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

基本信息

批准号：
10610905
负责人：
Nagavarakishore Pillarsetty
金额：
$ 71.29万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610905
关键词：
Address Aftercare Antigen Targeting Biodistribution CWR22Rv1 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 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 Qualifying 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 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

项目摘要

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.

抽象的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，将导致约 33,500 人死亡 2020 年美国患者的情况。为了满足对安全有效的新型治疗方法的迫切需求，并利用 mCRPC 病变中前列腺特异性膜抗原 (PSMA) 的高表达，其中，基于小分子的靶向放射性核素疗法（TRT）已被开发出来。尤其是含有 [225Ac]-PSMA-617 的 α 治疗剂 (TAT) 在以下方面已表现出惊人的反应：难治性患者的治疗——甚至在一部分患者中实现完全且持久的缓解。然而，许多有反应的患者由于非目标唾液腺毒性而停止了治疗。毒性（不可逆性口干症）和潜在的肾毒性对患者资格、最大剂量施加严格限制和最大剂量，严重限制[225Ac]-PSMA-617的使用，因此，迫切需要解决这一问题。和未满足的需要制定策略，可以减少这些治疗的不良副作用，而无需反过来，我们提出了一种减少唾液腺和肾脏的简单方法。通过添加 PSMA-11 来降低 [225Ac]-PSMA-617 的有效比活性 (ESA) 的毒性。初步研究，用 PSMA-11 降低 [68Ga]-PSMA-11 和 [177Lu]-PSMA-617 的 ESA 导致在小鼠模型中，唾液腺减少，肾脏摄取显着减少，且不影响肿瘤摄取我们组建了一支高素质的协作研究团队，其中包括前列腺癌。放射化学家、医学物理学家、核医学医师、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在减少 [225Ac]-PSMA-617 或其他 PSMA-TRT 药物在临床相关中的唾液腺和肾脏辐射剂量作为我们提案的一部分，我们将确定可减少唾液分泌的 ESA 范围。 [225Ac]-PSMA-617 的腺体和肾脏剂量增加 > 75%，且不影响小鼠的肿瘤辐射剂量大鼠；证明唾液腺和肾功能保持长期（治疗后约 2 年）消除肿瘤负担；证明该方法适用于其他 PSMA-TRT 药物；对所需剂量（5-10 毫克/患者）的 PSMA-11 进行 GLP 毒理学研究，以确定其安全性并确定其安全性；数据可供所有研究人员使用，以促进临床试验的进行。一旦建立，我们简单但创新的方法将能够促进近期临床转化的研究。通过减少对唾液腺的毒性来优化 [225Ac]-PSMA-617 和其他 PSMA-TRT 药物的治疗在不影响治疗效果的情况下，有助于延长 mCRPC 患者的生命，同时维持他们的生活质量。