In vivo efficacy evaluation of pyrvinium analogs in non small cell lung (NSCL) ca

吡维铵类似物在非小细胞肺 (NSCL) 中的体内疗效评估

• 批准号: 7486131
• 负责人: DeHua Yu
• 金额: $ 10.13万
• 依托单位: ITHERX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-19 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486131
• 关键词: A549; Adriamycin PFS; Animal Model; Anthelmintics; Blood Vessels; Caring; Cells; Characteristics; Class; Clinical; Combined Modality Therapy; Common Neoplasm; Condition; Cytotoxic agent; Data; Development; Dose; Drug Exposure; Environment; Evaluation; Funding; GRP94; Glucose; Glycolysis; Heterogeneity; Human; Hypoglycemia; Hypoxia; In Vitro; Lead; Lung; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Mediating; Medical; Medicine; Modeling; Mono-S; Morbidity - disease rate; New Agents; Non-Small-Cell Lung Carcinoma; Normal Cell; Nutrient; Outcome; Oxygen; Paclitaxel; Pathway interactions; Pharmaceutical Preparations; Property; Proteins; Public Health; Resistance; Resistance development; Role; Route; Solid Neoplasm; Specificity; Standards of Weights and Measures; Starvation; Testing; Therapeutic; Toxic effect; Treatment Protocols; Vascularization; Work; Xenograft Model; analog; antiangiogenesis therapy; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; cytotoxicity; deprivation; efficacy evaluation; glucose-regulated proteins; improved; in vivo; in vivo Model; killings; lung xenograft; man; mortality; neoplastic cell; neurotensin mimic 2; novel; novel strategies; novel therapeutics; pre-clinical; research clinical testing; response; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): Intratumoral heterogeneity is a common characteristic of solid tumors. Due to poor vascularization that leads to hypoxia and reduced glucose supply, cancer cells in the tumor core generally become dormant and more resistant to commonly used chemotherapeutic agents than actively dividing cancer cells in the outer layers. This renders many chemotherapeutic agents ineffective as the resistant tumor cells are never completely eradicated. Therefore, combination therapies that attack both inner and outer regions of the solid tumor are more likely to be effective. We and others recently identified pyrvinium for its anti-tumor activity with selective toxicity against cancer cells under glucose starvation. Subsequently we have synthesized several novel pyrvinium analogs with the similar exquisite specificity in attacking cancer cells under glucose deprivation but with improved drug-like properties. Additionally, we found that pyrvinium/analogs specifically block the transcriptional induction of two potential anti-cancer targets, namely GRP78 (glucose-regulated protein-78) and its analog GRP94, under glucose deprivation. The objective of this proposal is to assess novel analog as single agent and in combination with standard of care (Taxol and hypoglycemia-mimicking agent 2-deoxygluocse (2DG) in vivo to treat human non-small cell lung (NSCL) cancer in xenograft models. Taxol is highly effective in eradicating actively dividing cancer cells at the outer layer of the solid tumor. It also inhibits new blood vessel formation, thus increasing glucose deprivation within the core of the tumor, which could potentially further enhance the effect of pyrvinium/ analogs. 2DG is considered nontoxic agent and is also currently under clinical evaluation for cancer treatment in combination with other chemotherapy such as adriamycin and Taxol. It can potentially create artificial glucose deprivation environment in tumor and sensitize tumors to pyrvinium/analogs. In the proposed studies, we will first assess the systemic drug exposure in order to select the lead pyrvinium analog, route of administration and dose regimen for in vivo efficacy studies. Next, we will evaluate the anti-tumor activity of of pyrvinium analog as single agent and in combination therapy of Taxol and 2DG in A549 and NCI-H460 xenograft models of lung cancer, and compare the results to that of standard of care. The enhanced anti- tumor activity and/or increased therapeutic window observed in these studies would demonstrate the feasibility of a new agent or a new combination therapy based on pyrvinium analogs as a potentially new solid tumor treatment paradigm. PUBLIC HEALTH RELEVANCE: The inner core of most solid tumors is generally deprived of nutrients such as glucose and oxygen. Hence cancer cells in the core region become dormant and develop resistance to many chemotherapeutic agents. We and others identified pyrvinium, an antihelminthic medicine, for its unique preferential cytotoxicity to cancer cells under glucose deprivation and anti-tumor activity in vivo. We further synthesized and evaluated several pyrvinium derived analogs with improved "drug" like properties. We hypothesize that these new pyrvinium analogs would significantly enhance anti-tumor activity as a single agent or in combination with standard of care chemotherapeutic agents and hypoglycemia-mimicking agent against solid tumors. The following proposal outlines studies to test this hypothesis. The positive outcomes from the proposed studies may lead to the discovery of a novel class of agents with unique anti-tumor properties, as well as new combination strategies, for the treatment of solid tumors.

