Drugs Targeting Dormant Tumors as Anti-Metastatic Agents

描述（由申请人提供）：大多数癌症死亡发生于转移性肿瘤，而不仅仅是原发肿瘤。尽管在过去的十年里，许多新药都是针对肿瘤的，但总体癌症存活率的变化并不大。大多数治愈癌症的方法仍然是通过手术和早期发现，化疗药物只是推迟了不可避免的结果，为病人延长了几个月或几年的生命，但质量参差不齐。然而，药物筛选和临床试验模式旨在确定缩小原发肿瘤的药物，同时对偶然出现的转移性疾病有效。本项目的总体假设是，一种利用局部微环境抑制的转移性癌细胞进行药物筛选的新方法将产生对休眠微转移具有优先活性的药物，最终导致对转移具有活性的药物。我们使用中等流量筛选系统和化学文库确定了三种候选化合物-波尔多红（BDR）， Wool Violet 2R （WV）和3,4,5,6-四溴荧光素（TBF），它们对在正常抑制基质SISgel上生长的膀胱，前列腺，乳腺，胶质瘤和胃肿瘤细胞具有显著的抗增殖选择性，与在Matrigel上生长的活性对照物相比。此外，在人类膀胱癌侧翼异种移植物植入模型中，我们已经表明，三种候选药物的单药剂量能够减小抑制肿瘤的大小，其中一种化合物TBF也能够显著降低生长活跃的结肠异种移植物的生长速度和血管性。在第一个特定目标中，我们试图确定我们的三种候选化合物是否对另外两种肿瘤异种移植模型（MDA-MB-435转移性乳腺细胞和DU145转移性前列腺细胞）有活性，将其注射到胸腺小鼠的侧翼，在抑制基质SISgel或允许基质Matrigel中，并评估原发肿瘤生长和肿瘤血管性。在第二个特定目标中，我们将评估我们的三种候选化合物对原位植入MDA-MB-435乳房模型中肺转移灶的形成、原发肿瘤生长和肿瘤血管的影响。总之，这些研究将证明我们的候选化合物与体内活化的转移性肿瘤相比，对抑制的转移性肿瘤具有活性，以及我们的药物是否可用于预防转移，目前转移通常导致患者死亡。通过将细胞培养研究与人类癌症的动物模型联系起来，这一原理证明是我们商业计划中的一个基本要素。公共卫生相关性：大多数癌症死亡不是由原发肿瘤引起的，而是由转移性肿瘤引起的，其中许多肿瘤潜伏多年，但对化疗仍有耐药性。我们认为，许多这些复发是由于癌细胞被正常的细胞外基质（细胞生长的“底”）抑制所致。我们实验室的研究已经开发出一种新的筛选系统，可以识别可能杀死休眠癌细胞的药物。这项研究旨在证明在细胞培养中看到的杀伤活动发生在癌症的动物模型中，这将为我们的商业模式提供证据。

DESCRIPTION (provided by applicant): Most cancer deaths occur from metastatic tumors rather than from the primary tumor alone. Although many of the new drugs in the past decade are directed against tumors , changes in overall cancer survival have only been modest. Most cures of cancer are still through surgery and early detection, with chemotherapeutic agents simply delaying the inevitable and buying the patient some number of months or years of life of varying quality. Yet, the drug screening \and clinical trial paradigms are aimed at identifying drugs that shrink primary tumors with efficacy against metastatic disease emerging only fortuitously. The overall hypothesis of this project is that a novel drug screening approach using metastatic cancer cells suppressed by a local microenvironment would yield drugs that are preferentially active against dormant micrometastases, leading ultimately to drugs active against metastases. We used a medium throughput screening system and a chemical library to identify three candidate compounds - Bordeaux Red (BDR), Wool Violet 2R (WV) and 3,4,5,6-tetrabromofluorescein (TBF) which have significant anti-proliferative selectivity against suppressed bladder, prostate, breast, glioma and gastric tumor cells grown on a normal suppressive matrix called SISgel as compared to their actively growing counterparts on Matrigel. Further, in a human bladder cancer flank xenograft implant model, we have shown that metronomic dosing of all three candidate agents as monotherapy is capable of decreasing the size of suppressed tumors and that one of these compounds, TBF, is also capable of significantly reducing the growth rate and perhaps the vascularity of an actively growing colon xenograft. In the first specific aim, we seek to determine whether our three candidate compounds are active against two additional tumor xenograft models, MDA-MB-435 metastatic breast and DU145 metastatic prostate cells, injected into the flank of athymic mice either in the suppressive matrix SISgel or on the permissive matrix Matrigel, with primary tumor growth and tumor vascularity assessed. In the second specific aim the effect of our three candidate compounds on the formation lung metastases, primary tumor growth, and tumor vascularity in the orthotopically implanted MDA-MB-435 breast model will be assessed. Together these studies will give proof of principle that our candidate compounds are active against suppressed as compared to activated metastatic tumors in vivo and whether our agents can be used to prevent metastases, which currently often end up leading to patient death. This proof of principle represents an essential element in our business plan by connecting cell culture studies with animal models of human cancer. PUBLIC HEALTH RELEVANCE: Most cancer deaths are not due to the primary tumor but are due to metastatic tumors, many of which lie dormant for years while remaining resistant to chemotherapy. We believe that many of these recurrences are due to cancer cells that have been suppressed by a normal extracellular matrix, the "floor" that cells grow on. Research in our laboratories have developed a novel screening system that identifies drugs that potentially can kill dormant cancer cells. This study is seeking to prove that the killing activity seen in cell culture occurs in animal models of cancer, which will establish proof for our business model.