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

描述（由申请人提供）：美国每四例死亡中就有一例是由于癌症。在美国，整个癌症药物市场超过20亿美元。非常需要鉴定新的、有效的、基于小分子的癌症疗法。该提案旨在对一种新型靶向药物PX-12进行进一步的临床开发。ProIX制药公司已经证明了以下强有力的证据：1）氧化还原蛋白硫氧还蛋白-1（Trx-1）是癌细胞中缺氧诱导的HIF-1 α增加所必需的。Trx-q导致HIF-1 α反式激活活性和VEGF表达以及体内实验肿瘤中HIF-1 α应变和血管生成的增加。2)Trx-1的表达在许多人类原发性肿瘤中增加，其中其与侵袭性肿瘤生长和降低的患者存活率相关。3)胰腺肿瘤是高度缺氧的，并且表达高水平的HIF和Trx。4)小分子PX-12是Trx-1和缺氧诱导的实体瘤中HIF-1 α增加的有效抑制剂。5)一项1期临床试验表明，通过静脉输注给予PX-12对癌症患者耐受良好，并使Trx-1降低高达50- 80%。6)疗效定义为肿瘤缩小或疾病稳定，在32例接受PX-12治疗的晚期转移性患者中有7例观察到疗效。7)在21天内（1个周期）Trx降低>25%与患者生存率增加显著相关。该研究所基于的假设是PX-12是Trx-1、HIF-1 α和肿瘤血管生成的有效抑制剂，在I期临床试验中具有低患者毒性和良好疗效。胰腺癌由于其高Trx-1和HIF-1 α水平和血管生成特性，是测试PX-12的疾病特异性活性的理想肿瘤。ProIX Pharmaceuticals此次SBIR更新的目的是：1）在单轮吉西他滨治疗失败的患者中研究PX-12对胰腺癌的疗效，2）确定PX-12对Trx的抑制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).