Mitochondrial Targeted Metastatic Melanoma Therapy

描述(申请人提供)：转移性黑色素瘤预后很差，10年存活率为10%。一个主要的潜在原因是，由于对当前疗法的耐药性的产生，没有系统的治疗提供持久的好处。一种新的治疗黑色素瘤的潜在策略被提出，它利用癌细胞和非恶性细胞之间氧化代谢的差异来选择性地杀死黑色素瘤细胞。这种新的线粒体靶向干预利用一类基于三苯基膦(TPP)的小分子，相对于正常细胞选择性地增加超氧化物水平和氧化应激诱导的黑色素瘤细胞杀伤。我们的初步数据表明，与正常的黑素细胞相比，基于TPP的化合物可以被设计成选择性地杀死黑色素瘤细胞。我们进一步证明，基于TPP的化合物可以通过增加氧化应激来促进黑色素瘤细胞的死亡，并且这种作用可以通过氢过氧化氢代谢的抑制剂来增强。此外，口服10-TPP显著抑制小鼠黑色素瘤的生长，没有可测量的毒性。这项研究具有创新性，因为没有其他疗法针对黑色素瘤细胞与正常细胞线粒体氧化代谢的差异来选择性地杀死黑色素瘤细胞。这项研究意义重大，因为这些目标的成功可以为转移性黑色素瘤带来一种新的治疗模式，可能会为患者提供持久的好处。中心假设是基于TPP的疗法可以通过利用黑色素瘤细胞相对于非恶性细胞氧化代谢的差异来选择性地杀死黑色素瘤细胞相对于非恶性细胞。这一假设将在三个具体目标中得到验证：SA1：确定TPP结构活性关系(SAR)和选择性促进黑色素瘤细胞死亡和增加黑色素瘤细胞相对于非恶性黑素细胞的氧化应激的机制。SA2：确定基于TPP的药物在与标准的临床相关化疗药物和/或氢过氧化氢代谢抑制剂结合时选择性增强黑色素瘤细胞杀伤力的潜力。SA3：确定TPP SAR以及可能导致开发有效的联合疗法治疗异种移植模型中的人类黑色素瘤的给药途径。这些研究的成功完成将确定TPP药物的关键设计特征，这些药物选择性地促进黑色素瘤细胞与正常黑素细胞的死亡，并建立对基于TPP的联合疗法的详细机制理解，这些联合疗法最终可能导致耐受性良好的转移性黑色素瘤治疗方案，可以推进到人类临床试验。

DESCRIPTION (provided by applicant): Metastatic melanoma has a dismal prognosis, with 10-year survival rates of < 10%. A major underlying reason for this is that no systemic treatment provides durable benefit due to development of resistance to current therapies. A new potential strategy for treating melanoma is proposed that exploits differences in oxidative metabolism between cancerous and non-malignant cells to selectively kill melanoma cells. This new mitochondrial-targeted intervention utilizes a class of small molecules, based on triphenylphosphonium (TPP), to selectively increase superoxide levels and oxidative stress-induced melanoma cell killing, relative to normal cells. Our preliminary data demonstrate that TPP-based compounds can be designed to selectively kill melanoma cells relative to normal melanocytes. We further show that TPP-based compounds can be designed to promote melanoma cell death via increased oxidative stress and that the effect can be enhanced with inhibitors of hydroperoxide metabolism. In addition, orally-administered 10-TPP significantly suppressed melanoma tumor growth in mice, with no measurable toxicity. This research is innovative because no other therapy targets differences in mitochondrial oxidative metabolism in melanoma cells vs normal cells to selectively kill melanoma cells. This research is significant because the success of these aims can result in a new treatment paradigm for metastatic melanoma that can potentially provide durable benefit to patients. The central hypothesis is that TPP-based therapies can be developed to selectively kill melanoma cells relative to non-malignant cells by exploiting differences in oxidative metabolism of melanoma cells relative to non-malignant cells. This hypothesis will be tested in three Specific Aims: SA1: Identify TPP structure activity relationships (SAR) and mechanisms that selectively promote cell death and increase oxidative stress in melanoma cells, relative to non-malignant melanocytes. SA2: Determine the potential for TPP based drugs to selectively enhance melanoma cell killing when combined with standard clinically relevant chemotherapeutic agents and/or inhibitors of hydroperoxide metabolism. SA3: Identify TPP SAR as well as routes of administration that could result in the development of effective combined-modality therapies for human melanomas in xenograft models. Successful completion of these studies will identify key design traits of TPP-drugs that selectively promote melanoma cell death vs. normal melanocytes, as well as establish a detailed mechanistic understanding of TPP-based combination therapies that can ultimately lead to well-tolerated protocols for treating metastatic melanoma that can be advanced to human clinical trials.