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

描述（由申请方提供）：瘤内异质性是实体瘤的常见特征。由于导致缺氧和葡萄糖供应减少的不良血管形成，肿瘤核心中的癌细胞通常变得休眠，并且比外层中活跃分裂的癌细胞对常用化疗剂更具抗性。这使得许多化疗剂无效，因为耐药肿瘤细胞从未被完全根除。因此，攻击实体瘤内部和外部区域的联合疗法更可能有效。我们和其他人最近鉴定了pyrvinium的抗肿瘤活性，在葡萄糖饥饿下对癌细胞具有选择性毒性。随后，我们合成了几种新的吡咯烷类似物，它们在葡萄糖剥夺下攻击癌细胞时具有类似的精确特异性，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种潜在抗癌靶点的转录诱导，即GRP 78（葡萄糖调节蛋白-78）及其类似物GRP 94。该提案的目的是评估作为单一药剂以及与标准护理（紫杉醇和降糖模拟剂2-脱氧葡萄糖（2DG））组合的新型类似物在体内治疗异种移植物模型中的人非小细胞肺癌（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。它还抑制新血管形成，从而增加肿瘤核心内的葡萄糖剥夺，这可能进一步增强pyrvinium/类似物的作用。2DG被认为是无毒的药物，目前也在与其他化疗药物如阿霉素和紫杉醇联合治疗癌症的临床评价中。它可以潜在地在肿瘤中创造人工葡萄糖剥夺环境，并使肿瘤对吡咯烷铵/类似物敏感。在拟定的研究中，我们将首先评估全身药物暴露，以选择用于体内疗效研究的先导吡啶类似物、给药途径和给药方案。接下来，我们将在肺癌的A549和NCI-H460异种移植物模型中评估吡维铵类似物作为单一药剂以及在紫杉醇和2DG的组合疗法中的抗肿瘤活性，并将结果与护理标准的结果进行比较。在这些研究中观察到的增强的抗肿瘤活性和/或增加的治疗窗将证明基于吡咯啉类似物的新药剂或新组合疗法作为潜在的新实体瘤治疗范例的可行性。公共卫生相关性：大多数实体瘤的内核通常缺乏营养素，如葡萄糖和氧气。因此，核心区域的癌细胞变得休眠，并对许多化疗剂产生耐药性。我们和其他人鉴定了一种驱虫药pyrvinium，其独特的优先细胞毒性在葡萄糖剥夺和体内抗肿瘤活性下对癌细胞的作用。我们进一步合成并评估了几种具有改进的“药物”样性质的吡咯烷衍生物。我们假设这些新的吡咯啉类似物作为单一药剂或与标准护理化疗剂和降血糖模拟剂组合对抗实体瘤将显著增强抗肿瘤活性。以下建议概述了检验这一假设的研究。这些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组合策略。

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.