PSMAi-PARPi combination agents for the targeted Auger and alpha therapy of metastatic castration-resistant prostate cancer

PSMAi-PARPi 组合药物用于转移性去势抵抗性前列腺癌的靶向 Auger 和 alpha 疗法

• 批准号: 10508057
• 负责人: Michael Rod Zalutsky
• 金额: $ 41.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10508057
• 关键词: Affinity; Alpha Particle Emitter; Alpha Particles; American; American Cancer Society; Area; Beta Particle; Bilateral; Binding; Biodistribution; Biological Assay; Bone Marrow; Cancer Patient; Castration; Cause of Death; Cell Nucleus; Cells; Cessation of life; Chemicals; Chromatin; Clinical Research; Clinical Trials; Confocal Microscopy; DNA; DNA Damage; DNA Double Strand Break; DNA Repair Enzymes; DNA Repair Gene; Data; Deposition; Diffuse; Disease; Disulfides; Dose-Limiting; Electrons; Evaluation; FOLH1 gene; Future; Gland; Glutathione; Halogens; Hematology; High-LET Radiation; In Vitro; Infiltration; Kidney; Kinetics; LNCaP; Label; Lesion; Linear Energy Transfer; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Molecular Weight; Normal tissue morphology; Nuclear Protein; Nude Mice; Operative Surgical Procedures; Orchiectomy; PC3 cell line; PSA level; Patients; Pharmaceutical Preparations; Phase; Poly(ADP-ribose) Polymerases; Positioning Attribute; Production; Prostate Cancer therapy; Radiation Dose Unit; Radiation therapy; Radioconjugate; Radioisotopes; Radiolabeled; Red Marrow; Resistance; Salivary; Site; Specificity; Targeted Radiotherapy; Therapeutic; Therapy Evaluation; Tin; Tissues; Toxic effect; Treatment Efficacy; Tumor Cell Nuclei; Urea; Xenograft procedure; Xerophthalmia; Xerostomia; analog; androgen deprivation therapy; cancer therapy; castration resistant prostate cancer; cytotoxic; design; dosimetry; experimental study; flu; head-to-head comparison; in vivo; inhibitor; men; novel strategies; particle therapy; pinacolyl methylphosphonic acid; prostate cancer cell; radiation resistance; research clinical testing; response; serum PSA; targeted agent; targeted radiotherapeutic; tumor; uptake

Prostate cancer (PC) is the second most common cancer and the second leading cancer-related cause of death in men. The American Cancer Society has estimated that 248,530 new cases of prostate cancer and 34,130 prostate cancer-related deaths will occur in 2021. Androgen deprivation therapy (ADT) — either chemical castration or orchiectomy — is used as an initial therapy for PCs; however, most patients develop metastatic castration-resistant PC (mCRPC). Patients with mCRPC have less than a 16% chance of surviving for five years, making better therapeutic options a critical need. Radiolabeled prostate-specific membrane antigen inhibitors (PSMAi) are being investigated for the treatment of PC patients. One such agent, labeled with the β-emitter 177Lu (177Lu-PSMA-617) is in late stage of its Phase III clinical evaluation. Although it has shown promise, dose-limiting hematological toxicity due to diffuse red marrow infiltration of its long-range β-particles is a problem. Because of their higher capability to generate DNA double strand breaks than β-particles, high linear energy transfer (LET) alpha-particles (AP) should be more effective for treating resistant tumors. Furthermore, due to their short range in tissue, they should be ideal for treatment of micrometastatic lesions. PSMAi labeled with AP-emitting 225Ac have yielded response rates significantly higher than that of 177Lu-PSMA-617 with less severe bone marrow toxicity. However, due to their predominantly nonspecific uptake in salivary and lachrymal glands, xerostomia and xerophthalmia were significant issues. Auger electrons (AE) are high LET radiation when positioned near DNA and have very short range. They can be lethal when in the tumor cell nuclei but will have minimal off-target toxicity. Poly ADP-ribose polymerase 1 (PARP1) is a DNA repair protein that is highly expressed in cancers and to a lesser degree in normal tissues. Because PARP1 localizes adjacent to DNA, we propose to develop AE emitter (AEE)-labeled covalent conjugates of PSMAi and inhibitors of PARP1 (PARPi) for the targeted AEE therapy of mCRPC patients. The hypothesis is that the PSMAi part of the conjugate can achieve specific binding to PSMA in the PC cells and, PARP-1 being a nuclear protein, the PARPi moiety will help localize AEE in the tumor cell nuclei where the AEE will be most effective. In addition to AP, the heavy halogen 211At emits high LET recoil nuclei with a mean range in tissue of 82 and 105 nm, which is highly cytotoxic when the decay occurs within the nucleus. It also emits ~6 AEs per decay, which deposits more radiation dose than its AP within 10 nm of the decay site. For these reasons, 211At-labeled analogues also should be effective with these conjugates. The Specific Aims are: 1) Syntheses of PARPi-PSMAi radioconjugates for Auger and Alpha therapy; 2) In vitro evaluation of radioconjugates; 3) In vivo biodistribution of radioconjugates. Successful completion of this project is expected to identify an agent for its further extensive evaluation for targeted radiotherapy of mCRPC. It is hoped that such an agent can be potentially better than the current 177Lu- and 225Ac-labeled PSMA agents by yielding better therapeutic efficacy with minimal off-target toxicity.

