Development of transporter targeted platinum drugs for neuroblastoma

DESCRIPTION (provided by applicant): Neuroblastoma (NB) is the most common solid tumor in children. Cisplatin, a first generation platinum analog, is first-line therapy in the treatment f NB and together with other drugs can result in cures of the diseasein about 50% of children. Unfortunately, cisplatin is highly toxic and causes irreversible kidney damage and hearing loss. Cisplatin induced hearing loss is especially devastating in children because it results in lifelong learning difficulties. Moreover,the toxicities are dose-limiting. That is, high dose cisplatin, whch may be curative, cannot be administered. Neuroblastoma has a high level of expression of the norepinephrine transporter (NET), an influx transporter responsible for accumulating norepinephrine in neuroendocrine cells. Designing therapeutic agents to be transported by NET therefore confers a promising approach to achieve targeted delivery of cytotoxic agents in tumor cells, which could result in higher activity and reduced toxicity to other tissues. In preliminary studies we designed, synthesized and tested platinum analogs to target NET. We identified two lead compounds, which have enhanced potencies in NB cell lines expressing higher NET expression levels. The overall goal of our studiesis to perform pharmacokinetics and dose-limiting toxicity studies of these compounds relative to cisplatin in mice. In addition, the goal o this study is to identify a maximum tolerated dose (MTD), which is the highest dose that does not cause any measurable toxicity in the mice. These studies are crucial for the next phase in determining the efficacy of the lead NET targeted compounds in neuroblastoma mouse model. The proposed studies will confer high commercialization potential for the two lead compoundssince both analogs would be poised for critical Investigational New Drug (IND) enabling studies PUBLIC HEALTH RELEVANCE: The proposed research will lead to the development of a new medicine for the treatment of a life- threatening solid tumor inchildren, neuroblastoma. If successful, this research will lead to the development of a highly effective drug with fewer side effects and in particular, a drug that will not cause deafness, a common side effect of current therapies. The development of thismedication will make an enormous contribution to the treatment of the most common solid tumor in children