Virginia G. Piper Cancer Center, Scottsdale, AZ, USA.
Ann Surg. 2012 Jan;255(1):140-6. doi: 10.1097/SLA.0b013e3182402d21.
Traditional drug discovery methods have a limited role in rare cancers. We hypothesized that molecular technology including gene expression profiling could expose novel targets for therapy in adrenocortical carcinoma (ACC), a rare and lethal cancer. SPARC (secreted protein acidic rich in cysteine) is an albumin-binding matrix-associated protein that is proposed to act as a mechanism for the increased efficacy of a nanoparticle albumin-bound preparation of the antimicrotubular drug Paclitaxel (nab-paclitaxel).
The transcriptomes of 19 ACC tumors and 4 normal adrenal glands were profiled on Affymetrix U133 Plus2 expression microarrays to identify genes representing potential therapeutic targets. Immunohistochemical analysis for target proteins was performed on 10 ACC, 6 benign adenomas, and 1 normal adrenal gland. Agents known to inhibit selected targets were tested in comparison with mitotane in the 2 ACC cell lines (H295R and SW-13) in vitro and in mouse xenografts.
SPARC expression is increased in ACC samples by 1.56 ± 0.44 (μ ± SD) fold. Paclitaxel and nab-paclitaxel show in vitro inhibition of H295R and SW-13 cells at IC50 concentrations of 0.33 μM and 0.0078 μM for paclitaxel and 0.35 μM and 0.0087 μM for nab-paclitaxel compared with mitotane concentrations of 15.9 μM and 46.4 μM. In vivo nab-paclitaxel treatment shows a greater decrease in tumor weight in both xenograft models than mitotane.
Biological insights garnered through expression profiling of ACC tumors suggest further investigation into the use of nab-paclitaxel for the treatment of ACC.
传统的药物发现方法在罕见癌症方面作用有限。我们假设包括基因表达谱分析在内的分子技术可以为肾上腺皮质癌（ACC）的治疗提供新的靶点，ACC 是一种罕见且致命的癌症。富含半胱氨酸的酸性分泌蛋白（SPARC）是一种与白蛋白结合的基质相关蛋白，据推测它可以作为纳米颗粒白蛋白结合紫杉醇（nab-紫杉醇）药物增加疗效的机制。
使用 Affymetrix U133 Plus2 表达微阵列对 19 个 ACC 肿瘤和 4 个正常肾上腺组织的转录组进行了分析，以鉴定代表潜在治疗靶点的基因。对 10 个 ACC、6 个良性腺瘤和 1 个正常肾上腺组织进行了针对目标蛋白的免疫组织化学分析。在体外和小鼠异种移植模型中，用已知可抑制选定靶点的药物与米托坦比较，检测了 2 种 ACC 细胞系（H295R 和 SW-13）中的两种药物。
ACC 样本中 SPARC 的表达增加了 1.56 ± 0.44（μ ± SD）倍。紫杉醇和 nab-紫杉醇对 H295R 和 SW-13 细胞的体外抑制作用的 IC50 浓度分别为 0.33 μM 和 0.0078 μM（紫杉醇）和 0.35 μM 和 0.0087 μM（nab-紫杉醇），而米托坦的浓度分别为 15.9 μM 和 46.4 μM。体内 nab-紫杉醇治疗在两种异种移植模型中均使肿瘤重量的减少明显大于米托坦。
通过对 ACC 肿瘤的表达谱进行分析获得的生物学见解表明，进一步研究 nab-紫杉醇在 ACC 治疗中的应用具有重要意义。
