Novel Receptor-Targeting Theranostic Peptides for Prostate Cancer

描述（由申请人提供）：前列腺癌是男性中最常见的癌症，也是美国男性癌症相关死亡的第二大原因。不幸的是，对于转移性前列腺癌没有治愈的治疗方法。前列腺癌的早期诊断和及时手术切除为患者提供了治愈或延长生存期的最佳机会。目前的ProstaScint(R) SPECT（单光子发射计算机断层扫描）和[18F] FDG （2-[18F]氟-2-脱氧-d -葡萄糖）PET（正电子发射断层扫描）成像由于缺乏特异性而使用有限。为了提高前列腺癌的检测准确性，提高前列腺癌的治疗效果，迫切需要新的靶向受体的诊断和治疗药物。我们的策略是提高前列腺癌的检测准确性和提高治疗效果，重点是开发新的治疗（诊断和治疗）177lu标记的促性腺激素释放激素（GnRH）肽，以靶向GnRH受体（gnrrs）。由于GnRHR在人类前列腺癌细胞和标本上过表达，而在健康前列腺细胞上低表达，而在大多数正常组织细胞上不表达，因此GnRHR是本项目开发有效的前列腺癌特异性成像探针的独特目标。最近，我们首次发现了一种新的GnRH肽{111In-DOTA-Ahx-(D-Lys6-GnRH)}作为人类前列腺癌检测的成像探针。最近，我们发现D-Phe的引入显著提高了DOTA-D-Phe-Ahx-(D- lys6 - gnrh) （7.6 nM）的GnRHR结合亲和力，比DOTA-Ahx-(D- lys6 - gnrh) （36.1 nM）提高了4.8倍。在这个项目中，我们将进行构效关系（SAR）研究，以确定更有效的177lu标记的GnRH肽，用于基于独特的dota - d - ph - ahx -(D-Lys6-GnRH)结构的前列腺癌成像和治疗。具体而言，我们将在体外和体内合成并评价8种具有中性碳氢化合物和氨基酸连接体的新型GnRH肽。我们假设GnRH肽可以特异性结合GnRH受体，并将治疗性放射性核素（177Lu）靶向于人前列腺癌细胞，用于前列腺癌的成像和治疗。我们积极的初步结果有力地支持了我们的假设和研究设计。重要的是，我们组建了一支强大的多学科研究团队，拥有成熟的专业知识，非常适合开展这一激动人心的转化项目。该项目的成功将为前列腺癌检测和治疗的新型治疗药物的设计提供新的见解，并为未来（未来方向）开辟低能β -辐射（177Lu）、高能β -辐射（90Y）和α -辐射{212Pb/212Bi和213Bi}治疗人类前列腺癌的途径，为患者提供个性化的治疗药物，以满足个体需求（即肿瘤大小或转移）。小说鉴定

DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed cancer in males and the second leading cause of cancer- related death among men in the United States. Unfortunately, no curative treatment exists for metastatic prostate cancer. Early diagnosis of prostate cancer followed by prompt surgical removal provides patients the best opportunities for cures or prolonged survivals. Current ProstaScint(R) SPECT (single photon emission computed tomography) and [18F] FDG (2-[18F] fluoro-2-deoxy-D-glucose) PET (positron emission tomography) imaging have limited use by lack of specificity. Novel receptor-targeting diagnostic and therapeutic agents are urgently needed to improve the detection accuracy and enhance the therapeutic efficacy of prostate cancer. Our strategy to improve the detection accuracy and enhance the therapeutic efficacy of prostate cancer focuses on developing novel theranostic (diagnostic & therapeutic) 177Lu-labeled gonadotropin-releasing hormone (GnRH) peptides to target the GnRH receptors (GnRHRs). GnRHR is a distinct target in this project for developing effective prostate cancer-specific imaging probes due to its over-expression on human prostate cancer cells and specimens, and dramatic low expression on healthy prostate cells and no expression on most normal tissue cells. Recently, we have firstly identified a novel GnRH peptide {111In-DOTA-Ahx-(D-Lys6-GnRH)} as an imaging probe for human prostate cancer detection. Very recently, we found that the introduction of D- Phe dramatically improved the GnRHR binding affinity of DOTA-D-Phe-Ahx-(D-Lys6-GnRH) (7.6 nM) by 4.8- fold as compared to DOTA-Ahx-(D-Lys6-GnRH) (36.1 nM). In this project, we will perform structure-activity relationship (SAR) studies to identify more potent 177Lu-labeled GnRH peptides for prostate cancer imaging and therapy based on the unique DOTA-D-Phe-Ahx-(D-Lys6-GnRH) construct. Specifically, we will synthesize and evaluate 8 novel GnRH peptides with neutral hydrocarbon and amino acid linkers in vitro and in vivo. We hypothesize that the GnRH peptides can specifically bind the GnRH receptors and target theranostic radionuclide (177Lu) to human prostate cancer cells for prostate cancer imaging and therapy. Our positive preliminary results strongly support our hypothesis and research design. Importantly, we have assembled a strong multidisciplinary research team with established expertise that is uniquely suited to carry out this exciting translational project. The success of this project will provide a new insight into the design of novel theranostic agents for prostate cancer detection and treatment, as well as open the avenue of treating human prostate cancer with low-energy beta-radiation (177Lu), high-energy beta-radiation (90Y) and alpha- radiation {212Pb/212Bi and 213Bi} in the future (future directions), providing patients with personalized therapeutic agents to meet individual need (i.e. tumor size or metastases). Identification of novel theranostic peptides promoted by this project will pave the way for evaluation of this novel class of peptides in US FDA-approved clinical trials in the future, enhancing the opportunities of cures to patients with metastatic prostate cancer.