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: 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
• 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; 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

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cast割前列腺癌（MCRPC）是一种致命的，无法治愈的疾病，可杀死〜33,500 2020年美国的患者。应对安全有效的新型治疗的迫切需要 并利用MCRPC病变中前列腺特异性膜抗原（PSMA）的高表达 已经开发了基于小分子的靶向放射线疗法（TRT）。其中，有针对性 特别是[225AC] -PSMA-617的α治疗剂（TAT）已显示出罢工反应 难治性患者的治疗 - 甚至在一部分患者中达到完整而耐用的反应。 但是，许多反应的患者由于非目标毒性而停止治疗。唾液腺 毒性（不可逆的静脉毒素）和潜在的肾脏毒性对患者的可用性进行硬限制，最大剂量 和最大剂量数，严重限制了[225AC] -PSMA-617的使用。因此，有一个紧急的 并且未满足的需要制定可以减少这些治疗方法的不良副作用的策略 损害治疗效率。反过来，我们提出了一种简单的方法来减少唾液腺和肾脏 通过添加PSMA-111，通过降低[225AC] -PSMA-617的有效特异性活性（ESA）来毒性。在我们的 初步研究，减少[68GA] -PSMA-11和[177LU] -PSMA-617的ESA，pSMA-617导致 在小鼠模型中，显着降低了唾液腺和肾脏摄取，而不会损害肿瘤的吸收 前列腺癌。我们已经组建了一个高素质和协作的研究人员，包括 放射学家，医学物理学家，核医学医师，泌尿生殖学家，兽医 病理学家和毒理学家 - 明确地证明了我们方法的效率 [225AC] -PSMA-617的唾液腺和肾脏辐射剂量或临床相关的其他PSMA-TRT药物 鼠标和大鼠模型。作为我们建议的一部分，我们将确定将减少唾液的ESA范围 [225AC] -PSMA-617的腺体和肾脏剂量> 75％，没有损害小鼠的肿瘤辐射剂量，并且 老鼠；证明唾液腺和肾功能长期保持（治疗后2年），而 消除肿瘤伯恩；证明该方法对其他PSMA-TRT代理的适用性；进行 PSMA-11的GLP毒理学研究（5-10 mg/患者）以确定其安全性；并做 所有研究人员都可以使用数据，以促进临床试验。实验是作为指数进行的 促进近期临床翻译的研究。一旦建立，我们简单而创新的方法将 通过降低对唾液腺的毒性和 没有损害治疗效率的肾脏，并有助于延长MCRPC患者的寿命 保持生活质量。