro gene alteration and animal tumor model studies to patients with advanced Stage IV pancreatic cancer, as reflected by the anti-cancer activities of the tumor-specific anti-mitochondrial agent, CPI-613, in these studies.
通过基因改变，恶性转化和增殖与肿瘤细胞线粒体能量代谢的广泛改变有关。因此，抑制肿瘤细胞线粒体能量代谢的改变形式可能是癌症的有效治疗方法。本研究通过新型肿瘤特异性抗线粒体药物 CPI-613，从体外基因微阵列和动物疗效研究，到早期临床研究，对胰腺癌的线粒体功能障碍进行了转化评估。
用微阵列技术评估经 CPI-613 或假处理的人胰腺癌细胞 BxPC-3 和非转化 NIH-3T3 小鼠成纤维细胞（阴性对照）的基因谱。根据与载体治疗相比，肿瘤生长抑制的程度和生存时间的延长，评估 CPI-613 和吉西他滨在接种人胰腺癌细胞 BxPC-3 的异种移植小鼠中的抗癌功效。根据总生存（OS），评估单独使用 CPI-613 以及与吉西他滨联合治疗 IV 期胰腺癌患者的抗癌活性。
微阵列研究表明，CPI-613 下调了人胰腺癌细胞 BxPC-3 的 Cyclin D3、E1、E2、F、A2、B1 和 CDK2 基因的表达，但未下调非转化 NIH-3T3 小鼠成纤维细胞（阴性对照）的表达。在患有胰腺癌异种移植的小鼠中，每周腹腔内注射四次 CPI-613（25mg/kg/给药）或吉西他滨（50mg/kg/给药），与载体治疗相比，抑制肿瘤生长并延长生存时间。肿瘤生长抑制的程度约为 2 倍，生存时间延长约 4 倍，CPI-613 治疗的程度大于吉西他滨治疗的程度。在 IV 期晚期胰腺癌患者中，CPI-613 以 420-1300mg/m2 的剂量，每两周一次，连续三周，然后休息一周（即 3 周-1 周），作为单一疗法，三名患者的中位总生存期为 15 个月。CPI-613 以 150-320mg/m2 的剂量，每周两次，在 3 周-1 周的方案中，同时给予吉西他滨（1000mg/m2），每周一次，在 3 周-1 周的方案中，四名患者的中位总生存期为 17.8 个月。CPI-613 单药治疗和 CPI-613+吉西他滨治疗的这些中位 OS 值似乎长于接受 Abraxane+吉西他滨联合治疗或 FOLFININOX（中位 OS~12 个月）的患者。
胰腺癌细胞的功能失调线粒体可以从体外基因改变和动物肿瘤模型研究转化为晚期 IV 期胰腺癌患者，这反映在这些研究中，肿瘤特异性抗线粒体药物 CPI-613 的抗癌活性。
