Drugs Targeting Dormant Tumors as Anti-Metastatic Agents

针对休眠肿瘤的抗转移药物

• 批准号: 7537741
• 负责人: Michael A. Ihnat
• 金额: $ 12.25万
• 依托单位: DORMATARG, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537741
• 关键词: Address; Aftercare; Animal Cancer Model; Animal Model; Bladder; Blood Vessels; Breast; Businesses; Cells; Cessation of life; Clinical Trials; Colon; Cultured Cells; Cytotoxic agent; DU145; Disease; Disseminated Malignant Neoplasm; Dose; Doxorubicin; Drug Delivery Systems; Dyes; Early Diagnosis; Eosine Yellowish; Excision; Extracellular Matrix; Floor; Fluorescence Microscopy; Foundations; Future; Genus Cola; Glioma; Goals; Growth; Human; Implant; Indium; Intellectual Property; Internet; Invasive; Knowledge; Label; Laboratories; Lead; Legal patent; Libraries; Licensing; Life; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mammary Neoplasms; Measurement; Measures; Methods; Micrometastasis; Modeling; Neoplasm Metastasis; Nude Mice; Numbers; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Preclinical Drug Evaluation; Primary Neoplasm; Process; Prostate; Prostatic Neoplasms; Protein Synthesis Inhibitors; Public Health; Rate; Recurrence; Research; Resistance; Schedule; Screening procedure; Services; Site; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solid Neoplasm; Staining method; Stains; Stomach Neoplasms; Structure-Activity Relationship; System; Techniques; Technology; Testing; Time; Tumor-Derived; United States Food and Drug Administration; Viola; Wool; Xenograft Model; Xenograft procedure; base; cancer cell; cell killing; chemotherapeutic agent; chemotherapy; concept; cytotoxic; density; design; fluorescence imaging; in vivo; killings; malignant breast neoplasm; matrigel; mouse model; neoplastic cell; novel; prevent; research study; size; small molecule libraries; tumor; tumor growth; tumor xenograft

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.

描述(申请人提供)：大多数癌症死亡发生在转移性肿瘤，而不仅仅是原发肿瘤。尽管过去十年中的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。大多数癌症的治愈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事情，并为患者赢得了几个月或几年的不同质量的生命。然而，药物筛选和临床试验范例的目标是识别缩小原发肿瘤、对转移疾病有效的药物，这些药物只是偶然出现的。该项目的总体假设是，利用被局部微环境抑制的转移癌细胞进行药物筛选的新方法将产生优先对抗休眠微转移的药物，最终导致抗转移药物的活性。我们使用中通量筛选系统和化学库来鉴定三种候选化合物--波尔多红(BDR)、羊毛紫2R(WV)和3，4，5，6-四溴荧光素(TBF)，它们对生长在正常抑制基质SISGel上的受抑制的膀胱、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，而它们在Matrigel上生长活跃。此外，在人膀胱癌侧翼异种移植模型中，我们已经表明，作为单一疗法，所有三种候选药物的节律剂量都能够减少被抑制的肿瘤的大小，其中一种化合物TBF也能够显著降低活跃生长的异种结肠移植的生长速度和血管。在第一个特定目标中，我们试图确定我们的三个候选化合物是否对另外两个肿瘤移植模型，即MDA-MB-435转移的乳腺和DU145转移的前列腺细胞，注射到无菌小鼠的侧翼，无论是在抑制性基质SISGEL或允许基质Matrigel，以评估原发肿瘤的生长和肿瘤的血管。在第二个具体目标中，我们将评估我们的三个候选化合物对原位移植的MDA-MB-435乳腺模型中肺转移的形成、原发肿瘤的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激活的转移肿瘤相比，对抑制的肿瘤具有活性，以及我们的药物是否可以用于预防转移，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，这一原则证明代表了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于原发肿瘤，而是转移性肿瘤，其中许多处于休眠状态多年，对化疗仍有抵抗力。我们认为，这些复发中的许多是由于癌细胞受到正常细胞外基质的抑制，正常的细胞外基质是细胞生长的“底板”。我们实验室的研究已经开发出一种新的筛选系统，可以识别可能杀死潜伏的癌细胞的药物。这项研究试图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奠定基础。