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

描述(申请人提供)：肿瘤内的异质性是实体肿瘤的共同特征。由于血管生成不良，导致缺氧和葡萄糖供应减少，肿瘤核心的癌细胞通常变得休眠，对常用化疗药物的抵抗力比活跃的外层癌细胞更强。这使得许多化疗药物无效，因为耐药肿瘤细胞永远不会完全根除。因此，同时攻击实体瘤内部和外部区域的联合疗法更有可能有效。我们和其他人最近确定了吡喃的抗肿瘤活性，对葡萄糖饥饿下的癌细胞具有选择性毒性。随后，我们合成了几个新的吡喃类似物，它们在葡萄糖剥夺条件下攻击癌细胞具有类似的精致特异性，但具有更好的类药物特性。此外，我们还发现，在缺糖条件下，吡喃类化合物特异性地阻断了两个潜在的抗癌靶点，即GRP78(葡萄糖调节蛋白-78)及其类似物GRP94的转录诱导。这项建议的目的是评估新的类似物作为单一药物并联合标准护理(紫杉醇和体内低血糖模拟剂2-脱氧葡萄糖(2DG))治疗异种移植模型中的人非小细胞肺癌(NSCL)的效果。紫杉醇在清除实体瘤外层活跃分裂的癌细胞方面非常有效。它还抑制新血管的形成，从而增加肿瘤核心内的葡萄糖剥夺，这可能会进一步增强吡喃/类似物的效果。2DG被认为是无毒的，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。它有可能在肿瘤中创造人为的葡萄糖剥夺环境，并使肿瘤对吡喃/类似物增敏。在拟议的研究中，我们将首先评估全身药物暴露，以便选择吡喃铅类似物、给药途径和剂量方案进行体内疗效研究。接下来，我们将评估吡喃类似物作为单一药物以及紫杉醇和2DG联合治疗对A549和NCI-H460肺癌移植瘤模型的抗肿瘤活性，并将结果与标准护理进行比较。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基于吡喃类似物的新药物或新的联合疗法作为一种潜在的新的实体肿瘤治疗范例的可行性。与公共健康相关：大多数实体肿瘤的核心通常缺乏葡萄糖和氧气等营养物质。因此，核心区的癌细胞处于休眠状态，并对许多化疗药物产生抗药性。我们和其他人确认了吡喃，一种抗蠕虫药物，在体内对葡萄糖剥夺下的癌细胞具有独特的优先细胞毒性和抗肿瘤活性。我们进一步合成并评价了几个具有改进的类似药物性质的吡喃类似物。我们推测，这些新的吡喃类似物作为单一药物或与标准护理化疗药物和降血糖模拟药物联合使用将显著增强抗实体肿瘤的活性。下面的建议概述了检验这一假设的研究。拟议研究的积极结果可能会导致发现一类具有独特抗肿瘤特性的新型药物，以及用于治疗实体瘤的新的联合策略。

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.