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

基本信息

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
项目类别：
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

项目摘要

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) 是第二大常见癌症，也是第二大癌症相关死亡原因美国癌症协会估计，男性中新增 248,530 例前列腺癌病例，34,130 例。癌症相关死亡将于 2021 年发生。雄激素剥夺疗法 (ADT) — 化学药物去势或睾丸切除术——用作 PC 的初始治疗，但大多数患者会发生转移；去势抵抗性 PC (mCRPC) 患者的五年生存率低于 16%，迫切需要更好的治疗选择。 (PSMAi) 正在研究用于治疗 PC 患者，其中一种药物用 β-发射体 177Lu 标记。 (177Lu-PSMA-617) 正处于 III 期临床评估的后期阶段，尽管它已显示出希望，但剂量限制。由于其长程β-颗粒的弥漫性红骨髓浸润而导致的血液学毒性是一个问题。与 β 粒子相比，它们产生 DNA 双链断裂的能力更高，高线性能量转移 (LET) 此外，α粒子（AP）对于治疗耐药肿瘤应该更有效，因为它们的射程较短。在组织中，它们应该是治疗用 AP 发射 225Ac 标记的微转移病灶的理想选择。产生的缓解率显着高于 177Lu-PSMA-617，且骨髓严重程度较轻然而，由于它们主要在唾液腺和泪腺中非特异性吸收，因此会导致口干症。俄歇电子 (AE) 靠近时会产生高 LET 辐射。 DNA 的作用范围非常短，它们在肿瘤细胞中可能具有细胞核致死性，但脱靶程度极低。聚 ADP-核糖聚合酶 1 (PARP1) 是一种 DNA 修复蛋白，在癌症和癌症中高度表达。由于 PARP1 位于 DNA 附近，因此我们建议开发 AE。用于靶向 AEE 的 PSMAi 和 PARP1 抑制剂 (PARPi) 发射体 (AEE) 标记的共价缀合物假设偶联物的 PSMAi 部分可以实现特异性结合。 PARP-1 是一种核蛋白，PARPi 部分将有助于将 AEE 定位于 PC 细胞中的 PSMA AEE 最有效的肿瘤细胞核除了 AP 之外，重卤素 211At 也会发射高 LET。组织中平均范围为 82 和 105 nm 的反冲核，当衰变发生时具有高度细胞毒性它每次衰变还会发射约 6 个 AE，在 10 nm 内沉积的辐射剂量比其 AP 更多。由于这些原因，211At 标记的类似物也应该对这些缀合物有效。具体目标是： 1) 合成用于 Auger 和 Alpha 疗法的 PARPi-PSMAi 放射性结合物； 3）放射性结合物的体内生物分布成功完成。该项目预计将确定一种药物，用于进一步广泛评估靶向放射治疗 mCRPC。希望这种试剂可能比目前的 177Lu 和 225Ac 标记的 PSMA 更好。药物通过产生更好的治疗效果和最小的脱靶毒性。