描述（由申请人提供）：瘤内异质性是实体瘤的共同特征。由于血管化不良导致缺氧和葡萄糖供应减少，肿瘤核心的癌细胞通常处于休眠状态，对常用化疗药物的抵抗力比外层活跃分裂的癌细胞更强。这使得许多化疗药物无效，因为耐药的肿瘤细胞从未被完全根除。因此，同时攻击实体瘤内部和外部区域的联合治疗更有可能有效。我们和其他人最近发现吡啶具有抗肿瘤活性，对葡萄糖饥饿下的癌细胞具有选择性毒性。随后，我们合成了几种新的吡啶类似物，它们在葡萄糖剥夺下攻击癌细胞时具有相似的精细特异性，但具有改进的药物样性质。此外，我们发现pyrvinium/类似物在葡萄糖剥夺下特异性阻断两个潜在抗癌靶点GRP78（葡萄糖调节蛋白-78）及其类似物GRP94的转录诱导。本提案的目的是评估新的类似物作为单一药物和联合标准护理药物（紫杉醇和低血糖模拟剂2-脱氧葡萄糖（2DG））在体内治疗异种移植模型中的人类非小细胞肺癌（NSCL）。紫杉醇在根除实体瘤外层活跃分裂的癌细胞方面非常有效。它还会抑制新血管的形成，从而增加肿瘤核心的葡萄糖剥夺，这可能会进一步增强pyrvinium/类似物的作用。2DG被认为是无毒药物，目前也在与阿霉素和紫杉醇等其他化疗药物联合治疗癌症的临床评估中。它可能在肿瘤中创造人工葡萄糖剥夺环境，并使肿瘤对吡啶/类似物敏感。在拟建的研究中，我们将首先评估全身药物暴露，以选择铅吡啶类似物、给药途径和给药方案进行体内疗效研究。接下来，我们将在A549和NCI-H460肺癌异种移植模型中，评价pyrvinium类似物单药和紫杉醇与2DG联合治疗的抗肿瘤活性，并与标准治疗的结果进行比较。在这些研究中观察到的增强的抗肿瘤活性和/或增加的治疗窗口将证明一种新的药物或基于吡啶类似物的新的联合治疗作为一种潜在的新的实体肿瘤治疗范例的可行性。公共卫生相关性：大多数实体肿瘤的内核通常缺乏营养物质，如葡萄糖和氧气。因此，核心区域的癌细胞处于休眠状态，并对许多化疗药物产生耐药性。我们和其他人发现吡啶是一种抗蠕虫药物，在体内葡萄糖剥夺和抗肿瘤活性下对癌细胞具有独特的优先细胞毒性。我们进一步合成并评价了几种具有改进的“药物”性质的吡啶衍生物类似物。我们假设这些新的吡啶类似物作为单一药物或与标准化疗药物和低血糖模拟药物联合使用，对实体瘤的抗肿瘤活性显著增强。下面的建议概述了验证这一假设的研究。所提出的研究的积极结果可能导致发现一类具有独特抗肿瘤特性的新型药物，以及用于治疗实体肿瘤的新的联合策略。