Mitochondrial Targeted Metastatic Melanoma Therapy

线粒体靶向转移性黑色素瘤治疗

基本信息

批准号：
8886965
负责人：
Michael King Schultz
金额：
$ 15.06万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-02 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8886965
关键词：
Antioxidants Apoptosis Auranofin BRAF gene Biological Assay Buthionine Sulfoximine Cancerous Cell Death Cell Death Inhibition Cell Respiration Cells Clinical Trials Combination Drug Therapy Combined Modality Therapy Complex DNA Sequence Alteration Dacarbazine Data Development Disease Drug Kinetics Drug resistance Effectiveness Electron Transport FDA approved Glucose Glutathione Disulfide Health Human Hydrogen Peroxide In Situ Nick-End Labeling In Vitro Incidence Intervention Intraperitoneal Injections Lead Measurable Melanoma Cell Metabolism Metastatic Melanoma Methods Mitochondria Mus Necrosis Non-Malignant Normal Cell Operative Surgical Procedures Oral Organ Oxidation-Reduction Oxidative Stress Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Protocols documentation Radiolabeled Relative (related person)Research Resistance development Route Structure Structure-Activity Relationship Superoxides Survival Rate Testing Therapeutic Agents Toxic effect Treatment Efficacy Trypan Blue Variant Xenograft Model base cancer cell cancer diagnosis cell killing chemotherapeutic agent clinically relevant cytotoxicity design drug mechanism drug structure effective therapy falls glucose metabolism in vivo inhibitor/antagonist innovation killings melanocyte melanoma mitochondrial membrane neoplastic cell novel outcome forecast oxidation oxidative damage radiotracer research study response small molecule standard measure standard of care success targeted treatment trait tumor tumor growth

项目摘要

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.

描述（由申请人提供）：转移性黑色素瘤的预后令人沮丧，10年的存活率<10％。造成这种情况的一个主要根本原因是，由于对当前疗法的抵抗力发展，没有系统治疗可提供持久的益处。提出了一种治疗黑色素瘤的新潜在策略，它可以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措施基于Triphenylphosponium（TPP）利用一类小分子，以选择性地增加了超氧化物水平和相对于正常细胞的氧化应激诱导的黑色素瘤细胞杀死。我们的初步数据表明，基于TPP的化合物可以设计为选择性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，基于TPP的化合物可以通过增加的氧化应激来促进黑色素瘤细胞死亡，并且可以通过氢过氧代谢的抑制剂来增强效果。此外，口服的10-TPP在小鼠中显着抑制了黑色素瘤的肿瘤生长，没有可测量的毒性。这项研究具有创新性，因为没有其他治疗目标是黑色素瘤细胞与正常细胞中线粒体氧化代谢的差异以选择性地杀死黑色素瘤细胞。这项研究很重要，因为这些目标的成功可能会导致转移性黑色素瘤的新治疗范式，从而有可能为患者提供持久的好处。中心假设是，可以开发基于TPP的疗法来选择性地杀死黑色素瘤细胞相对于非恶性细胞，通过利用黑色素瘤细胞相对于非恶性细胞的氧化代谢差异。该假设将以三个特定的目的进行检验：SA1：与非恶性黑色素细胞相对于非恶性细胞的TPP结构活性关系（SAR）和机制，这些机制有选择地促进细胞死亡并增加黑素瘤细胞中的氧化应激。 SA2：确定基于TPP的药物与标准临床相关的化学治疗剂和/或氢过氧化物代谢的抑制剂相结合时，可以选择性地增强黑色素瘤细胞杀伤。 SA3：确定TPP SAR以及可能导致异种移植模型中人类黑色素瘤有效合并模式疗法的给药途径。这些研究的成功完成将确定TPP-drugs的关键设计特征，这些特征有选择地促进黑色素瘤细胞死亡与正常的黑色素细胞，并建立对基于TPP的组合疗法的详细机械理解，最终可以为治疗转移性黑色素瘤提供良好的方案，从而可以将其推进到人类临床试验中。