Minimizing salivary gland and renal toxicity arising from PSMA-targeted alpha therapy

最大限度地减少 PSMA 靶向 α 疗法引起的唾液腺和肾毒性

• 批准号: 10446375
• 负责人: Nagavarakishore Pillarsetty
• 金额: $ 68.73万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446375
• 关键词: Address; Aftercare; Antigen Targeting; Biodistribution; Cancer Patient; Cessation of life; Chemicals; Clinic; Clinical Trials; Collection; Communities; Data; Discipline of Nuclear Medicine; Disease; Dose; Dose-Limiting; Drug Kinetics; Effectiveness; Eligibility Determination; FOLH1 gene; Genitourinary system; Human; I-antigen; Immunohistochemistry; In complete remission; Institution; Intellectual Property; Irreversible Toxicity; Kidney; Kinetics; LNCaP; Lead; Lesion; Ligands; Maintenance; Malignant neoplasm of prostate; Medical; Methodology; Methods; Modeling; Mus; Neoplasm Metastasis; Oncologist; Organ; PC3 cell line; Pathologist; Patients; Peptides; Performance; Pharmacology and Toxicology; Physicians; Physiological; Positron-Emission Tomography; Preparation; Production; Quality of life; Radiation Dose Unit; Radiation therapy; Radioisotopes; Radionuclide therapy; Radiopharmaceuticals; Rattus; Reducing Agents; Refractory; Renal function; Research; Research Personnel; Safety; Saliva; Salivary Glands; Salvage Therapy; Serum; Structure of base of prostate; Testing; Toxic effect; Toxicology; Treatment Efficacy; Treatment Side Effects; Tumor Burden; Xenograft Model; Xenograft procedure; Xerostomia; acute toxicity; base; burden of illness; castration resistant prostate cancer; clinical translation; clinically relevant; effective therapy; exhaust; experimental study; in vivo; innovation; mouse model; nephrotoxicity; novel; patient subsets; prostate cancer model; response; side effect; small molecule; tumor; tumor xenograft; uptake

ABSTRACT Metastatic castration-resistant prostate cancer (mCRPC) is a lethal, incurable disease that will kill ~33,500 patients in the US in 2020. Responding to the urgent need for novel treatments that are safe and efficacious, and leveraging the high expression of prostate specific membrane antigen (PSMA) in mCRPC lesions, several small-molecule-based targeted radionuclide therapies (TRTs) have been developed. Among them, targeted alpha therapy agent (TAT) with [225Ac]-PSMA-617 in particular has demonstrated striking responses in the treatment of refractory patients — even achieving complete and durable responses in a subset of patients. However, many responding patients have discontinued treatment due to non-target toxicity. Salivary gland toxicity (irreversible xerostomia) and potential renal toxicity place hard limits on patient eligibility, maximum dose and maximum number of doses, severely restricting the use of [225Ac]-PSMA-617. As such, there is an urgent and unmet need to develop strategies that can reduce the unwanted side effects of these treatments without compromising treatment efficacy. We in turn are proposing a simple method to reduce salivary gland and kidney toxicity by reducing the effective specific activity (ESA) of [225Ac]-PSMA-617 by addition of PSMA-11. In our preliminary studies, reducing the ESA of [68Ga]-PSMA-11 and [177Lu]-PSMA-617 with PSMA-11 led to significantly reduced salivary gland and kidney uptake without compromising tumor uptake in mouse models of prostate cancer. We have assembled a highly qualified and collaborative team of researchers — including radiochemists, medical physicists, nuclear medicine physicians, genitourinary oncologists, veterinary pathologists and toxicologists — to unequivocally demonstrate the efficacy of our methodology for reducing the salivary gland and renal radiation dose of [225Ac]-PSMA-617 or other PSMA-TRT agents in clinically relevant mouse and rat models. As part of our proposal, we will determine the range of ESAs that will reduce salivary gland and kidney dose of [225Ac]-PSMA-617 by > 75% without compromising tumor radiation dose in mice and rats; demonstrate that salivary gland and renal function are maintained long-term(~2 years post-treatment) while eliminating tumor burden; demonstrate the methodology’s applicability to other PSMA-TRT agents; conduct a GLP toxicology study of PSMA-11 at required doses (5–10 mgs/patient) to establish its safety; and make the data available to all researchers in order to facilitate clinical trials. The experiments are being conducted as IND- enabling studies for near-term clinical translation. Once established, our simple but innovative approach will refine treatment with [225Ac]-PSMA-617 and other PSMA-TRT agents by reducing toxicity to salivary glands and kidneys without compromising treatment efficacy and help to extend the lives of mCRPC patients while maintaining their quality of life.

摘要 转移性去势抵抗性前列腺癌（mCRPC）是一种致命的、无法治愈的疾病， 2020年，美国患者。为了满足对安全有效的新型治疗方法的迫切需求， 利用前列腺特异性膜抗原（PSMA）在mCRPC病变中的高表达， 已经开发了基于小分子的靶向放射性核素疗法（TRT）。其中，针对 α治疗剂（达特）与[225 Ac]-PSMA-617的联合应用尤其在 治疗难治性患者-甚至在一部分患者中实现完全和持久的反应。 然而，许多缓解患者由于非靶向毒性而停止治疗。唾液腺 毒性（不可逆性口干症）和潜在的肾毒性对患者的合格性、最大剂量 和最大剂量数，严重限制了[225 Ac]-PSMA-617的使用。因此，有一个紧迫的 和未满足的需求，开发可以减少这些治疗的不良副作用的策略， 损害治疗效果。我们又提出了一个简单的方法，以减少唾液腺和肾脏 通过添加PSMA-11降低[225 Ac]-PSMA-617的有效比活性（ESA）来降低毒性。在我们 初步研究，用PSMA-11降低[68 Ga]-PSMA-11和[177 Lu]-PSMA-617的ESA导致 显著降低唾液腺和肾脏摄取，而不影响小鼠模型中的肿瘤摄取。 前列腺癌我们组建了一支高素质的合作研究团队，包括 放射化学家、医学物理学家、核医学医生、泌尿生殖肿瘤学家、兽医 病理学家和毒理学家-明确证明我们的方法减少 [225 Ac]-PSMA-617或其他PSMA-TRT药物的唾液腺和肾脏放射剂量 小鼠和大鼠模型。作为我们建议的一部分，我们将确定将减少唾液分泌的ESA的范围。 在小鼠中，[225 Ac]-PSMA-617的腺体和肾脏剂量降低> 75%而不损害肿瘤辐射剂量， 大鼠;证明唾液腺和肾功能长期维持（给药后约2年）， 消除肿瘤负荷;证明该方法对其他PSMA-TRT药物的适用性;进行 以所需剂量（5-10 mg/患者）进行PSMA-11的GLP毒理学研究，以确定其安全性;并使 所有研究人员都可以获得数据，以促进临床试验。这些实验正在进行，作为IND- 使研究能够用于近期临床转化。一旦建立，我们简单但创新的方法将 通过降低对唾液腺的毒性来改进[225 Ac]-PSMA-617和其他PSMA-TRT药物的治疗， 在不影响治疗疗效的情况下，帮助延长mCRPC患者的生命， 维持他们的生活质量。