Safety/Efficacy of Liposomal Reversan, a novel MRP1 modulator for Cancer Therapy

描述（由申请人提供）：对抗癌症的主要问题之一是肿瘤对当前癌症治疗的固有或获得性抗性，特别是与多药转运蛋白（MDT;例如P-糖蛋白（P-gp）和多药相关蛋白（MRP 1））相关的抗性。早期P-gp抑制剂的临床失败，导致非特异性毒性或与常规化疗药物的药代动力学相互作用，显著降低了制药公司开发MDT抑制剂的积极性。然而，与这些转运蛋白相关的耐药性仍然是一个严重的问题，必须利用从以前的失败中获得的知识和经验重新研究针对这些蛋白质的抑制剂的开发，以显着增加成功的机会。该提案中概述的研究围绕着Reversan的优化，Reversan是一种MRP1抑制剂，在没有毒性的情况下超过了许多已知的MDT抑制剂的活性。我们的目标是将Reversan开发为与标准化疗一起使用的抗癌剂，以使用Reversan或Reversan-药物组合的脂质体制剂来改善这些常规药剂的功效。用于体内递送的脂质体媒介物为分子的肿瘤递送提供了重要特征，包括降低的全身清除率、由于正常组织对配制药剂的摄取减少而导致的降低的全身毒性，以及同时由于肿瘤对配制药剂的摄取增加而导致的改善的功效。根据该提案生成的数据将构成涉及其他常规药物的研究的合理设计以及使用Reversan组合的临床试验的基础，以评估Reversan作为抗癌药物的潜力。该项目的重要性在于它有可能为药物难治性癌症（如神经母细胞瘤）确定新的治疗策略，这些癌症目前由于MRP1或MDT引起的固有和获得性耐药性而面临有限的治疗选择。公共卫生相关性：对抗癌症的主要问题之一是对当前癌症治疗的耐药性，特别是由将标准癌症药物泵出癌细胞的多药转运蛋白引起的耐药性。这些转运蛋白的抑制剂，如Reversan-该提案的重点，当与标准化疗一起使用时，通过允许药物停留在肿瘤细胞中，可以大大增加对肿瘤细胞的杀伤。因此，Reversan有可能改善因多药耐药而治疗选择有限的患者的临床结局。

DESCRIPTION (provided by applicant): One of the major problems in the fight against cancer is the intrinsic or acquired resistance of tumors to current cancer treatments, particularly that associated with multidrug transporters (MDT; e.g. P-glycoprotein (P-gp) and the multidrug associated protein (MRP1)). The clinical failures of early P-gp inhibitors, which either caused non-specific toxicity or pharmacokinetic interactions with conventional chemotherapy agents, has significantly diminished the enthusiasm of pharmaceutical companies to develop MDT inhibitors. Nevertheless, drug resistance associated with these transporters is still a serious problem and the development of inhibitors against these proteins must be revisited using the knowledge and experience gained from previous failures to significantly increase the chances for success. The studies outlined in this proposal center around the optimization of Reversan, a MRP1 inhibitor that surpasses the activity of many known inhibitors of this MDT in the absence of toxicity. Our goal is to develop Reversan as an anti-cancer agent to be used together with standard chemotherapy to improve the efficacy of these conventional agents using liposomal formulations of Reversan or Reversan-drug combinations. Liposomal vehicles for in vivo delivery offer important features for tumor delivery of molecules, including decreased systemic clearance rates, decreased systemic toxicity as a result of decreased uptake of formulated agents by normal tissues and at the same time improved efficacy due to increased uptake of the formulated agents by tumors. The data generated under this proposal will form the basis for the rational design of studies involving other conventional agents as well as for clinical trials using Reversan combinations to assess the potential of Reversan as an anti-cancer agent. The significance of this project lies in its potential for identifying new treatment strategies for drug refractory cancers, such as neuroblastoma, that are currently faced with limited treatment options due to inherent and acquired drug resistance caused by MRP1 or MDTs in general. PUBLIC HEALTH RELEVANCE: One of the major problems in the fight against cancer is resistance to current cancer treatments, particularly resistance caused by multidrug transporters that pump standard cancer drugs out of cancer cells. Inhibitors of these transporters, such as Reversan-the focus of this proposal, when used together with standard chemotherapy should greatly increase the killing of tumor cells by allowing the drugs to stay in tumor cells. Thus, Reversan has the potential to improve the clinical outcome for patients with limited treatment options due to multidrug resistance.