前列腺癌(PC)是第二常见的癌症，也是与癌症相关的第二大致死原因 在男人身上。美国癌症协会估计，新增前列腺癌病例248,530例，新增34,130例 与前列腺癌相关的死亡将在2021年发生。雄激素剥夺疗法(ADT)--任何一种药物 去势或切除--被用作PC的初始治疗；然而，大多数患者发生转移 抗去势PC(MCRPC)。患有mCRPC的患者存活五年的可能性不到16%， 使更好的治疗选择成为迫切需要。放射性标记前列腺特异性膜抗原抑制物 (PSMAi)正在研究用于治疗PC患者。一种这样的试剂，标记有β发射器177Lu (177Lu-PSMA-617)处于III期临床评估的后期阶段。尽管它显示出了希望，但剂量限制 由于其长程β-颗粒的弥漫性红骨髓渗透而产生的血液学毒性是一个问题。因为. 它们比β粒子产生dna双链断裂的能力更高，线性能量转移(LET)更高。 α-粒子(AP)治疗耐药肿瘤应更为有效。此外，由于它们的射程较短， 在组织中，它们应该是治疗微转移病变的理想选择。用AP发射的225Ac标记PSMAi 其有效率显著高于177Lu-PSMA-617，骨髓反应较轻 毒性。然而，由于它们主要在唾液和泪腺中非特异性摄取，口干症 和干眼症是重要的问题。俄歇电子(AE)在近距离放置时具有很高的LET辐射 而且射程很短。它们在肿瘤细胞核内是致命的，但偏离靶点的可能性很小。 毒性。多聚ADP核糖聚合酶1(PARP1)是一种DNA修复蛋白，在肿瘤和肿瘤组织中高度表达。 在正常组织中程度较轻。由于PARP1定位于DNA附近，我们建议发展AE 发射体(AEE)标记的PSMAi与靶向AEE的PARP1抑制剂(PARPI)共价偶合物 MCRPC患者的治疗。假设偶联物的PSMAi部分可以实现特异性结合 PARP-1是一种核蛋白，PARPI部分将有助于在PC细胞中定位AEE AEE最有效的部位是肿瘤细胞核。除AP外，重卤素211At还发射高LET 反冲核在组织中的平均射程为82和105 nm，当衰变发生时，它具有高度的细胞毒性 在原子核内。每衰变一次，它还会释放约6个AEs，这会在10 nm范围内沉积比AP更多的辐射剂量 腐烂地点的。由于这些原因，~(211)At标记的类似物也应该与这些偶联物一起有效。 具体目标是：1)合成用于俄歇和阿尔法治疗的PARPI-PSMAi放射性结合物；2)在 放射性结合物的体外评价；3)放射性结合物的体内生物分布。成功完成 预计将为其靶向放射治疗的进一步广泛评估确定一种试剂 MCRPC。人们希望这种试剂有可能比目前的177Lu和225Ac标记的PSMA更好 通过产生更好的治疗效果和最小的脱靶毒性。