Highly selective targeted theranostics for prostate cancers

前列腺癌的高选择性靶向治疗诊断

基本信息

批准号：
10468166
负责人：
James Peter Basilion
金额：
$ 64.59万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-11 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10468166
关键词：
Adverse event Affinity Androgens Animal Model Animals Antibodies Antibody-drug conjugates Antigen Targeting Antigens Antineoplastic Agents Binding Biochemical Biological Markers Cancer Etiology Canis familiaris Carcinoma Cell Death Cessation of life Chemicals Chemoresistance Clinical Clinical Trials Collection Combined Modality Therapy Companions Complex Cytotoxic agent Data Diagnosis Disease Dose Drug Delivery Systems Drug Synergism Drug resistance Drug toxicity Effectiveness Exhibits FOLH1 gene Future Generations Genetic Goals Hematologic Neoplasms Hormones Human Immune response Immunocompetent Immunologics Implant Ligands Light Local Therapy Localized Disease Location Malignant Neoplasms Malignant neoplasm of prostate Methodology Methods Microtubules Modification Molecular Weight Movement Mus Normal Cell Normal tissue morphology Operative Surgical Procedures PUVA Photochemotherapy Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Photosensitizing Agents Physiology Prodrugs Prostate Cancer therapy Prostate carcinoma Radiation therapy Radical Prostatectomy Reactive Oxygen Species Recurrence Refractory Relapse Reporting Resistance Risk Site Solid Neoplasm Structure of base of prostate Systemic Therapy Technology Testing Therapeutic Therapeutic Effect Time Tissues Toxic effect Toxicology Translations Trastuzumab United States Weight cancer biomarkers cancer cell cancer heterogeneity cancer therapy cell killing chemotherapy clinical application clinical efficacy clinical translation combat cost efficient design disorder risk drug clearance drug development drug efficacy efficacy evaluation efficacy study efficacy trial high risk human model humanized antibody improved irradiation men minimally invasive mouse model multimodality novel novel therapeutics overexpression phthalocyanine prevent prostate cancer model response screening serum PSA side effect small molecule systemic toxicity targeted delivery targeted imaging targeted treatment theranostics treatment strategy tumor virtual

项目摘要

Abstract. Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer death in men in the United States. Although surgery and radiation therapy in patients with low risk disease appear appropriate and effective, those with high-risk localized disease almost always become hormone refractory and then rapidly progress. New treatment strategy is urgently needed for patients with high-risk localized prostate cancer, particularly an approach that considers the use of a multimodal approach and that includes both local and systemic therapies. Cytotoxic drugs are broadly used to treat hematological malignancies and solid tumors and, under certain clinical conditions, have changed the natural course of some of these diseases. While effective, due to their intrinsic mode of action, they may also cause significant off-target adverse events that could preclude their full clinical efficacy, possibly resulting in early discontinuation of medication and a consequent increased risk of tumor relapse or recurrence. Alternative approaches to both maintain the effectiveness of chemotherapeutic drugs and minimize systemic toxicity include conjugation of cytotoxic agents to humanized antibodies (also known as Antibody Drug Conjugates, ADCs). The durable clinical responses reported with brentuximab vedotin (SGN-35: Seattle Genetics/Takeda) and trastuzumab emtansine (T-DM1; Roche in partnership with ImmunoGen), which have recently obtained regulatory approval, have profoundly changed the outlook for ADC cancer therapy. These approaches, although showing strong potential, are extremely expensive, and less complex and more cost-efficient methodologies are needed. Here we describe the use of a novel ligand for prostate specific membrane antigen (PSMA, a biomarker for prostate cancer) to target a potent microtubule inhibiting agent, MMAE, and a photodynamic therapy (PDT) agent, IR700, selectively to prostate cancers. The design of this new drug molecule utilizes a prodrug approach and simultaneously delivers two drugs selectively to prostate cancer. By selective delivery of two drugs with different therapeutic mechanisms to cancer cells, improved antitumor activity with less toxicity is expected. The reduction in toxicity is expected due to anticipated drug synergy (requiring lower drug doses), site specific prodrug activation, and rapid clearance of the drug molecule, preventing off target delivery. This molecule will be developed using two animal models of prostate cancer, heterotopic human prostate cancer in mice and spontaneous prostate cancer in companion dogs. Both MMAE and IR700 therapy have been noted to stimulate immune response against cancer and we will preliminarily tested this in the immunocompetent companion dogs. Dog pathology and physiology of prostate cancer is very similar to humans and dogs are often used in drug development trials. Since efficacy trials in mice are not predictive of human results, efficacy studies in dogs will substantially encourage clinical translation of the developed agent.

抽象的。前列腺癌 (PCa) 是最常见的恶性肿瘤，也是第二大癌症原因美国男性死亡。尽管低风险疾病患者的手术和放射治疗出现如果适当且有效，那些患有高风险局部疾病的人几乎总是会变得激素难治性并且然后快速进步。高危局限性前列腺患者急需新的治疗策略癌症，特别是考虑使用多模式方法并且包括局部治疗的方法和全身治疗。细胞毒性药物广泛用于治疗血液恶性肿瘤和实体瘤，并且在某些情况下临床条件改变了其中一些疾病的自然病程。虽然有效，但由于它们内在的作用模式，它们也可能导致严重的脱靶不良事件，从而妨碍其充分发挥作用。临床疗效，可能导致提前停止用药，从而增加风险肿瘤复发或复发。维持化疗有效性的替代方法药物和最小化全身毒性包括将细胞毒性剂与人源化抗体结合（也称为抗体药物偶联物 (ADC)。 brentuximab vedotin 报告的持久临床反应（SGN-35：Seattle Genetics/Takeda）和曲妥珠单抗 emtansine（T-DM1；罗氏与最近获得监管部门批准的ImmunoGen）深刻改变了ADC的前景癌症治疗。这些方法虽然显示出强大的潜力，但极其昂贵，而且成本较低需要复杂且更具成本效益的方法。在这里，我们描述了前列腺特异性膜抗原（PSMA，一种生物标志物）的新型配体的用途前列腺癌）靶向有效的微管抑制剂 MMAE 和光动力疗法 (PDT) 代理，IR700，选择性地治疗前列腺癌。这种新药物分子的设计采用了前药方法并同时选择性地向前列腺癌递送两种药物。通过选择性地递送两种药物对癌细胞的不同治疗机制，有望提高抗肿瘤活性并降低毒性。这由于预期的药物协同作用（需要较低的药物剂量）、部位特异性，预计毒性会降低前药激活，药物分子快速清除，防止脱靶递送。该分子将使用两种前列腺癌动物模型开发，即小鼠异位人类前列腺癌和伴侣犬自发性前列腺癌。 MMAE 和 IR700 疗法都被认为可以刺激针对癌症的免疫反应，我们将在免疫能力强的伴侣犬中进行初步测试。狗的前列腺癌病理和生理与人类非常相似，狗经常被用于治疗前列腺癌。药物开发试验。由于小鼠的功效试验不能预测人类的结果，因此狗的功效研究将极大地鼓励所开发药物的临床转化。