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：
10296947
负责人：
James Peter Basilion
金额：
$ 56.4万
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/10296947
关键词：
Adverse event Affinity Androgens Animal Model Animals Antibodies Antibody-drug conjugates Antigen Targeting Antigens Antineoplastic Agents Binding Biochemical Biological Markers Blood group antigen S 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，也是癌症的第二大原因美国男性死亡。尽管低风险疾病患者的手术和放射治疗出现适当有效的，患有高风险局部疾病的患者几乎总是会成为激素难治性和然后快速进步。高风险局部前列腺的患者迫切需要新的治疗策略癌症，尤其是一种考虑使用多式联运方法的方法，包括本地和全身疗法。细胞毒性药物广泛用于治疗血液学恶性肿瘤和实体瘤，在某些情况下临床状况改变了其中一些疾病的自然病程。虽然有效，但由于他们固有的作用方式，它们还可能引起重大的脱离目标不良事件，可能排除他们的全部临床疗效，可能导致早期终止药物，因此增加了肿瘤复发或复发。保持化学治疗的有效性的替代方法药物并最大程度地减少全身毒性包括将细胞毒性剂与人性化抗体结合（也是称为抗体药物缀合物，ADC）。 Brentuximab Vedotin报道的持久临床反应（SGN-35：西雅图遗传学/武田）和Trastuzumab Emtansine（T-DM1； Roche与最近获得了监管批准的免疫原）深刻改变了ADC的前景癌症治疗。这些方法虽然表现出强大的潜力，但非常昂贵，更少需要复杂，更具成本效益的方法。在这里，我们描述了一种新型配体用于前列腺特异性膜抗原（PSMA，生物标志物对于前列腺癌）靶向有效的微管抑制剂，MMAE和光动力疗法（PDT）代理，IR700，有选择地对前列腺癌。这种新药分子的设计利用了前药方法并同时选择两种药物来进行前列腺癌。通过选择性输送两种药物对癌细胞的不同治疗机制，预计会改善抗肿瘤活性，毒性较小。这由于预期的药物协同作用（需要较低的药物剂量），预计毒性会降低。前药激活和药物分子的快速清除，以防止目标递送。该分子会使用两种前列腺癌的动物模型，小鼠和同伴狗中的自发前列腺癌。已经注意到MMAE和IR700疗法刺激对癌症的免疫反应，我们将在免疫能力的伴侣犬中初步对其进行测试。前列腺癌的狗病理学和生理学与人类非常相似，狗经常在药物开发试验。由于小鼠的疗效试验无法预测人类的结果，因此狗的功效研究将基本上鼓励开发药物的临床翻译。