Novel Receptor-Targeting Theranostic Peptides for Prostate Cancer

描述(申请人提供)：前列腺癌是美国男性中最常见的癌症，也是男性癌症相关死亡的第二大原因。不幸的是，转移性前列腺癌目前还没有根治方法。早期诊断前列腺癌，然后立即手术切除，为患者提供了治愈或延长生存的最佳机会。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)由于缺乏特异性而限制了其应用。为了提高前列腺癌的检测准确率和提高治疗效果，迫切需要新型的受体靶向诊疗药物。为了提高前列腺癌检测的准确性和提高治疗效果，我们的战略重点是开发针对GnRH受体(GnRHR)的新型治疗(诊断和治疗)177Lu标记的促性腺激素释放激素(GnRH)多肽。在这个项目中，GnRHR是开发有效的前列腺癌特异性成像探针的明确目标，因为它在人类前列腺癌细胞和标本上过度表达，在健康的前列腺细胞上表达极低，在大多数正常组织细胞上不表达。最近，我们首次发现了一种新的促性腺激素释放激素多肽{111In-DOTA-AHX-(D-Lys6-GnRH)}作为人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，是DOTA-AHX-(D-Lys6-GnRH)(36.1 nM)的4.8倍。在这个项目中，我们将基于独特的DOTA-D-Phe-AHX-(D-Lys6-GnRH)结构，进行结构-活性关系(SAR)研究，以寻找更有效的用于前列腺癌成像和治疗的177Lu标记的GnRH多肽。具体地说，我们将在体内外合成8个具有中性碳氢化合物和氨基酸连接物的新的GnRH多肽并进行评价。我们推测GnRH多肽可以特异性地结合GnRH受体，并靶向于人前列腺癌细胞的放射核素(177Lu)，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，特别适合执行这一令人兴奋的翻译项目。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)开辟低能量贝塔辐射(177Lu)、高能贝塔辐射(90Y)和阿尔法辐射(212Pb/212Bi和213Bi)治疗前列腺癌的途径，为患者提供满足个性化需求(即肿瘤大小或转移)的个性化治疗剂。小说的鉴定 该项目推广的抗癌多肽将为未来在美国FDA批准的临床试验中对这类新型多肽的评估铺平道路，增加转移性前列腺癌患者的治疗机会。

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.