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诊断的癌症，也是美国男性中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不存在治愈性治疗。早期诊断前列腺癌，然后迅速手术切除，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[18 F] FDG（2-[18 F]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。因此，迫切需要新型的受体靶向诊断和治疗药物来提高前列腺癌的检测准确性和治疗效果。我们的策略，以提高检测准确性和提高前列腺癌的治疗效果的重点是开发新的治疗诊断（诊断和治疗）177 Lu标记的促性腺激素释放激素（GnRH）肽，以靶向GnRH受体（GnRH受体）。GnRHR是该项目中用于开发有效的前列腺癌特异性成像探针的独特靶标，因为其在人前列腺癌细胞和标本上过表达，在健康前列腺细胞上显著低表达，在大多数正常组织细胞上不表达。最近，我们首次鉴定了一种新的GnRH肽{111 In-DOTA-Ahx-（D-Lys 6-GnRH）}作为人前列腺癌检测的成像探针。最近，我们发现，与DOTA-Ahx-（D-Lys 6-GnRH）（36.1 nM）相比，D-Phe的引入显著提高了DOTA-D-Phe-Ahx-（D-Lys 6-GnRH）（7.6 nM）的GnRHR结合亲和力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177 Lu标记的GnRH肽用于前列腺癌成像和治疗的基础上独特的DOTA-D-Phe-Ahx-（D-Lys 6-GnRH）构建。具体来说，我们将合成和评估8个新的GnRH肽与中性烃和氨基酸接头在体外和体内。我们假设GnRH肽可以特异性地结合GnRH受体并将治疗诊断放射性核素（177 Lu）靶向人前列腺癌细胞用于前列腺癌成像和治疗。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，我们已经组建了一支强大的多学科研究团队，拥有成熟的专业知识，非常适合开展这一令人兴奋的翻译项目。该项目的成功将为设计用于前列腺癌检测和治疗的新型治疗诊断剂提供新的见解，并为未来使用低能β-辐射（177 Lu）、高能β-辐射（90 Y）和α-辐射{212 Pb/212 Bi和213 Bi}治疗人类前列腺癌开辟途径（未来的方向），为患者提供个性化的治疗剂以满足个体需求（即肿瘤大小或转移）。鉴定新 本项目推广的治疗诊断肽将为未来在美国FDA批准的临床试验中评估这类新型肽铺平道路，提高转移性前列腺癌患者的治愈机会。

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.