Melanoma Therapy via peptide targeted alpha-radiation

描述（由申请人提供）：本提案的长期目标是开发和商业化一种有效的恶性黑色素瘤治疗剂。黑色素瘤的发病率正在上升。在美国，目前黑色素瘤的累积终生风险为1：75，约20%发生转移性疾病。转移性恶性黑色素瘤对目前的化疗和免疫治疗方案具有耐药性。播散性疾病患者的中位生存期为4-15个月。显然，需要一种新的有效的黑色素瘤治疗方法。 我们实验室开发了一种新的靶向黑色素瘤的α-黑素细胞刺激激素类似物。肽[DOTA]- ReCCMSH被设计为用α粒子发射放射性核素进行放射性标记。阿尔法粒子辐射是高度集中和非常强大的。只有少数α粒子发射的放射性核素是必要的，导致细胞死亡。放射性标记的[DOTA] ReCCMSH对黑色素瘤肿瘤细胞上存在的黑皮质素-1受体具有低纳摩尔亲和力，并且在结合后迅速内化。体内生物分布研究表明，放射性标记的[DOTA]- ReCCMSH显示出高肿瘤摄取和延长的肿瘤保留特性，以及快速清除动力学。 假设通过[DOTA]-ReCCMSH的α粒子发射放射性核素的黑素瘤特异性沉积将导致肿瘤细胞死亡。该II期STTR提案的具体目的是扩大高比活性[DOTA]-ReCCMSH的生产，并确定其在人和小鼠黑色素瘤动物模式中的最大耐受剂量和治疗功效。此外，将在小鼠和猪中使用非放射性标记的[DOTA]-ReCCMSH进行急性毒性研究，以证明肽靶向载体无毒。这些研究的结果将用于支持向美国食品药品监督管理局提交的研究性新药申请，以进行I期临床试验。 [DOTA]-ReCCMSH靶向α粒子发射辐射至转移性疾病患者的黑色素瘤肿瘤。

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to develop and commercialize an effective therapeutic agent for malignant melanoma. The incidence of melanoma is on the increase. The current cumulative life-time risk for melanoma is 1:75 in the US, with approximately 20% developing metastatic disease. Metastatic malignant melanoma is resistant to current chemo- and immuno- therapy regimens. Median survival for patients with disseminated disease ranges 4-15 months. Clearly there is a need for a new and efficacious melanoma treatments. A novel rhenium (Re) cyclized alpha-melanocyte stimulating hormone analog that targets melanoma has been developed in our laboratory. The peptide [DOTA]- ReCCMSH was designed to be radiolabeled with Alpha-particle emitting radionuclides. Alpha-particle radiation is highly focused and very potent. Only a few Alpha-particle emitting radionulcides are necessary to cause cell death. Radiolabeled [DOTA] ReCCMSH has low nanomolar affinity for the melanocortin-1 receptor present on melanoma tumor cells and is rapidly internalized upon binding. In vivo biodistrubution studies have shown that radiolabeled [DOTA]- ReCCMSH displays high tumor uptake and extended tumor retention properties coupled with rapid clearance kinetics. It is hypothesized that melanoma specific deposition of Alpha-particle emitting radionuclides by [DOTA]-ReCCMSH will result in tumor cell death. The specific aims of this Phase-ll STTR proposal are to scale up production of high specific activity [DOTA]-ReCCMSH and determine its maximum tolerated dose and therapeutic efficacy in human and mouse melanom animal modes. In addition, acute toxicity studies will be performed in mouse and swine with the non-radiolabeled [DOTA]-ReCCMSH to demonstrate that the peptide-targeting vehicle is non-toxic. The results of these studies will be used to support an investigational new drug application to the Food and Drug Administration for phase-l clinical trials. [DOTA]-ReCCMSH targeting of Alpha-particle emitting radiation to melanoma tumors in patients with metastatic disease.