Thioredoxin Inhibitor, PX-12, in Phase II Clinical Trial

描述(申请人提供)：在美国，每四个人中就有一个死于癌症。美国的抗癌药物市场总额超过20亿美元。迫切需要确定新的、有效的、基于小分子的癌症治疗方法。这项建议寻求承担新的靶向药物PX-12的进一步临床开发。ProIX PharmPharmticals已经证明有以下强有力的证据：1)氧化还原蛋白硫氧还蛋白-1(TRX-1)是缺氧诱导癌细胞HIF-1α增加所必需的。在体内实验肿瘤中，TRX-Q导致HIF-1α反式激活活性和血管内皮生长因子的表达增加，以及HIF-1α的应变和血管生成增加。2)TRX-1在许多人类原发肿瘤中的表达增加，与肿瘤的侵袭性生长和患者的生存时间降低有关。3)胰腺肿瘤高度缺氧，高水平表达HIF和TRX。4)小分子PX-12是TRX-1和缺氧诱导的实体瘤中HIF-1α的有效抑制剂。5)1期临床试验表明，静脉注射PX-12。癌症患者对输液的耐受性很好，TRX-1的降幅高达50-80%。6)在接受PX-12治疗的32例晚期转移患者中，有7例有效，定义为肿瘤减少或病情稳定。7)在21天内(1个周期)，TRX降低25%与患者存活率的增加显著相关。这项研究的假设是，PX-12是TRX-1、HIF-1α和肿瘤血管生成的有效抑制剂，患者毒性低，在一期临床试验中疗效良好。胰腺癌，由于其高水平的TRX-1和HIF-1α水平以及血管生成特性，是检测PX-12疾病特异性活性的理想肿瘤。ProIX制药公司此次更新SBIR的目的是：1)研究PX-12对单轮吉西他滨治疗失败的胰腺癌患者的疗效；2)确定PX-12抑制TRX是否转化为肿瘤血流(血管生成)的改变。

DESCRIPTION (provided by applicant): One in every four deaths in the US is due to cancer. The overall cancer drug market exceeds $2 billion in the USA. There is significant need to identify novel, effective, small molecule-based cancer therapies. This proposal seeks to undertake further clinical development of a novel targeted agent, PX-12. ProIX Pharmaceuticals has demonstrated there is strong evidence for the following: 1) The redox protein thioredoxin-1 (Trx-1) is necessary for the hypoxia-induced increase in HIF-1 alpha in cancer cells. Trx-q causes an increase in HIF-1 alpha transactivating activity and expression of VEGF as well as HIF-1 alpha straining and angiogenesis in experimental tumors in vivo. 2) The expression of Trx-1 is increased in many human primary tumors where it is associated with aggressive tumor growth and decreased patient survivial. 3) Pancreatic tumors are highly hypoxic and express both high levels of HIF and Trx. 4) The small molecule, PX-12 is a potent inhibitor of Trx-1 and the hypoxia induced increase of HIF-1 alpha in a solid tumors. 5) A Phase 1 clinical trial has shown that administration of PX-12 via an i.v. infusion is well tolerated by cancer patients and decreases Trx-1 up to 50-80%. 6) Efficacy, defined as tumor reduction or stable disease, was seen in 7 of 32 advanced metastatic patients treated with PX-12. 7) Trx lowering >25% over a 21 day period (1 cycle) was significantly correlated to increased patient survival. The hypothesis upon which the study is based is that PX-12 is an effective inhibitor of Trx-1, HIF-1 alpha and tumor angiogenesis, with low patient toxicities and good efficacy in Phase 1 clinical trial. Pancreatic cancer, because of its high Trx-1 and HIF-1 alpha levels and angiogenic character is an ideal tumor in which to test the disease specific activity of PX-12. The objectives of this SBIR renewal by ProIX Pharmaceuticals are to: 1) study the efficacy of PX-12 against pancreatic cancer in patients who have failed a single round of gemcitabine therapy and 2) to determine whether PX-12 inhibition of Trx translates a modification in tumor blood flow(angiogenesis).