Mitochondrial Targeted Metastatic Melanoma Therapy

描述（申请人提供）：转移性黑色素瘤预后差，10年生存率<10%。一个主要的潜在原因是，由于对当前疗法产生耐药性，没有全身性治疗提供持久的益处。提出了一种治疗黑色素瘤的新的潜在策略，该策略利用癌细胞和非恶性细胞之间的氧化代谢差异来选择性地杀死黑色素瘤细胞。这种新的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，TPP为基础的化合物可以被设计为选择性地杀死黑色素瘤细胞相对于正常的黑色素细胞。我们进一步表明，TPP为基础的化合物可以被设计为促进黑色素瘤细胞死亡，通过增加氧化应激和效果可以增强与氢过氧化物代谢的抑制剂。此外，口服给药的10-TPP显着抑制小鼠黑色素瘤肿瘤的生长，没有可测量的毒性。这项研究是创新的，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提供一种新的治疗模式，可能为患者提供持久的益处。中心假设是，可以开发基于TPP的疗法，通过利用黑素瘤细胞相对于非恶性细胞的氧化代谢差异，相对于非恶性细胞选择性地杀死黑素瘤细胞。该假设将在三个特定目标中进行测试：SA 1：确定TPP结构活性关系（SAR）和机制，相对于非恶性黑素细胞，选择性地促进黑色素瘤细胞的细胞死亡和增加氧化应激。SA2：确定当与标准临床相关化疗剂和/或氢过氧化物代谢抑制剂组合时，基于TPP的药物选择性增强黑色素瘤细胞杀伤的潜力。SA3：确定TPP SAR以及可能导致开发异种移植模型中人黑色素瘤的有效联合模式疗法的给药途径。 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相对于正常黑色素细胞的死亡，并建立对基于TPP的组合疗法的详细机制理解，最终可以导致用于治疗转移性黑色素瘤的耐受性良好的方案，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.